Biomedical subjects

K D Anderson

Publications and source records attributed to K D Anderson.

At least 37 records · Page 2Linked to original sources

PubMed2001

Gremlin negatively modulates BMP-4 induction of embryonic mouse lung branching morphogenesis.

Bone morphogenetic protein-4 (BMP-4) is a key morphogen for embryonic lung development that is expressed at high levels in the peripheral epithelium, but the mechanisms that modulate BMP-4 function in early mouse lung branching morphogenesis are unclear. Here, we studied the BMP-4 antagonist Gremlin, which is a member of the DAN family of BMP antagonists that can bind and block BMP-2/4 activity. The expression level of gremlin in embryonic mouse lungs is highest in the early embryonic pseudoglandular stage [embryonic days (E) 11.5-14.5] and is reduced during fetal lung maturation (E18.5 to postnatal day 1). In situ hybridization indicates that gremlin is diffusely expressed in peripheral lung mesenchyme and epithelium, but relatively high epithelial expression occurs in branching buds at E11.5 and in large airways after E16.5. In E11.5 lung organ culture, we found that exogenous BMP-4 dramatically enhanced peripheral lung epithelial branching morphogenesis, whereas reduction of endogenous gremlin expression with antisense oligonucleotides achieved the same gain-of-function phenotype as exogenous BMP-4, including increased epithelial cell proliferation and surfactant protein C expression. On the other hand, adenoviral overexpression of gremlin blocked the stimulatory effects of exogenous BMP-4. Therefore, our data support the hypothesis that Gremlin is a physiologically negative regulator of BMP-4 in lung branching morphogenesis.

Animals↗

PubMed2001

Novel mechanisms in murine nitrofen-induced pulmonary hypoplasia: FGF-10 rescue in culture.

We evaluated the role of the key pulmonary morphogenetic gene fibroblast growth factor-10 (Fgf10) in murine nitrofen-induced primary lung hypoplasia, which is evident before the time of diaphragm closure. In situ hybridization and competitive RT-PCR revealed a profound disturbance in the temporospatial pattern as well as a 10-fold decrease in mRNA expression level of Fgf10 but not of the inducible inhibitor murine Sprouty2 (mSpry2) after nitrofen treatment. Exogenous FGF-10 increased branching not only of control lungs [13% (right) and 27% (left); P < 0.01] but also of nitrofen-exposed lungs [23% (right) and 77% (left); P < 0.01]. Expression of mSpry2 increased 10-fold with FGF-10 in both nitrofen-treated and control lungs, indicating intact downstream FGF signaling mechanisms after nitrofen treatment. We conclude that nitrofen inhibits Fgf10 expression, which is essential for lung growth and branching. Exogenous FGF-10 not only stimulates FGF signaling, marked by increased mSpry2 expression, in both nitrofen-treated and control lungs but also substantially rescues nitrofen-induced lung hypoplasia in culture.

Adaptor Proteins, Signal Transducing↗

PubMed2001

Bradykinin B1 receptor up-regulation by interleukin-1beta and B1 agonist occurs through independent and synergistic intracellular signaling mechanisms in human lung fibroblasts.

Bradykinin B1 receptors (B1R) are rapidly induced after tissue trauma and are thought to be involved in maintaining the inflammatory response. Little is known about the intracellular signaling pathways mediating B1R induction in response to stress and inflammation. Here, we show that up-regulation of B1R by B1R agonist and interleukin-1beta (IL-1beta) occur through distinct but synergistic pathways in IMR-90 human lung fibroblasts. Incubation of cells with the B1R agonist desArg10kallidin (desArg10KD; 100 nM) and IL-1beta (500 pg/ml) resulted in a 3- and 4-fold increase, respectively, in B1R by 6 h, whereas coincubation of these factors produced up to a 20-fold increase. Furthermore, coincubation increased the potency of IL-1beta by 2-fold. Both the individual and the synergistic responses were sensitive to genistein, a general tyrosine kinase inhibitor. On the other hand, only the desArg10KD response and the synergistic response were sensitive to the p38 mitogen-activated protein kinase inhibitor SB 203580. Furthermore, only the synergistic response was sensitive to the nuclear factor-kappaB inhibitor pyrrolidine dithiocarbamate. Despite B1R up-regulation in A549 human lung epithelial cells by desArg10KD or IL-1beta individually, these factors did not act synergistically in this cell line. In conclusion, our results reinforce the view that kinins act in concert with proinflammatory cytokines to enhance selectively the inflammatory response of certain lung cells to kinins through distinct but synergistic intracellular signaling mechanisms. Thus, kinins may exert a pivotal role in maintaining and modulating feed-forward inflammatory processes in the lung.

