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Biomedical subjects

R A Lang

Publications and source records attributed to R A Lang.

At least 19 recordsLinked to original sources
PubMed2006

Transoral diverticulostomy with a modified Endo-Gia stapler: results after 4 years of experience.

BACKGROUND: The incidence of Zenker's diverticulum is low (2/100,000). Standard surgical treatment is cricopharyngeal myotomy with diverticulectomy. Various minimally invasive surgical approaches pursued recently have treated Zenker's diverticulum adequately. The functional minimally invasive therapy is performed alternatively using an Endo-Gia stapler inserted transorally to perform an esophageal diverticulostomia, or using thermal coagulation applied by a carbon dioxide (CO2) or argon plasma laser. The key to a successful procedure is adequate exposure of the diverticulum by insertion of a pharynx spreader before the surgery. METHODS: Since 1996, 31 patients who underwent minimally invasive diverticulostomies performed in our clinic have been included prospectively in the current study. All the patients were examined endoscopically before and after surgery. Furthermore, the intraesophageal and intragastric pressure was examined by transesophageal manometry, and the pH in the esophagus and stomach was determined by pH-metry. A barium swallow was performed to exclude leakage at the stapler suture line as proof of sufficient anastomoses. Manometry showed that the upper esophageal sphincter functioned normally before and after surgery. The results were compared with those of patients undergoing conventional procedures. RESULTS: The median follow-up period after resection of the diverticulum was 46 months. Both the Gastrointestinal Quality-of-Life Index (GQLI) (p < 0.001) and the modified dysphagia score (GHDS) increased significantly, indicating that the operations were successful. The minimally invasive procedure is faster than cricopharyngeal myotomy and significantly safer. It is better tolerated by patients, and they are discharged earlier. CONCLUSION: Transoral esophagodiverticulosomy has become the standard procedure for Zenker's diverticulum in the authors' department. The endoscopic minimally invasive approach proved to be safer than standard surgical procedures. It offers a significantly shorter operation time and postoperative hospital stay (p < 0.001).

Adult↗
PubMed2006

Laparoscopic partial myectomy: an experimental reflux model.

BACKGROUND: A number of different surgical procedures have been described for the treatment of gastroesophageal reflux disease. Moreover, modifications and completely new techniques are being introduced on a regular basis. Nonetheless, in most cases of novel laparoscopic techniques profound experimental data have not been collected prior to their clinical introduction. Due to the lack of an animal model of inadequate esophageal sphincter function, most experimental studies on antireflux procedures were done on normally functioning esophageal sphincters. METHODS: It is well-known that myotomy alone cannot induce sphincter insufficiency in animal models. In addition, complete myectomy is associated with severe mortality and, therefore, is not useful as an experimental model. This study introduces a new model of laparoscopic partial in vivo myectomy. The procedure described here forms a myectomy of the esophagus using scissors and a sponge on the side of the greater gastric curvature. The size of the myectomy is approximately 6 x 1.5 cm and was successfully performed in a consecutive series of eight experimental animals (male German house pigs). RESULTS: Following an intensive team training on dead animals, the procedure was performed with success via the laparoscope in all study animals (n = 8). The sphincter pressure as determined by manometry was significantly reduced from 7.7 mmHg (range, 4.5-9.1; preoperative values) to 2.2 mmHg (range, 0-6.8; early postoperative values) and 2.3 mmHg (range, 0-3.7) at 8 weeks after surgery (p < 0.001). In addition, the length of the lower esophageal sphincter as well as the sphincter pressure vector volume were significantly reduced early as well as at 8 weeks after laparoscopic myectomy. Furthermore, endoscopy and reflux testing were pathologic compared with control animals. CONCLUSIONS: Laparoscopic partial myectomy results in complete sphincter insufficiency with only little procedure-related morbidity. This procedure allows for the experimental evaluation of surgical procedures on the gastroesophageal junction. Future modifications of surgical antireflux procedures can therefore be evaluated in an experimental setting prior to their clinical introduction.

Animals↗
PubMed2005

How safe are laparoscopic intracorporeal anastomoses?

