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PubMed2006

The process chain for peptidomic biomarker discovery.

Over the last few years the interest in diagnostic markers for specific diseases has increased continuously. It is expected that they not only improve a patient's medical treatment but also contribute to accelerating the process of drug development. This demand for new biomarkers is caused by a lack of specific and sensitive diagnosis in many diseases. Moreover, diseases usually occur in different types or stages which may need different diagnostic and therapeutic measures. Their differentiation has to be considered in clinical studies as well. Therefore, it is important to translate a macroscopic pathological or physiological finding into a microscopic view of molecular processes and vice versa, though it is a difficult and tedious task. Peptides play a central role in many physiological processes and are of importance in several areas of drug research. Exploration of endogenous peptides in biologically relevant sources may directly lead to new drug substances, serve as key information on a new target and can as well result in relevant biomarker candidates. A comprehensive analysis of peptides and small proteins of a biological system corresponding to the respective genomic information (peptidomics(R)methods) was a missing link in proteomics. A new peptidomic technology platform addressing peptides was recently presented, developed by adaptation of the striving proteomic technologies. Here, concepts of using peptidomics technologies for biomarker discovery are presented and illustrated with examples. It is discussed how the biological hypothesis and sample quality determine the result of the study. A detailed study design, appropriate choice and application of technology as well as thorough data interpretation can lead to significant results which have to be interpreted in the context of the underlying disease. The identified biomarker candidates will be characterised in validation studies before use. This approach for discovery of peptide biomarkes has potential for improving clinical studies.

Biomarkers↗
PubMed2006

Inappropriate activation of the androgen receptor by nonsteroids: involvement of the Src kinase pathway and its therapeutic implications.

The inappropriate activation of androgen receptor (AR) by nonsteroids is considered a potential mechanism in the emergence of hormone-refractory prostate tumors, but little is known about the properties of these "pseudoactivated" AR. Here, we present the first comprehensive analysis closely examining the properties of AR activated by the neuropeptide bombesin that distinguish it from androgen-activated AR. We show that bombesin-activated AR (a) is required for bombesin-induced growth of LNCaP cells, (b) has a transcriptional profile overlapping with, but not identical to, androgen-activated AR, (c) activates prostate-specific antigen by preferentially binding to its proximal promoter, and (d) assembles a distinct coactivator complex. Significantly, we found that Src kinase is critical for bombesin-induced AR-mediated activity and is required for translocation and transactivation of AR. Additionally, we identify c-Myc, a Src target gene, to be activated by bombesin and a potential coactivator of AR-mediated activity specific to bombesin-induced signaling. Because Src kinase is often activated by other nonsteroids, such as other neuropeptides, growth factors, chemokines, and cytokines, our findings have general applicability and provide rationale for investigating the efficacy of the Src kinase pathway as a target for the prevention of relapsed prostate cancers.

Bombesin↗
PubMed2007

hTERT is expressed in cancer cell lines despite promoter DNA methylation by preservation of unmethylated DNA and active chromatin around the transcription start site.

hTERT, which encodes the catalytic subunit of telomerase and is expressed in most immortalized and cancer cells, has been reported to have increased DNA methylation in its promoter region in many cancers. This pattern is inconsistent with observations that DNA methylation of promoter CpG islands is typically associated with gene silencing. Here, we provide a comprehensive analysis of promoter DNA methylation, chromatin patterns, and expression of hTERT in cancer and immortalized cells. Methylation-specific PCR and bisulfite sequencing of the hTERT promoter in breast, lung, and colon cancer cells show that all cancer cell lines retain alleles with little or no methylation around the transcription start site despite being densely methylated in a region 600 bp upstream of the transcription start site. By real-time reverse transcription-PCR, all cancer cell lines express hTERT. Chromatin immunoprecipitation (ChIP) analysis reveals that both active (acetyl-H3K9 and dimethyl-H3K4) and inactive (trimethyl-H3K9 and trimethyl-H3K27) chromatin marks are present across the hTERT promoter. However, using a novel approach combining methylation analysis of ChIP DNA, we show that active chromatin marks are associated with unmethylated DNA, whereas inactive marks of chromatin are associated with methylated DNA in the region around the transcription start site. These results show that DNA methylation patterns of the hTERT promoter (-150 to +150 around the transcription start) are consistent with the usual dynamics of gene expression in that the absence of methylation in this region and the association with active chromatin marks allow for the continued expression of hTERT.