Cells, Cultured↗

PubMed2000

The molecular basis of lung morphogenesis.

To form a diffusible interface large enough to conduct respiratory gas exchange with the circulation, the lung endoderm undergoes extensive branching morphogenesis and alveolization, coupled with angiogenesis and vasculogenesis. It is becoming clear that many of the key factors determining the process of branching morphogenesis, particularly of the respiratory organs, are highly conserved through evolution. Synthesis of information from null mutations in Drosophila and mouse indicates that members of the sonic hedgehog/patched/smoothened/Gli/FGF/FGFR/sprouty pathway are functionally conserved and extremely important in determining respiratory organogenesis through mesenchymal-epithelial inductive signaling, which induces epithelial proliferation, chemotaxis and organ-specific gene expression. Transcriptional factors including Nkx2.1, HNF family forkhead homologues, GATA family zinc finger factors, pou and hox, helix-loop-helix (HLH) factors, Id factors, glucocorticoid and retinoic acid receptors mediate and integrate the developmental genetic instruction of lung morphogenesis and cell lineage determination. Signaling by the IGF, EGF and TGF-beta/BMP pathways, extracellular matrix components and integrin signaling pathways also directs lung morphogenesis as well as proximo-distal lung epithelial cell lineage differentiation. Soluble factors secreted by lung mesenchyme comprise a 'compleat' inducer of lung morphogenesis. In general, peptide growth factors signaling through cognate receptors with tyrosine kinase intracellular signaling domains such as FGFR, EGFR, IGFR, PDGFR and c-met stimulate lung morphogenesis. On the other hand, cognate receptors with serine/threonine kinase intracellular signaling domains, such as the TGF-beta receptor family are inhibitory, although BMP4 and BMPR also play key inductive roles. Pulmonary neuroendocrine cells differentiate earliest in gestation from among multipotential lung epithelial cells. MASH1 null mutant mice do not develop PNE cells. Proximal and distal airway epithelial phenotypes differentiate under distinct transcriptional control mechanisms. It is becoming clear that angiogenesis and vasculogenesis of the pulmonary circulation and capillary network are closely linked with and may be necessary for lung epithelial morphogenesis. Like epithelial morphogenesis, pulmonary vascularization is subject to a fine balance between positive and negative factors. Angiogenic and vasculogenic factors include VEGF, which signals through cognate receptors flk and flt, while novel anti-angiogenic factors include EMAP II.

Animals↗

PubMed2000

The ciliary neurotrophic factor and its receptor, CNTFR alpha.

