ISSN:0031-3998    

出版商:OVID    

年代:2003

数据来源: OVID

ISSN:0031-3998    

出版商:OVID    

年代:2003

数据来源: OVID

摘要:

Abbreviations: Ihh, Indian Hedgehog, PTHrP, PTH-related protein, PTHR1, PTH-related protein receptor, HME, hereditary multiple exostoses, Hh, Hedgehog, Ttv, Tout-velu, HS, heparin sulfateThere are many crucial genes and signaling pathways in the proper development of an organism. Pathologies may arise from a deregulation of these pathways. The Indian Hedgehog–PTH-related protein (Ihh-PTHrP) pathway is vital in the proper development of endochondral bones, such as the long bones. The Ihh-PTHrP pathway regulates the rate at which chondrocytes within the growth plate proliferate and differentiate. Thus, this pathway allows for the longitudinal growth of bones. However, a disruption in this pathway may lead to enchondromas and osteochondromas, which are both childhood cartilaginous neoplasms. Recently, our lab identified a mutant receptor for PTHrP in enchondroma samples. Mice expressing this mutant receptor and mice with increased Ihh activity develop conditions similar to human enchondromatosis. Linkage analysis shows an association between EXT genes and osteochondromas in hereditary multiple exostoses syndrome. Studies inDrosophilaand mice suggest EXT gene products play a role in the diffusion of hedgehog proteins. A mutation in EXT genes may result in an abnormal Ihh diffusion pattern leading to an osteochondroma. There are agents that inhibit Hedgehog signaling. These agents may be useful in the treatment of enchondromas and osteochondromas. This review will discuss the discovery of the Ihh-PTHrP pathway and its involvement in neoplasia, and will suggest possible novel therapeutic agents in the treatment of these cartilaginous neoplasms.

ISSN:0031-3998    

出版商:OVID    

年代:2003

数据来源: OVID

ISSN:0031-3998    

出版商:OVID    

年代:2003

数据来源: OVID

摘要:

Microdeletion of chromosome 22q11.2 is commonly associated with congenital cardiovascular defects that involve development of cranial neural crest cells (NCC) that emigrate through the pharyngeal arches.UFD1lis one of several candidate genes for 22q11.2 deletion syndrome (22q11DS).UFD1lencodes a protein whose yeast counterpart is involved in a ubiquitin-dependent proteolytic degradation pathway; however, the role of UFD1L in NCC development remains unknown. Mouse embryos that lackUfd1ldie before organogenesis. We have therefore studied the function of Ufd1l in the chick system. ChickUfd1lencoded a 307–amino acid protein that was highly conserved with mouse and human UFD1L. Chick Ufd1l was expressed in the developing neural tube, NCC, and mesenchyme of the head and pharyngeal arch structures, as well as in the conotruncal region (cardiac outflow tract), consistent with the clinical features of 22q11DS. To determine loss-of-function effects of chick Ufd1l in NCC, we infected cardiac NCC with a retrovirus expressing antisense Ufd1l transcripts in chick embryos before their migration. Morphologic analysis of infected embryos at a later developmental stage demonstrated that functional attenuation of chick Ufd1l in cardiac NCC resulted in an increased incidence of conotruncal septation defects. These data suggest that Ufd1l may play a role in cardiac NCC during conotruncal septation.

ISSN:0031-3998    

出版商:OVID    

年代:2003

数据来源: OVID

摘要:

The channel proteins responsible for the cardiac transient outward K+current (Ito) of human and rodent heart are composed, in part, of pore-forming Kv4.3 or Kv4.2 principal subunits. Recent reports implicate K+channel interacting proteins (members of the neuronal Ca2+-binding protein family) as subunits of the Itochannel complex. We reported that another Ca2+-binding protein, frequenin [or neuronal calcium center protein-1 (NCS-1)], also functions as a Kv4 auxiliary subunit in the brain. By examining cardiac expression of NCS-1, the aim of this study was to examine the potential physiologic relevance of this protein as an additional regulator of cardiac Ito. Immunoblot analysis demonstrates NCS-1 protein to be expressed in adult mouse ventricle at levels comparable to that found in some brain regions. Cardiac NCS-1 protein expression levels are much higher in fetal and neonatal mouse hearts when compared with the adult. Immunocytochemical analysis of isolated neonatal mouse ventricular myocytes demonstrates co-localization of NCS-1 and Kv4.2 proteins at the sarcolemma. Given its high levels of expression in the heart, NCS-1 should be considered an important potential Kv4 regulatory subunit, particularly in the immature heart.

ISSN:0031-3998    

出版商:OVID    

年代:2003

数据来源: OVID

摘要:

In the extremely preterm infant, high transepidermal water loss (TEWL) can result in severe dehydration. TEWL has been attributed to the structural properties of the epidermis but might also be influenced by mechanisms that facilitate water transport. To investigate whether aquaporins (AQP) may be involved in the extreme losses of water through immature skin, we examined the presence and cellular distributions of AQP-1 and AQP-3 in embryonic and adult rat skin by immunohistochemistry. The expression of AQP mRNA in skin was analyzed with the use of semiquantitative reverse transcription-PCR. In rat pups of different embryonic (E) and postnatal (P) ages (days), TEWL and skin hydration were measured. AQP-1 was detected in dermal capillaries, and AQP-3 was abundant in basal epidermal layers. Both AQP displayed several times higher expression in embryonic than in adult skin. TEWL was highest at embryonic day 18 (E18) (133 ± 18 g/m2h) and lower at E20 (25 ± 1 g/m2h) and P4 (9 ± 2 g/m2h). Skin hydration measured as skin electrical capacitance paralleled TEWL, being highest in fetal skin (794 ± 15 pF at E18) and decreasing to 109 ± 11 pF at E20 and to 0 ± 0 pF at P4. We conclude that, as in infants, water loss through the skin of rats decreases markedly with maturation during the perinatal period. The expression and cellular localization of the AQP are such that they might influence skin hydration and water transport and contribute to the high losses of water through the immature skin.