Alleles↗
PubMed2006

Proteomic profiling identifies cyclooxygenase-2-independent global proteomic changes by celecoxib in colorectal cancer cells.

Celecoxib, a selective inhibitor of the enzyme cyclooxygenase-2 (COX-2), has been shown to be a promising chemoprevention agent. The chemopreventive efficacy of celecoxib is believed to be a consequence of its COX-2-dependent and COX-2-independent effects on a variety of cellular processes including proliferation, apoptosis, angiogenesis, and immunosurveillance. In an attempt to identify proteomic markers modulated by celecoxib that are independent of its inhibitory effect on COX-2, the colorectal cancer cell line HCT-116, a nonexpresser of COX-2, was treated with celecoxib. We used the powerful, state-of-the-art two-dimensional difference gel electrophoresis technology coupled with mass spectrometric sequencing to compare global proteomic profiles of HCT-116 cells before and after treatment with celecoxib. Among the differentially expressed proteins identified following celecoxib treatment were proteins involved in diverse cellular functions including glycolysis, protein biosynthesis, DNA synthesis, mRNA processing, protein folding, phosphorylation, redox regulation, and molecular chaperon activities. Our study presents a comprehensive analysis of large-scale celecoxib-modulated proteomic alterations, at least some of which may be mechanistically related to the COX-2-independent chemopreventive effect of celecoxib.

Blotting, Western↗
PubMed2002

Applications for microarrays in renal biology and medicine.

Groundbreaking recent developments, such as the near completion of human and mouse genome sequencing efforts and the emergence of robust microarray (gene chip) technologies, enabling comprehensive analysis of transcriptomes, provide new opportunities of unprecedented scale for researchers of kidney biology and disease. Combined with advanced computational and mathematical approaches for microarray data analysis, microarray applications promise to revolutionize our understanding of molecular mechanisms of kidney development and renal pathogenesis. New knowledge in this field will facilitate new approaches for molecular diagnostics, drug discovery, and eventually "personalized" renal medicine. In this review, we outline current and future research applications of microarray and computational approaches in renal biology and disease. We describe basic steps in microarray data analysis and introduce advanced computational approaches to optimize data mining of vast microarray datasets.

Genomics↗
PubMed2003

Gene expression analysis of atopic dermatitis-like skin lesions induced in NC/Nga mice by mite antigen stimulation under specific pathogen-free conditions.

BACKGROUND: Atopic dermatitis (AD) is a chronic relapsing inflammation characterized by pruritic and eczematous skin lesions usually observed in patients with a familial history of atopic diseases, but its exact etiology is unclear. An animal model is indispensable for the analysis of the pathogenesis and the development of new drugs to treat this disease. Here, we compare changes in gene expression profiles in the AD-like skin lesions of NC/Nga or BALB/c mice stimulated intradermally by mite antigen under specific pathogen-free (SPF) conditions. METHODS: Mite Extract-Dp was injected intradermally into the right and left pinnae and into the skin of the back of NC/Nga or BALB/c mice in 2 places once per 3 days, and the clinical symptoms and the ear thickness were measured. On day 14 or day 28 after starting mite extract injection, we collected plasma and pinnae from NC/Nga or BALB/c mice. The amount of total immunoglobulin E (IgE) in plasma was assayed. We analyzed mRNA transcripts in pinnae using real-time quantitative PCR for the murine counterparts of several known allergy-related genes. Moreover, genome-wide gene expression in pinnae from NC/Nga mice was analyzed using high-density oligonucleotide arrays (GeneChip, Affymetrix). RESULTS: From 2 weeks after stimulation, marked skin inflammation was induced in the pinnae of NC/Nga but not BALB/c mice. However, IgE levels in sera rose equally in both strains. Quantitative PCR analysis and comprehensive GeneChip analysis of the AD-like pinna skin lesions revealed that their development was accompanied by changes in expression of more than 1,000 genes. These included cytokines, cytokine receptors, proteases, and adhesion molecules. Furthermore, genes thus far not reported in association with AD were also affected. CONCLUSION: From these results, the NC/Nga mouse model using mite sensitization under SPF conditions could be useful for elucidating the mechanisms of AD pathogenesis and developing more effective therapy for AD.