Ciliary neurotrophic factor (CNTF) is expressed in glial cells within the central and peripheral nervous systems. CNTF stimulates gene expression, cell survival or differentiation in a variety of neuronal cell types such as sensory, sympathetic, ciliary and motor neurons. In addition, effects of CNTF on oligodendrocytes as well as denervated and intact skeletal muscle have been documented. CNTF itself lacks a classical signal peptide sequence of a secreted protein, but is thought to convey its cytoprotective effects after release from adult glial cells by some mechanism induced by injury. Interestingly, mice that are homozygous for an inactivated CNTF gene develop normally and initially thrive. Only later in adulthood do they exhibit a mild loss of motor neurons with resulting muscle weakness, leading to the suggestion that CNTF is not essential for neural development, but instead acts in response to injury or other stresses. The CNTF receptor complex is most closely related to, and shares subunits with the receptor complexes for interleukin-6 and leukemia inhibitory factor. The specificity conferring alpha subunit of the CNTF complex (CNTFR alpha), is extremely well conserved across species, and has a distribution localized predominantly to the nervous system and skeletal muscle. CNTFR alpha lacks a conventional transmembrane domain and is thought to be anchored to the cell membrane by a glycosyl-phosphatidylinositol linkage. Mice lacking CNTFR alpha die perinatally, perhaps indicating the existence of a second developmentally important CNTF-like ligand. Signal transduction by CNTF requires that it bind first to CNTFR alpha, permitting the recruitment of gp130 and LIFR beta, forming a tripartite receptor complex. CNTF-induced heterodimerization of the beta receptor subunits leads to tyrosine phosphorylation (through constitutively associated JAKs), and the activated receptor provides docking sites for SH2-containing signaling molecules, such as STAT proteins. Activated STATs dimerize and translocate to the nucleus to bind specific DNA sequences, resulting in enhanced transcription of responsive genes. The neuroprotective effects of CNTF have been demonstrated in a number of in vitro cell models as well as in vivo in mutant mouse strains which exhibit motor neuron degeneration. Intracerebral administration of CNTF and CNTF analogs has also been shown to protect striatal output neurons in rodent and primate models of Huntington's disease. Treatment of humans and animals with CNTF is also known to induce weight loss characterized by a preferential loss of body fat. When administered systemically, CNTF activates downstream signaling molecules such as STAT-3 in areas of the hypothalamus which regulate food intake. In addition to its neuronal actions, CNTF and analogs have been shown to act on non-neuronal cells such as glia, hepatocytes, skeletal muscle, embryonic stem cells and bone marrow stromal cells.

Animals↗

PubMed2000

Overexpression of HuD, but not of its truncated form HuD I+II, promotes GAP-43 gene expression and neurite outgrowth in PC12 cells in the absence of nerve growth factor.

We have previously shown that the RNA-binding protein HuD binds to a regulatory element in the growth-associated protein (GAP)-43 mRNA and that this interaction involves its first two RNA recognition motifs (RRMs). In this study, we investigated the functional significance of this interaction by overexpression of human HuD protein (pcHuD) or its truncated form lacking the third RRM (pcHuD I+II) in PC12 cells. Morphological analysis revealed that pcHuD cells extended short neurites containing GAP-43-positive growth cones in the absence of nerve growth factor (NGF). These processes also contained tubulin and F-actin filaments but were not stained with antibodies against neurofilament M protein. In correlation with this phenotype, pcHuD cells contained higher levels of GAP-43 without changes in levels of other NGF-induced proteins, such as SNAP-25 and tau. In mRNA decay studies, HuD stabilized the GAP-43 mRNA, whereas HuD I+II did not have any effect either on GAP-43 mRNA stability or on the levels of GAP-43 protein. Likewise, pcHuD I+II cells showed no spontaneous neurite outgrowth and deficient outgrowth in response to NGF. Our results indicate that HuD is sufficient to increase GAP-43 gene expression and neurite outgrowth in the absence of NGF and that the third RRM in the protein is critical for this function.

Animals↗

PubMed2000

Technical advances in pediatric laparoscopy have had a beneficial impact on splenectomy.

PURPOSE: The aim of this study was to demonstrate the effects of recent technical advances on the safety and benefits of pediatric laparoscopic splenectomy. METHODS: A retrospective review was conducted of patients undergoing laparoscopic splenectomy from January 1998 to January 2000. Technical advances utilized during this period included the harmonic scalpel, a specialized flexible hilar retractor, a larger, wire-rimmed specimen bag, and lateral patient positioning. RESULTS: Laparoscopic splenectomy was performed successfully on 18 patients aged 3 to 17 years (median, 9). The indications were hereditary spherocytosis (n = 10), idiopathic thrombocytopenic purpura (n = 5), and other (n = 3). Eight patients had concomitant procedures including cholecystectomy (n = 3), resection of an accessory spleen (n = 3), and other (n = 2). The median operating time, including the concomitant procedures, was 125 minutes (range, 70 to 235). Patients tolerated a regular diet on median postoperative day 1 (range, 1 to 3), and 16 were discharged home on or before postoperative day 2. None of the patients required blood product transfusion or conversion to an open technique. There were no complications, and all patients had returned to usual activity by 2 weeks. CONCLUSION: With recent technological advances, the laparoscopic approach has become easy to perform, safe, and should be considered the procedure of choice for pediatric splenectomy.

Adolescent↗

PubMed2000

A standardized feeding regimen for hypertrophic pyloric stenosis decreases length of hospitalization and hospital costs.