BACKGROUND: A recent German Multicenter Study comprising 3 070 laparoscopic colorectal resections indicates that complete intracorporeal anastomoses are performed in only 1.8 % cases. The aim of our study was to review and analyse the safety of complete intracorpeal anastomosis. METHODS: In a literature survey we searched for complete intracorporeal anastomosis with different key words. RESULTS: In agreement with the literature, technically demanding hand-sutured anastomoses are no common practice. Intracorporeal anastomosis is usually done using endoscopic linear stapling devices or a conventional circular stapler by performing end-to-end, end-to-side, and side-to-side anastomoses. These techniques are more frequently used in the upper than in the lower gastrointestinal tract. CONCLUSIONS: The data published so far, however, indicates that completely intracorporeal performed anastomoses are safe in the hands of laparoscopically experienced surgeons. This technique implies very low percentages of postoperative stenoses (0-10 %) and, furthermore, very low percentages of postoperative anastomotic leakages (0-8 %).

Anastomosis, Surgical↗
PubMed2004

Tyrosine phosphorylation sites on FRS2alpha responsible for Shp2 recruitment are critical for induction of lens and retina.

Early development of the lens and retina depends upon reciprocal inductive interactions between the embryonic surface ectoderm and the underlying neuroepithelium of the optic vesicle. FGF signaling has been implicated in this signal exchange. The docking protein FRS2alpha is a major mediator of FGF signaling by providing a link between FGF receptors (FGFRs) and a variety of intracellular signaling pathways. After FGF stimulation, tyrosine-phosphorylated FRS2alpha recruits four molecules of the adaptor protein Grb2 and two molecules of the protein tyrosine phosphatase Shp2, resulting in activation of the Ras/extracellular signal-regulated kinase (ERK) and phosphatidylinositol-3 kinase/Akt signaling pathways. In this report, we explore the role of signaling pathways downstream of FRS2alpha in eye development by analyzing the phenotypes of mice that carry point mutations in either the Grb2-(Frs2alpha(4F)) or the Shp2-binding sites (Frs2alpha(2F)) of FRS2alpha. Although Frs2alpha(4F/4F) mice exhibited normal early eye development, all Frs2alpha(2F/2F) embryos were defective in eye development and showed anophthalmia or microphthalmia. Consistent with the critical role of FRS2alpha in FGF signaling, the level of activated extracellular signal-regulated kinase in Frs2alpha(2F/2F) embryos was significantly lower than that observed in wild-type embryos. Furthermore, expression of Pax6 and Six3, molecular markers for lens induction, were decreased in the Frs2alpha(2F/2F) presumptive lens ectoderm. Similarly, the expression of Chx10 and Bmp4, genes required for retinal precursor proliferation and for lens development, respectively, was also decreased in the optic vesicles of Frs2alpha(2F/2F) mice. These experiments demonstrate that intracellular signals that depend on specific tyrosine residues in FRS2alpha lie upstream of gene products critical for induction of lens and retina.

Adaptor Proteins, Signal Transducing↗
PubMed2001

Misexpression of IGF-I in the mouse lens expands the transitional zone and perturbs lens polarization.

Insulin-like growth factor-I (IGF-I) has been implicated as a regulator of lens development. Experiments performed in the chick have indicated that IGF-I can stimulate lens fiber cell differentiation and may be involved in controlling lens polarization. To assess IGF-I activity on mammalian lens cells in vivo, we generated transgenic mice in which this factor was overexpressed from the alphaA-crystallin promoter. Interestingly, we observed no premature differentiation of lens epithelial cells. The pattern of lens polarization was perturbed, with an apparent expansion of the epithelial compartment towards the posterior lens pole. The distribution of immunoreactivity for MIP26 and p57(KIP2) and a modified pattern of proliferation suggested that this morphological change was best described as an expansion of the germinative and transitional zones. The expression of IGF-I signaling components in the normal transitional zone and expansion of the transitional zone in the transgenic lens both suggest that endogenous IGF-I may provide a spatial cue that helps to control the normal location of this domain.

Animals↗
PubMed2001

Early eye development in vertebrates.

This review provides a synthesis that combines data from classical experimentation and recent advances in our understanding of early eye development. Emphasis is placed on the events that underlie and direct neural retina formation and lens induction. Understanding these events represents a longstanding problem in developmental biology. Early interest can be attributed to the curiosity generated by the relatively frequent occurrence of disorders such as cyclopia and anophthalmia, in which dramatic changes in eye development are readily observed. However, it was the advent of experimental embryology at the turn of the century that transformed curiosity into active investigation. Pioneered by investigators such as Spemann and Adelmann, these embryological manipulations have left a profound legacy. Questions about early eye development first addressed using tissue manipulations remain topical as we try to understand the molecular basis of this process.

Animals↗
PubMed2001

The upstream ectoderm enhancer in Pax6 has an important role in lens induction.