Animals↗
PubMed2004

Molecular mechanisms associated with chromosomal and microsatellite instability in sporadic glioblastoma multiforme.

OBJECTIVE: Two chromosomal instability (CIN) pathways are described in glioblastoma multiforme (GBM), type 1 and type 2, which can be observed in up to 70% of the cases. Microsatellite instability (MSI) plays a pathogenic role in sporadic cancers such as colon, gastric and endometrial carcinomas with deficient mismatch repair (MMR). We aimed to perform a comprehensive analysis of the relationship between CIN and MSI mechanisms in sporadic glioblastomas. METHODS: 129 GBMs were examined (109 newly diagnosed and 20 relapses) investigating MSI, immunohistochemical expression of MMR proteins as well as sequencing and promoter methylation of hMLH1. We characterized the molecular changes frequently correlated with CIN in MSI+ GBMs and compared them with 26 microsatellite-stable tumors. RESULTS: Low-level MSI was observed in 11 of 129 (8.5%) cases and was higher in relapses than in primary GBMs (25 vs. 5.5%, p = 0.027). High-level MSI was not found in any case. A deficient expression of MLH1 and PMS2 without hMLH1 inactivation was observed only in one giant cell GBM. 55% of the MSI+ GBMs showed a profile which did not correspond to one of the known CIN pathways. An inverse association was observed between MSI and mutations of both p53 and PTEN. CONCLUSIONS: Our data suggest that CIN and MSI contribute to the genomic instability in GBMs via independent pathways. Since MSI was significantly more frequent in relapses, it might play a role in the malignant progression of GBM.

Adolescent↗
PubMed2006

Comparative morphology of the avian cerebellum: I. Degree of foliation.

Despite the conservative circuitry of the cerebellum, there is considerable variation in the shape of the cerebellum among vertebrates. One aspect of cerebellar morphology that is of particular interest is the degree of folding, or foliation, of the cerebellum and its functional significance. Here, we present the first comprehensive analysis of variation in cerebellar foliation in birds with the aim of determining the effects that allometry, phylogeny and development have on species differences in the degree of cerebellar foliation. Using both conventional and phylogenetically based statistics, we assess the effects of these variables on cerebellar foliation among 91 species of birds. Overall, our results indicate that allometry exerts the strongest effect and accounts for more than half of the interspecific variation in cerebellar foliation. In addition, we detected a significant phylogenetic effect. A comparison among orders revealed that several groups, corvids, parrots and seabirds, have significantly more foliated cerebella than other groups, after accounting for allometric effects. Lastly, developmental mode was weakly correlated with relative cerebellar foliation, but incubation period and fledging age were not. From our analyses, we conclude that allometric and phylogenetic effects exert the strongest effects and developmental mode a weak effect on avian cerebellar foliation. The phylogenetic distribution of highly foliated cerebella also suggests that cognitive and/or behavioral differences play a role in the evolution of the cerebellum.

Analysis of Variance↗
PubMedDate not supplied

Acetylcholinesterase activity of synaptic plasma membranes during ageing: effect of L-acetylcarnitine.