BACKGROUND/PURPOSE: Before the institution of a standardized feeding regimen (SFR) for hypertrophic pyloric stenosis (HPS) at the authors' institution, the postoperative feeding regimen and, thus, the length of hospitalization for HPS patients was variable. The aim of this study was to evaluate whether a SFR would affect the length of hospitalization or hospital costs for HPS patients. METHODS: A 5-year retrospective analysis was performed on 242 patients who underwent pyloromyotomy via a standard right upper quadrant incision. The length of hospitalization and hospital costs were compared in these patients before and after the institution of a standardized postoperative feeding regimen. RESULTS: The SFR decreased total length of hospitalization by 19.4% (3.1 days v2.5 days, P = .002), postoperative length of stay by 21% (1.9 days v 1.5 days, P< .001), total costs by 11.9% (P= .05), direct costs by 7.7% (P= .22), and indirect costs by 18.6% (P= .003). This occurred despite a small increase in costs per day. The SFR did not change the complication rate (5.3% before SFR v6.1% after SFR, P = 1.0). CONCLUSION: A postoperative standardized feeding regimen for patients with HPS decreased length of hospitalization and hospital costs without adverse effects.

Costs and Cost Analysis↗

PubMed2000

The RNA-binding protein HuD is required for GAP-43 mRNA stability, GAP-43 gene expression, and PKC-dependent neurite outgrowth in PC12 cells.

The RNA-binding protein HuD binds to a regulatory element in the 3' untranslated region (3' UTR) of the GAP-43 mRNA. To investigate the functional significance of this interaction, we generated PC12 cell lines in which HuD levels were controlled by transfection with either antisense (pDuH) or sense (pcHuD) constructs. pDuH-transfected cells contained reduced amounts of GAP-43 protein and mRNA, and these levels remained low even after nerve growth factor (NGF) stimulation, a treatment that is normally associated with protein kinase C (PKC)-dependent stabilization of the GAP-43 mRNA and neuronal differentiation. Analysis of GAP-43 mRNA stability demonstrated that the mRNA had a shorter half-life in these cells. In agreement with their deficient GAP-43 expression, pDuH cells failed to grow neurites in the presence of NGF or phorbol esters. These cells, however, exhibited normal neurite outgrowth when exposed to dibutyryl-cAMP, an agent that induces outgrowth independently from GAP-43. We observed opposite effects in pcHuD-transfected cells. The GAP-43 mRNA was stabilized in these cells, leading to an increase in the levels of the GAP-43 mRNA and protein. pcHuD cells were also found to grow short spontaneous neurites, a process that required the presence of GAP-43. In conclusion, our results suggest that HuD plays a critical role in PKC-mediated neurite outgrowth in PC12 cells and that this protein does so primarily by promoting the stabilization of the GAP-43 mRNA.

Animals↗

PubMed2000

Telomerase in alveolar epithelial development and repair.

Telomerase expression and activity were examined in the developing lung and in the adult lung during repair after injury. Both whole lung tissue and primary cultures of type 2 alveolar epithelial cells (AEC2) isolated from fetal and adult rodents were analyzed for 1) telomerase expression by immunohistochemistry and 2) telomerase activity with a telomerase repeat amplification protocol. We found that telomerase was expressed in a temporally regulated manner in fetal lung through the late stages of gestation, with peak expression just before birth. Expression persisted for a brief period in neonates, then decreased to nearly undetectable levels by postnatal day 9. Telomerase expression and activity were reinduced in normally quiescent adult lung by in vivo treatment with hyperoxia. In populations of AEC2 isolated from both developing and repairing lungs, telomerase expression and activity showed a strong correlation with the proliferation marker proliferating cell nuclear antigen. It has been suggested that telomerase expression and activity are hallmarks of stem or progenitor cells. Our observations suggest that a telomerase-positive subpopulation is present within the general AEC2 population. Telomerase may act as a marker for the proliferative status of this subpopulation.

Age Factors↗

PubMed2000

Recruitment behavior and program directors: how ethical are their perspectives about the match process?