The Pax6 gene has a central role in development of the eye. We show, through targeted deletion in the mouse, that an ectoderm enhancer in the Pax6 gene is required for normal lens formation. Ectoderm enhancer-deficient embryos exhibit distinctive defects at every stage of lens development. These include a thinner lens placode, reduced placodal cell proliferation, and a small lens pit and lens vesicle. In addition, the lens vesicle fails to separate from the surface ectoderm and the maturing lens is smaller and shows a delay in fiber cell differentiation. Interestingly, deletion of the ectoderm enhancer does not eliminate Pax6 production in the lens placode but results in a diminished level that, in central sections, is apparent primarily on the nasal side. This argues that Pax6 expression in the lens placode is controlled by the ectoderm enhancer and at least one other transcriptional control element. It also suggests that Pax6 enhancers active in the lens placode drive expression in distinct subdomains, an assertion that is supported by the expression pattern of a lacZ reporter transgene driven by the ectoderm enhancer. Interestingly, deletion of the ectoderm enhancer causes loss of expression of Foxe3, a transcription factor gene mutated in the dysgenetic lens mouse. When combined, these data and previously published work allow us to assemble a more complete genetic pathway describing lens induction. This pathway features (1) a pre-placodal phase of Pax6 expression that is required for the activity of multiple, downstream Pax6 enhancers; (2) a later, placodal phase of Pax6 expression regulated by multiple enhancers; and (3) the Foxe3 gene in a downstream position. This pathway forms a basis for future analysis of lens induction mechanism.

Animals↗
PubMed2001

Fgf receptor signaling plays a role in lens induction.

We describe experiments showing that fibroblast growth factor receptor (Fgfr) signaling plays a role in lens induction. Three distinct experimental strategies were used: (1) using small-molecule inhibitors of Fgfr kinase activity, we showed that both the transcription level and protein expression of Pax6, a transcription factor critical for lens development, was diminished in the presumptive lens ectoderm; (2) transgenic mice (designated Tfr7) that expressed a dominant-negative Fgf receptor exclusively in the presumptive lens ectoderm showed defects in formation of the lens placode at E9.5 but in addition, showed reduced levels of expression for Pax6, Sox2 and Foxe3, all markers of lens induction; (3) by performing crosses between Tfr7 transgenic and Bmp7-null mice, we showed that there is a genetic interaction between Fgfr and Bmp7 signaling at the induction phases of lens development. This manifested as exacerbated lens development defects and lower levels of Pax6 and Foxe3 expression in Tfr7/Tfr7, Bmp7(+/-) mice when compared with Tfr7/Tfr7 mice alone. As Bmp7 is an established lens induction signal, this provides further evidence that Fgfr activity is important for lens induction. This analysis establishes a role for Fgfr signaling in lens induction and defines a genetic pathway in which Fgfr and Bmp7 signaling converge on Pax6 expression in the lens placode with the Foxe3 and Sox2 genes lying downstream.

Animals↗
PubMed2001

[How safe is intracorporeal anastomosis?].

A recent German multi-centre study comprising 3070 laparoscopic colorectal resections indicates that complete intracorporeal anastomoses are done in only 1.8%. In agreement with the literature, technically demanding hand-sutured anastomoses are no common practice either. Intracorporeal anastomosis is usually done using endoscopic linear stapling devices or the conventional circular stapler by performing end-to-end, end-to-side, and side-to-side anastomoses. These techniques are more frequently used in the upper than in the lower gastrointestinal tract. The date published so far, however, indicate that the complete intracorporeal anastomosis is a save technique in the hands of laparoscopically experienced surgical teams. This technique has very low rates of postoperative stenoses (0-10%) and, furthermore, very low rates of postoperative anastomotic leakages (0-8%).

Anastomosis, Surgical↗
PubMed2000

Endogenous and ectopic gland induction by FGF-10.

FGF-10, a member of the fibroblast growth factor family, is expressed in mesodermally derived cell populations during embryogenesis. During normal ocular development, FGF-10 is expressed in the perioptic mesenchyme adjacent to the Harderian and lacrimal gland primordia. In this report, we provide evidence that FGF-10 is both necessary and sufficient to initiate glandular morphogenesis. Lens-specific expression of FGF-10 was sufficient to induce ectopic ocular glands within the cornea. In addition, lacrimal and Harderian glands were not seen in FGF-10 null fetuses. Based on these results we propose that FGF-10 is an inductive signal that initiates ocular gland morphogenesis.