A physiopathological role for acetylcholine (ACh) was hypothesized during ageing and related neurodegenerative diseases, e.g. dementia. This research was aimed to study acetylcholinesterase (AChE) activity during development and ageing of the frontal cerebral cortex of 4-, 8-, 12-, 16-, 20- and 24-month-old rats. This study was performed on synaptic plasma membranes, the specific subcellular compartment where the enzyme is located in vivo both in control animals and after in vivo acute treatment with L-acetylcarnitine. Maximum AChE activity was unaffected by age, and L-acetylcarnitine treatment increased enzyme activity in synaptic plasma membranes of 8-month-old rats. A comprehensive analysis of these results suggests: (a) the observed alterations in protein can substantially affect neurochemical data if results are presented as specific activities per unit protein; (b) energy metabolism plays the major role in the disturbed ACh metabolism during ageing and (c) the understanding of the mode of action of L-acetylcarnitine in treatment of dementia.

Acetylcarnitine↗
PubMed1990

Traumatic bilateral renal infarction.

Spontaneous recovery from biopsy-verified bilateral post-traumatic renal infarction in a 20-year-old patient is described, with clinical and renal stability maintained after 60 months of follow-up. A comprehensive analysis of recorded data yields no similar example, but several cases claiming subsequent viability after varying types of management bear clinical and histologic similarities. Management options may be influenced by these data.

Accidents, Traffic↗
PubMed2005

Differential expression of matrix metalloproteinases and their inhibitors in human and mouse lung development.

Lung development is a highly orchestrated process characterized by timed expression and activation of growth factor and protease/antiprotease systems. This interplay is essential in regulating vasculogenesis, alveolarization, and epithelial to mesenchymal transition during lung development. Alterations in the proteolytic/antiproteolytic balance of the lung have been associated with several respiratory diseases characterized by changes in the lung extracellular matrix (ECM). Here, we characterized the expression pattern of matrix metalloproteases (MMP) and their inhibitors, the tissue inhibitors of metalloproteases (TIMP), in human and mouse lung development. Using MMP/TIMP expression arrays, RT-PCR, Western Blotting, and ELISA analyses, we demonstrate that fetal human lung is characterized by a dominant proteolytic profile with high MMP-2 and little TIMP-3 expression. Adult human lung, in contrast, exhibits a more anti-proteolytic profile with decreased MMP-2 and increased TIMP-3 expression. MMP-14, MMP-20, TIMP-1, and TIMP-2 were constitutively expressed, irrespective of the developmental stage. Similar results were obtained using mouse lungs of different developmental stages, with the addition that in mouse lung, TIMP-2 and TIMP-3 were upregulated as lung development progressed. Exposure of neonatal mice to chronic hypoxia (10% O2), a stimulus that leads to an arrest of lung development, resulted in upregulation of MMP-2 with a concomitant downregulation of TIMP-2. These results provide a comprehensive analysis of MMP and TIMP expression during human and mouse lung development. MMP-2, TIMP-2, and TIMP-3 may be key regulatory enzymes during lung development, possibly through their complex action on ECM components, membrane receptor ectodomain shedding, and growth factor bioactivity.

Animals↗
PubMed2005

The transcriptional response of human endothelial cells to infection with Bartonella henselae is dominated by genes controlling innate immune responses, cell cycle, and vascular remodelling.

The bacterial pathogen Bartonella henselae (Bh) is responsible for a broad range of clinical manifestations, including the formation of vascular tumours as the result of pathogen-triggered vasoproliferation. In vitro, the interaction of Bh with human umbilical vein endothelial cells (Huvec) involves (i) cytoskeletal rearrangements in conjunction with bacterial internalization, (ii) nuclear factor kappaB (NFkappaB)-dependent proinflammatory activation, (iii) the inhibition of apoptosis, and (iv) the modulation of angiogenic properties such as proliferation, migration, and tubular differentiation. To study the transcriptional signature of these pathogen-triggered changes of Huvec, we performed transcriptional profiling with Affymetrix U133 GeneChips. At 6 h or 30 h of infection, a total of 706 genes displayed a clear and statistically significant change of expression (>2.5-fold, t-test p-value<0.05). These included 314 up-regulated genes dominated by the innate immune response. The gene list comprises subsets of tumour necrosis factor alpha (TNFalpha, 99 genes) and interferon alpha (IFNalpha, 30 genes) inducible genes, which encode components of the NF-kappaB-dependent proinflammatory response and the type I IFN-dependent anti-infective response, respectively. The remaining set of 197 up-regulated genes mirrors other cellular changes induced by Bh, in particular proliferation and proangiogenic activation. The set of 362 down-regulated genes includes 41TNFalpha - or IFNalpha-suppressible genes, and 52 genes involved in cell cycle control or progression. This comprehensive analysis of Bh-triggered changes of the Huvec transcriptome identified candidate genes putatively involved in controlling innate immune responses, cell cycle, and vascular remodelling, and may thus provide the basis for functional studies of the molecular mechanisms underlying these pathogen-induced cellular processes.