OBJECTIVE: This study examined family practice residency directors' perspectives on the 1999 National Resident Matching Program (NRMP) process and identified directors' expectations for students' recruitment behavior. METHODS: Subjects were the family practice residency program directors. A 22-item written questionnaire was mailed to each director. The questions related to the directors' perceptions of the following issues: applicants interviewing in more than one specialty, communication initiated by programs or applicants, commitments made to applicants and by applicants, ethical dilemmas faced by the program director, and the NRMP process itself. Descriptive statistics were reported. RESULTS: Only a few of the residency program directors (9.1%) felt that it was ethically wrong for an applicant to interview in more than one specialty. However, most program directors (83%) indicated that the knowledge of an applicant interviewing in more than one specialty had a "significant" negative or "some" negative effect on the applicant's rank order. Ninety-five percent of program directors indicated that they engage in follow-up communication with applicants following the formal interview. Almost all program directors (98%) reported that at least some applicants contact them following the formal interview to inform them that the program was a "high" or No. 1 rank-order choice. The majority of program directors (94%) felt that the NRMP process placed their program in the position of having to be dishonest with applicants to match their top choices. CONCLUSIONS: The results of the study indicate that the actions of many program directors and applicants may not be consistent with the written policies of the NRMP.

Administrative Personnel↗

PubMed2000

The urology residency matching program in practice.

PURPOSE: We evaluate behaviors and attitudes among resident applicants and program directors related to the American Urological Association (AUA) residency matching program and recommend changes to improve the match. MATERIALS AND METHODS: Written questionnaires were mailed to 519 resident applicants and 112 program directors after the 1999 American Urological Association match. Subjects were asked about their observations, behaviors and opinions towards the match. RESULTS: Questionnaires were returned by 230 resident applicants and 94 program directors (44% and 83% response rates, respectively.) Of the resident applicants 75% spent $1,001 to $5,000 for interviewing. Of the program directors 47% recalled that applicants asked how programs would rank the applicant and 61% of applicants recalled that program directors asked applicants how they would rank programs. Dishonesty was acknowledged by 31% of program directors and 44% of resident applicants. Of program directors 82% thought applicants "lied", while 67% of applicants thought that programs "lied" (quotations indicate questionnaire language). Participants characterized their own dishonesty as "just playing the game" or they "did not feel badly." Of program directors 81% and of applicants 61% were "skeptical" or "did not believe" when informed they were a "high" or "number 1" selection. Being asked about marital status was recalled by 91% of male and 100% of female (p = 0. 02), if they had children by 53% of male and 67% of female, (p = 0. 03), and intent to have children by 25% of male and 62% of female (p <0.001), applicants, respectively. Free-form comments were written by 132 resident applicants and 28 program directors. The most frequent comments suggested the need to improve ethical behavior, modify the process so applications could be transmitted electronically and modify interviews to reduce applicant financial burden. Nine female applicants commented on their perceptions of sexual discrimination during the interviews. CONCLUSIONS: Resident applicants and program directors violate match code rules frequently. Program directors and resident applicants are skeptical of each other. Patterns of faculty behavior differ based on applicant gender. Interviews are costly for applicants. We recommend that 1) programs adopt policies to enhance fairness, 2) applications be filed electronically, 3) programs assist resident applicants with interview accommodation to reduce financial burden and 4) a post-interview code of limited or noncommunication be adopted.

Administrative Personnel↗

PubMed1999

Is match ethics an oxymoron?

BACKGROUND: Graduate medical education has undergone economic and structural changes-changes that have placed increasing pressure on medical students and programs to match effectively. This study documents the experiences, perceptions, and ethical dilemmas of medical students with the 1998 match process. METHODS: Surveyed were 437 senior students from three medical schools. Students were questioned about: interviewing practices, communication with programs, commitments made, ethical dilemmas faced, and the match process itself. Data were analyzed using Student's t test, the chi-square test, and descriptive statistics. RESULTS: In all, 314 (72%) students responded. Programs expect postinterview communication from students (57%). Students perceive that programs are making "informal" commitments (43%), lying to them (33%), and encouraging their unethical behavior in order to match (21%). Ethical dilemmas are related to requests for informal commitments. CONCLUSIONS: The NRMP's ruling that denounces prematch commitments is being broken by students and programs alike, resulting in the promotion of unprofessional behavior and gamesmanship.