Animals↗
PubMed2000

The role of carcinoembryonic antigen for the detection of recurrent disease following curative resection of large-bowel cancer.

BACKGROUND AND AIMS: During recent years, a discussion about cost-effectiveness and importance of follow-up evaluation after curative resection of large-bowel cancer has developed. It is not known whether the determination of carcino-embryonic antigen (CEA) plays a crucial role in the early detection of recurrent disease. PATIENTS/METHODS: We conducted an analysis of the prospective follow-up database of 1321 patients after curative resection of colorectal cancer in our institution between 1990 and 1998 to evaluate the role of CEA in the early detection of recurrent disease. RESULTS: Of the 1321 patients included in our study, 306 developed recurrent disease following curative resection (23.2%). These patients with recurrent disease were divided into: Group I. No pre-operative CEA determination/insufficient follow-up (n=47; 15.4%). Group II. No elevation of CEA with primary cancer (n=156; 51.0%): (IIa) elevation with recurrent disease (n=62); (IIb) no elevation at any time point (n=53); and (IIc) role of CEA not completely elucidated (n=41). Thirteen patients of group II underwent curative relapse surgery (8.3%). Group III. Elevated CEA with primary cancer (n=103; 33.7%): (IlIa) no increase with recurrent disease (n=21); (IIIb) increase with other symptoms of recurrent disease (n=45); and (IIIc) increased values as an early symptom of recurrent disease (n=37). Sixteen patients of group III underwent curative relapse surgery (15.5%). In patients after relapse surgery, recurrent disease developed again after a median time of 12 months (mean 17.9+/-3.8 months). CONCLUSIONS: Our findings indicate that 2.8% of all patients (12.1% of patients with recurrent disease) who underwent curative resection of colorectal cancer profit from follow-up CEA determinations. With careful observation of CEA kinetics, 6.2% (n=82) of all patients or 26.8% of patients with recurrent disease could profit from routine follow-up CEA determinations. In 9.5% of patients with recurrent disease, curative resection of relapse was achieved and these patients remained disease free for a median time of 12 months. Regular CEA measurements remain an important part of routine patient care after curative resection of colorectal cancer.

Adult↗
PubMed2000

FGF10 is an inducer and Pax6 a competence factor for lacrimal gland development.

We investigated the mechanism of tissue induction and specification using the lacrimal gland as a model system. This structure begins its morphogenesis as a bud-like outgrowth of the conjunctival epithelium and ultimately forms a branched structure with secretory function. Using a reporter transgene as a specific marker for gland epithelium, we show that the transcription factor Pax6 is required for normal development of the gland and is probably an important competence factor. In investigating the cell-cell signaling required, we show that fibroblast growth factor (FGF) 10 is sufficient to stimulate ectopic lacrimal bud formation in ocular explants. Expression of FGF10 in the mesenchyme adjacent to the presumptive lacrimal bud and absence of lacrimal gland development in FGF10-null mice strongly suggest that it is an endogenous inducer. This was supported by the observation that inhibition of signaling by a receptor for FGF10 (receptor 2 IIIb) suppressed development of the endogenous lacrimal bud. In explants of mesenchyme-free gland epithelium, FGF10 stimulated growth but not branching morphogenesis. This suggested that its role in induction is to stimulate proliferation and, in turn, that FGF10 combines with other factors to provide the instructive signals required for lacrimal gland development.

Animals↗
PubMed1999

Macrophages kill capillary cells in G1 phase of the cell cycle during programmed vascular regression.

Programmed capillary regression occurs during normal development of the eye and serves as a useful model for assessing the forces that drive vascular involution. Using a combination of S-phase labeling and liposome-mediated macrophage elimination, we show that during regression, macrophages induce apoptosis of both pericytes and endothelial cells in a cell cycle stage-dependent manner. Target cells are signaled to die by macrophages approximately 15 hours after S-phase labeling and this corresponds to a point in mid-G1 phase of the cell cycle. The tight correlation between the restriction point of the cell cycle and the point where the macrophage death signal is received suggests that the mitogen, matrix and cytoskeletal signals essential for cell-cycle progression may be inhibited by macrophages as a means of inducing cell death. Furthermore, these experiments show that cells from two distinct lineages are induced to die as a consequence of macrophage action, and this provides evidence that macrophage-induced cell death may be a general phenomenon during development and homeostasis.

Animals↗
PubMed1999

Pax6 induces ectopic eyes in a vertebrate.