Bartonella henselae↗
PubMed1994

Three-dimensional reconstruction of intracoronary ultrasound images. Rationale, approaches, problems, and directions.

Although intracoronary ultrasonography allows detailed tomographic imaging of the arterial wall, it fails to provide data on the structural architecture and longitudinal extent of arterial disease. This information is essential for decision making during therapeutic interventions. Three-dimensional reconstruction techniques offer visualization of the complex longitudinal architecture of atherosclerotic plaques in composite display. Progress in computer hardware and software technology have shortened the reconstruction process and reduced operator interaction considerably, generating three-dimensional images with delineation of mural anatomy and pathology. The indications for intravascular ultrasonography will grow as the technique offers the unique capability of providing ultrasonic histology of the arterial wall, and the need for a three-dimensional display format for comprehensive analysis is increasingly recognized. Consequently, three-dimensional imaging is being rapidly implemented in the catheterization laboratories for guidance of intracoronary interventions and detailed assessment of their results. However exciting the prospects may be, three-dimensional reconstructions at present remain partially artificial because the true spatial position of the imaging catheter tip is not recorded, and shifts in its location and curves of the arterial lumen result in pseudoreconstructions rather than true reconstructions. In this report, we address the principles of three-dimensional reconstruction with a critical review of its limitations. Potential solutions for refinement of this exciting imaging modality are presented.

Algorithms↗
PubMed1995

Predictors of 30-day mortality in the era of reperfusion for acute myocardial infarction. Results from an international trial of 41,021 patients. GUSTO-I Investigators.

BACKGROUND: Despite remarkable advances in the treatment of acute myocardial infarction, substantial early patient mortality remains. Appropriate choices among alternative therapies and the use of clinical resources depend on an estimate of the patient's risk. Individual patients reflect a combination of clinical features that influence prognosis, and these factors must be appropriately weighted to produce an accurate assessment of risk. Prior studies to define prognosis either were performed before widespread use of thrombolysis or were limited in sample size or spectrum of data. Using the large population of the GUSTO-I trial, we performed a comprehensive analysis of relations between baseline clinical data and 30-day mortality and developed a multivariable statistical model for risk assessment in candidates for thrombolytic therapy. METHODS AND RESULTS: For the 41,021 patients enrolled in GUSTO-I, a randomized trial of four thrombolytic strategies, relations between clinical descriptors routinely collected at initial presentation, and death within 30 days (which occurred in 7% of the population) were examined with both univariable and multivariable analyses. Variables studied included demographics, history and risk factors, presenting characteristics, and treatment assignment. Risk modeling was performed with logistic multiple regression and validated with bootstrapping techniques. Multivariable analysis identified age as the most significant factor influencing 30-day mortality, with rates of 1.1% in the youngest decile (< 45 years) and 20.5% in patients > 75 (adjusted chi 2 = 717, P < .0001). Other factors most significantly associated with increased mortality were lower systolic blood pressure (chi 2 = 550, P < .0001), higher Killip class (chi 2 = 350, P < .0001), elevated heart rate (chi 2 = 275, P < .0001), and anterior infarction (chi 2 = 143, P < .0001). Together, these five characteristics contained 90% of the prognostic information in the baseline clinical data. Other significant though less important factors included previous myocardial infarction, height, time to treatment, diabetes, weight, smoking status, type of thrombolytic, previous bypass surgery, hypertension, and prior cerebrovascular disease. Combining prognostic variables through logistic regression, we produced a validated model that stratified patient risk and accurately estimated the likelihood of death. CONCLUSIONS: The clinical determinants of mortality in patients treated with thrombolytic therapy within 6 hours of symptom onset are multifactorial and the relations complex. Although a few variables contain most of the prognostic information, many others contribute additional independent prognostic information. Through consideration of multiple characteristics, including age, medical history, physiological significance of the infarction, and medical treatment, the prognosis of an individual patient can be accurately estimated.