Career Choice↗

PubMed1999

Venous ischemia as a cause of ureteral necrosis in transplanted ureters.

BACKGROUND: Urologic complications after pediatric renal transplantation can adversely effect the outcome and may result in decreased graft survival. Efforts to prevent these complications are worthwhile. This study investigates the incidence of these complications in a clinical transplant program and reports on an animal model used to investigate one possible cause. METHODS: In the clinical study, the results of a pediatric renal transplant program at a large children's hospital for a 5(1/2)-year period were reviewed with special attention paid to patients suffering ureteral necrosis. In the experimental study, 9 swine underwent laparotomy, bilateral complete infrahilar ureteric dissection, and extravesical ureteroneocystostomy. On the left side only, the renal and adrenal veins were ligated. The arterial supply remained intact. The right side did not undergo vessel ligation and served as the control. Three pigs each were killed at 3, 8, and 15 days. Kidneys, ureters and a cuff of bladder were examined histologically. RESULTS: In the clinical study 75 renal transplants were performed with a total of 5 cases of early ureteral necrosis. Two of these 5 displayed venous congestion and ischemia, and 2 were associated with kidneys displaying primary nonfunction of the graft. Seventy-one of 75 grafts are continuing to function. One of the 4 early graft losses also had an ischemic ureter. In the experimental study all right kidneys and ureters were normal. All left kidneys had complete hemorrhagic necrosis. Necrosis also was found in 5 of 9 proximal left ureters and in 7 of 9 distal left ureters. Viable left ureters displayed moderate to severe submucosal and periureteric hemorrhage. Four of 9 ureters displayed more damage distally than proximally. The extent of necrosis was similar at 3, 8, and 15 days. CONCLUSION: In both clinical and experimental studies, venous congestion and subsequent ischemia have been shown to be important causes of ureteral necrosis after renal transplantation.

Adolescent↗

PubMed1999

The umbilical fold approach to pyloromyotomy: is it a safe alternative to the right upper-quadrant approach?

BACKGROUND: Hypertrophic pyloric stenosis has been approached using two standard incisions for pyloromyotomy: the circumumbilical (UMB) and the right upper quadrant (RUQ). The UMB approach produces an almost undetectable scar but has been associated with more complications. STUDY DESIGN: A 5-year retrospective analysis was performed on 344 patients (90 UMB and 254 RUQ) to compare technical and wound complications. The effect of prophylactic antibiotics on wound infection was also evaluated. RESULTS: The intraoperative complication rate was 5.5% (13.3% UMB versus 2.8% RUQ; p = 0.001). The mucosal perforation rate was 3.5% (8.9% UMB versus 1.6% RUQ; p = 0.003). Mucosal perforations increased the mean +/- SD length of hospitalization in UMB patients (3.9 +/- 0.8 versus 2.4 +/- 1.1 days; p < 0.001). The serosal tear rate was 2.0% (4.4% UMB versus 1.2% RUQ; p=0.08). The postoperative complication rate was 5.8% (14.4% UMB versus 2.8% RUQ; p < 0.001), and the wound infection rate was 2.6% (6.7% UMB versus 1.2% RUQ; p = 0.01). Antibiotic prophylaxis decreased the rate of wound infection to 1.8% and eliminated the statistical difference between the groups (4.5% UMB versus 0% RUQ; p=0.16). The rate of other postoperative complications was 3.2% (7.8% UMB versus 1.6% RUQ; p = 0.009). Duration of hospital stay did not differ between the groups overall (2.6+/-1.12 days for UMB versus 2.7+/-1.5 days for RUQ; p = 0.35). CONCLUSIONS: The UMB approach to pyloromyotomy was cosmetically superior but increased complication rates. Technical complications were easily corrected and length of stay was not affected. Wound infections were decreased in both groups by the use of prophylactic antibiotics.

Adult↗

PubMed1999

Abrogation of cyclin D1 expression predisposes lung cancer cells to serum deprivation-induced apoptosis.