We report here that misexpression of the transcription factor Pax6 in the vertebrate Xenopus laevis leads to the formation of differentiated ectopic eyes. Multiple molecular markers indicated the presence of mature lens fiber cells, ganglion cells, Müller cells, photoreceptors and retinal pigment epithelial cells in a spatial arrangement similar to that of endogenous eyes. Lineage tracing experiments showed that lens, retina and retinal pigment epithelium arose as a consequence of the cell-autonomous function of Pax6. These experiments also reveal that the cell autonomous activity of misexpressed Pax6 causes the ectopic expression of a number of genes including Rx, Otx2, Six3 and endogenous Pax6, each of which has been implicated in eye development. The formation of ectopic and endogenous eyes could be suppressed by coexpression of a dominant-negative form of Pax6. These data show that in vertebrates, as in the invertebrate Drosophila melanogaster, Pax6 is both necessary and sufficient to trigger the cascade of events required for eye formation.

Animals↗
PubMed1999

VEGF deprivation-induced apoptosis is a component of programmed capillary regression.

The pupillary membrane (PM) is a transient ocular capillary network, which can serve as a model system in which to study the mechanism of capillary regression. Previous work has shown that there is a tight correlation between the cessation of blood flow in a capillary segment and the appearance of apoptotic capillary cells throughout the segment. This pattern of cell death is referred to as synchronous apoptosis (Lang, R. A., Lustig, M., Francois, F., Sellinger, M. and Plesken, H. (1994) Development 120, 3395-3404; Meeson, A., Palmer, M., Calfon, M. and Lang, R. A. (1996) Development 122, 3929-3938). In the present study, we have investigated whether the cause of synchronous apoptosis might be a segmental deficiency of either oxygen or a survival factor. Labeling with the compound EF5 in a normal PM indicated no segmental hypoxia; this argued that oxygen deprivation was unlikely to be the cause of synchronous apoptosis. When rat plasma was used as a source of survival factors in an in vitro PM explant assay, inhibition of vascular endothelial growth factor (VEGF) all but eliminated the activity of plasma in suppressing apoptosis. This argued that VEGF was an important plasma survival factor. Furthermore, inhibition of VEGF in vivo using fusion proteins of the human Flk-1/KDR receptor resulted in a significantly increased number of capillaries showing synchronous apoptosis. This provides evidence that VEGF is necessary for endothelial cell survival in this system and in addition, that VEGF deprivation mediated by flow cessation is a component of synchronous apoptosis.

Animals↗
PubMed1998

GRIFIN, a novel lens-specific protein related to the galectin family.

The vertebrate lens is a relatively simple cellular structure that has evolved to refract light. The ability of the lens to focus light on the retina derives from a number of properties including the expression at high levels of a selection of soluble proteins referred to as the crystallins. In the present study, we have used differential cDNA display techniques to identify a novel, highly abundant and soluble lens protein. Though related to the family of soluble lectins called galectins, it does not bind beta-galactoside sugars and has atypical sequences at normally conserved regions of the carbohydrate-binding domain. Like some galectin family members, it can form a stable dimer. It is expressed only in the lens and is located at the interface between lens fiber cells despite the apparent lack of any membrane-targeting motifs. This protein is designated GRIFIN (galectin-related inter-fiber protein) to reflect its exclusion from the galectin family given the lack of affinity for beta-galactosides. Although the abundance, solubility, and lens-specific expression of GRIFIN would argue that it represents a new crystallin, its location at the fiber cell interface might suggest that its primary function is executed at the membrane.

Amino Acid Sequence↗
PubMed1998

A highly conserved lens transcriptional control element from the Pax-6 gene.

We have identified a short segment of the mouse Pax-6 gene 5' flanking region that is necessary and sufficient for reporter construct expression in components of the eye derived from non-neural ectoderm. This transcriptional control element has a highly conserved nucleotide sequence over 341 bp and is located approximately 3.5 kb upstream of the start-point for transcription from the most proximal promoter (PO) of the Pax-6 gene. The level of identity between the human and mouse Pax-6 genes in this region is 93%. When combined either with its natural promoter or a heterologous minimal promoter, this element directs reporter construct expression to a region of surface ectoderm overlying the optic cup beginning at E8.5-9.0 (12-14 somites). Subsequently, expression is restricted to the lens (primarily the lens epithelium) and the corneal epithelium. This element will provide an important tool in future transgenic analyses of lens formation and will allow identification of transcription factors with a central function in lens development.

Amino Acid Sequence↗