Aged↗
PubMed2006

Role and results of surgery in acute type B aortic dissection: insights from the International Registry of Acute Aortic Dissection (IRAD).

BACKGROUND: The clinical profiles and outcomes of patients treated surgically for acute type B aortic dissection (ABAD) are often reported for those in small series or for those cared for at a single institution over a long time period, during which a continuous evolution in techniques has occurred. Accordingly, we sought to evaluate the clinical features and surgical results of patients enrolled in the International Registry of Acute Aortic Dissection by identifying primary factors that influenced surgical outcome and estimating average surgical mortality for ABAD in the current era. METHODS AND RESULTS: A comprehensive analysis of 290 clinical variables and their relation to surgical outcomes for 82 patients who required surgery for ABAD (from a population of 1256 patients; mean+/-SD age, 60.6+/-15.0 years; 82.9% male) and who were enrolled in the International Registry of Acute Aortic Dissection was performed. The overall in-hospital mortality was 29.3%. Factors associated with increased surgical mortality based on univariate analysis were preoperative coma or altered consciousness, partial thrombosis of the false lumen, evidence of periaortic hematoma on diagnostic imaging, descending aortic diameter >6 cm, right ventricle dysfunction at surgery, and shorter time from the onset of symptoms to surgery. Factors associated with favorable outcomes included radiating pain, normotension at surgery (systolic blood pressure 100 to 149 mm Hg), and reduced hypothermic circulatory arrest time. The 2 independent predictors of surgical mortality were age >70 years (odds ratio, 4.32; 95% confidence interval, 1.30 to 14.34) and preoperative shock/hypotension (odds ratio, 6.05; 95% confidence interval, 1.12 to 32.49). CONCLUSIONS: The present study provides insights into current-day clinical profiles and surgical outcomes of ABAD. Knowledge about different preoperative clinical conditions may help surgeons in making treatment decisions among these high-risk patients.

Acute Disease↗
PubMed2002

Targeted proteomic profiling of renal Na(+) transporter and channel abundances in angiotensin II type 1a receptor knockout mice.

The renal tubule transporters responsible for Na(+) and water transport along the nephron have been identified and cloned, permitting comprehensive analysis of transporter protein abundance changes in complex physiological models by using a "targeted proteomics" approach. Here, we apply this approach to screen renal homogenates from mice in which the gene for the angiotensin II type 1a (AT(1a)) receptor has been deleted (versus wild-type mice) to determine which sodium transporters and channels are regulated by the AT(1a) receptor at the protein abundance level. In mice maintained on a low NaCl diet (<0.02% NaCl), (1) the abundances of 2 aldosterone-regulated transporters were markedly decreased in knockout versus wild-type mice, namely, the thiazide-sensitive cotransporter and the alpha-subunit of the amiloride-sensitive Na(+) channel (alpha-ENaC); (2) the abundances of beta-ENaC and gamma-ENaC were markedly increased; and (3) there were no significant changes in the abundances of the proximal tubule Na+-H(+) exchanger or the Na(+)-K(+)-2Cl(-) cotransporter of the thick ascending limb. When the experiment was repeated on higher NaCl diets (0.4% or 6% NaCl), the decrease in alpha-ENaC abundance persisted, whereas the other changes were abolished. Analysis of serum aldosterone concentration in AT(1a) knockout mice and wild-type mice on the low NaCl diet revealed the absence of a decrease with AT(1a) gene deletion (11.8 +/- 2.3 nmol/L for knockout mice and 5.7 +/- 0.8 nmol/L for wild-type mice [significantly increased]). These results reveal that the AT(1a) receptor plays an important role in regulation of Na(+) transporter and channel proteins in the "post-macula densa" region of the renal tubule via a mechanism that is not dependent on altered circulating aldosterone concentrations.