Cyclin D1 antisense (D1AS)-transfected lung epithelial cell lines were serum deprived and then analyzed for three hallmarks of apoptosis: appearance of single-strand DNA breaks, alteration of apoptosis-related protein expression, and induction of chromatin condensation. Single-strand DNA breaks appeared at significant levels 24 h after serum deprivation, whereas induction of chromatin condensation was observed after 72 h. The antioxidants dimethyl sulfoxide, ascorbate, and glutathione, as well as insulin-like growth factor-I, inhibited induction of DNA damage in this assay. Additionally, proliferating cell nuclear antigen expression is completely suppressed in the D1AS cells, indicating a mechanism to explain the reduced capacity for DNA repair. Increased expression of cyclin D1, which is a common lesion in lung cancer, may thus prevent induction of apoptosis in an oxidizing and growth factor-poor environment. Reducing cyclin D1 expression in lung cancer cells by expression of D1AS RNA disrupted these protective pathways.

Antioxidants↗

PubMed1998

Relative resistance of striatal neurons containing calbindin or parvalbumin to quinolinic acid-mediated excitotoxicity compared to other striatal neuron types.

To evaluate the relative ability of those striatal neuron types containing calbindin or parvalbumin to withstand a Ca(2+)-mediated excitotoxic insult, we injected the NMDA receptor-specific excitotoxin quinolinic acid (QA) into the striatum in mature adult rats and 2 months later examined the relative survival of striatal interneurons rich in parvalbumin and striatal projection neurons rich in calbindin. To provide standardization to the survival of striatal neuron types thought to be poor in Ca2+ buffering proteins, the survival was compared to that of somatostatin-neuropeptide Y (SS/NPY)-containing interneurons and enkephalinergic projection neurons, which are devoid of or relatively poorer in such proteins. The various neuron types were identified by immunohistochemical labeling for these type-specific markers and their relative survival was compared at each of a series of increasing distances from the injection center. In brief, we found that parvalbuminergic, calbindinergic, and enkephalinergic neurons all showed a generally comparable gradient of neuronal loss, except just outside the lesion center, where calbindin-rich neurons showed significantly enhanced survival. In contrast, striatal SS/NPY interneurons were more vulnerable to QA than any of these three other types. These observed patterns of survival following intrastriatal QA injection suggest that calbindin and parvalbumin content does not by itself determine the vulnerability of striatal neurons to QA-mediated excitotoxicity in mature adult rats. For example, parvalbuminergic striatal interneurons were not impervious to QA, while cholinergic striatal interneurons are highly resistant and SS/NPY+ striatal interneurons are highly vulnerable. Both cholinergic and SS/NPY+ interneurons are devoid of any known calcium buffering protein. Similarly, calbindin does not prevent striatal projection neuron vulnerability to QA excitotoxicity. Nonetheless, our data do suggest that calbindin may offer striatal neurons some protection against moderate excitotoxic insults, and this may explain the reportedly slightly greater vulnerability of striatal neurons that are poor in calbindin to ischemia and Huntington's disease.

Animals↗

PubMed1998

Inhibition of vascular and epithelial differentiation in murine nitrofen-induced diaphragmatic hernia.

Neonates with congenital diaphragmatic hernia (DH) die of pulmonary hypoplasia and persistent pulmonary hypertension. We used immunohistochemical localization of alpha-smooth muscle actin (alpha-SMA), platelet endothelial cell adhesion molecule (PECAM)-1, thyroid transcription factor (TTF)-1, surfactant protein (SP) A, SP-C, and competitive RT-PCR quantitation of TTF-1, SP-A, SP-C, and alpha-SMA mRNA expression to characterize the epithelial and vascular phenotype of lungs from ICR fetal mice with a nitrofen-induced DH. Nitrofen (25 mg) was gavage fed to pregnant mice on day 8 of gestation. Fetal mice were delivered on day 17. The diaphragm was examined for a defect, and the lungs were either fixed, sectioned, and immunostained or processed for mRNA isolation. In comparison with control lungs, DH lungs showed increased expression of alpha-SMA mRNA, fewer and more muscular arterioles (alpha-SMA), less well-developed capillary networks (PECAM-1), delayed epithelial development marked by a persistence of TTF-1 in the periphery, and decreased SP-A mRNA and SP-A expression. These data suggest that in the murine nitrofen-induced DH, as in human congenital DH, pulmonary insufficiency is due to an inhibition of peripheral pulmonary development including terminal airway and vascular morphogenesis.

Actins↗