ISSN:0031-3998    

出版商:OVID    

年代:2003

数据来源: OVID

摘要:

The expression of antimicrobial peptides and proteins is an important innate immune defense mechanism that has recently been shown to be essential for cutaneous defense against invasive bacterial disease. Newborns have an immature cellular immune defense system that leads to increased susceptibility to infections. Here we show that skin from embryonic and newborn mice, as well as human newborn foreskin, express antimicrobial peptides of the cathelicidin and &bgr;-defensin gene families. Immunohistochemistry andin situhybridization demonstrated abundant cathelicidin protein and mRNA is present in normal skin during the perinatal period. Quantitative real-time PCR showed mouse cathelicidin expression (CRAMP) is 10- to 100-fold greater in the perinatal period than adult. Murine &bgr;-defensins-1 and -4 and human &bgr;-defensin-2 were also present in newborn skin. Combined, human cathelicidin (LL-37/hCAP/18) and &bgr;-defensin-2 demonstrated synergistic antimicrobial activity and efficiently killed group BStreptococcus, an important neonatal pathogen. Antimicrobial peptides may therefore provide a compensatory innate defense mechanism during development of cellular immune response mechanisms in the newborn period.

ISSN:0031-3998    

出版商:OVID    

年代:2003

数据来源: OVID

摘要:

Deviations in the rate of intrauterine growth may change organ system development, resulting in cardiovascular disease in adult life. Arterial endothelial dysfunction often plays an important role in these diseases. The effects of two interventions that reduce fetal growth, chronic hypoxia and protein malnutrition, on arterial endothelial function were investigated. Eggs of White Leghorn chickens were incubated either in room air or in 15% O2from d 6 until d 19 of the 21-d incubation. Protein malnutrition was induced by removal of 10% of the total albumen content at d 0.In vitroreactivity of the femoral artery in response to vasodilators was measured at d 19. Both chronic hypoxia and protein malnutrition reduced embryonic body weight at d 19 by 14% without affecting relative brain weight. Chronic hypoxia or protein malnutrition did not change sensitivity to the exogenous nitric oxide donor, sodium nitroprusside (5.74 ± 0.15versus5.85 ± 0.23 and 6.05 ± 0.18versus6.01 ± 0.34, respectively). Whereas protein malnutrition did not modify arterial sensitivity to acetylcholine (7.00 ± 0.10versus7.12 ± 0.05), chronic hypoxia reduced sensitivity to this endothelium-dependent vasodilator (6.57 ± 0.07versus7.02 ± 0.06). In the presence ofN&ohgr;-nitro-l-arginine methyl ester, this difference in sensitivity to acetylcholine was no longer apparent (6.31 ± 0.13versus6.27 ± 0.06), indicating that chronic exposure to hypoxia reduced sensitivity to acetylcholine by lowering nitric oxide release. In additional experiments, a decrease in basal nitric oxide release in arteries of 3- to 4-wk-old chickens that had been exposed toin ovochronic hypoxia was observed (increase in K+contraction: −0.16 ± 0.33 N/mversus0.68 ± 020 N/m). Protein malnutrition and chronic hypoxia both induce disproportionate growth retardation, but only the latter impairs arterial endothelial function. Intrauterine exposure to chronic hypoxia induces changes in arterial endothelial properties that may play a role in the development of cardiovascular disease in adult life.

ISSN:0031-3998    

出版商:OVID    

年代:2003

数据来源: OVID

摘要:

The upper airway resistance syndrome (UARS) is associated with neurobehavioral morbidity in children. The diagnostic gold standard for UARS is esophageal manometry. However, this is invasive. Furthermore, upper airway obstructive events in sleeping children frequently terminate without visible electrocortical (EEG) arousal. The pulse transit time (PTT) is a noninvasive marker of blood pressure and, therefore, subcortical arousal. Blood pressure elevation, associated with respiratory arousal from sleep, results in a drop in the PTT. We hypothesized that: 1) the PTT is a more sensitive measure of respiratory arousal than EEG; and 2) the PTT arousal index can distinguish children with UARS from those with primary snoring. Polysomnography, including esophageal manometry and PTT, was measured prospectively in 24 symptomatic children and 10 normal controls. Apnea, hypopnea, and respiratory effort-related arousal events terminated in a PTT arousal 91%, 83%, and 80% of the time, and in an EEG arousal in 55%, 51%, and 43% (allp< 0.05), respectively. The PTT arousal index was significantly greater in children with UARS (6.8 events/h) than primary snoring (2.2 events/h) (p< 0.05). We conclude that, in children, PTT arousals are a more sensitive measure of obstructive events than visible EEG arousals.

ISSN:0031-3998    

出版商:OVID    

年代:2003

数据来源: OVID