Angiotensin II↗
PubMedDate not supplied

Optimizing a linear algorithm for real-time robotic control using chronic cortical ensemble recordings in monkeys.

Previous work in our laboratory has demonstrated that a simple linear model can be used to translate cortical neuronal activity into real-time motor control commands that allow a robot arm to mimic the intended hand movements of trained primates. Here, we describe the results of a comprehensive analysis of the contribution of single cortical neurons to this linear model. Key to the operation of this model was the observation that a large percentage of cortical neurons located in both frontal and parietal cortical areas are tuned for hand position. In most neurons, hand position tuning was time-dependent, varying continuously during a 1-sec period before hand movement onset. The relevance of this physiological finding was demonstrated by showing that maximum contribution of individual neurons to the linear model was only achieved when optimal parameters for the impulse response functions describing time-varying neuronal position tuning were selected. Optimal parameters included impulse response functions with 1.0- to 1.4-sec time length and 50- to 100-msec bins. Although reliable generalization and long-term predictions (60-90 min) could be achieved after 10-min training sessions, we noticed that the model performance degraded over long periods. Part of this degradation was accounted by the observation that neuronal position tuning varied significantly throughout the duration (60-90 min) of a recording session. Altogether, these results indicate that the experimental paradigm described here may be useful not only to investigate aspects of neural population coding, but it may also provide a test bed for the development of clinically useful cortical prosthetic devices aimed at restoring motor functions in severely paralyzed patients.

Action Potentials↗
PubMed2005

Growth of pulmonary microvasculature in ventilated preterm infants.

RATIONALE: Density-based morphometric studies have demonstrated decreased capillary density in infants with bronchopulmonary dysplasia (BPD) and in BPD-like animal models, leading to the prevailing view that microvascular development is disrupted in BPD. OBJECTIVE: To perform a comprehensive analysis of the early and late effects of ventilation on pulmonary microvascular growth in preterm infants. METHODS: Postmortem lung samples were collected from ventilated preterm infants who died between 23 and 29 wk ("short-term ventilated") or between 36 and 39 wk ("long-term ventilated") corrected postmenstrual age. Results were compared with age-matched infants or stillborn infants ("early" and "late" control subjects). Microvascular growth was studied by anti-platelet endothelial cell adhesion molecule (PECAM)-1 immunohistochemistry, quantitative stereology, analysis of endothelial cell proliferation, and Western blot analysis of pulmonary PECAM-1 protein levels. MEASUREMENTS: Measurements were made of capillary density, volume of air-exchanging parenchyma, volume of microvascular endothelial cells, Ki67 labeling index of endothelial cells, and PECAM-1/actin protein levels. MAIN RESULTS: Lungs of long-term ventilated infants showed a significant (more than twofold) increase in volume of air-exchanging parenchyma and a 60% increase in total pulmonary microvascular endothelial volume compared with late control subjects, associated with 60% higher pulmonary PECAM-1 protein levels. The marked expansion of the pulmonary microvasculature in ventilated lungs was, at least partly, attributable to brisk endothelial cell proliferation. The microvasculature of ventilated lungs appeared immature, retaining a saccular architectural pattern. CONCLUSIONS: The pulmonary microvasculature of ventilated preterm infants displayed marked angiogenesis, nearly proportionate to the growth of the air-exchanging lung parenchyma. These results challenge the paradigm of microvascular growth arrest as a major pathogenic factor in BPD.

Blotting, Western↗