Biomedical subjects
M Sachs
Publications and source records attributed to M Sachs.
[Victor Schmieden (1874-1945) and his contribution to the development of modern surgery].
Victor Schmieden (1874-1945) was the second Professor on ordinary for surgery (1919-1945) at the Frankfurt University, which was newly established in 1914. Among his numerous publications, especially the following contributed to the development of modern surgery: in 1915 during the first world war he proposed the operative treatment (laparotomy) of abdominal shot-wounds, in 1920 he established the operative treatment (pericardectomy) of patients with a calcified pericarditis (armour heart). In 1926 he described the adenomas (polyps) of the colon as a precursor of colorectal cancer (dysplasia-carcinoma sequence) and proposed total colectomy to patients with polyposis coli.
[From the history of surgical instruments: 6. Sauerbruch's instruments for thoracic surgery].
The historical development of thoracic surgery, which was established in Germany in the years 1904/1905 and the armamentarium of the chest designed by Ferdinand Sauerbruch (1875-1951) are described. Sauerbruch designed between 1904 and 1920 many instruments to facilitate thoracic surgery, e.g. several rib retractors, a special rib shear for the first rib, a rib shear for all ribs other than the first. Furthermore he designed a special lung grasping forceps with rubber covered jaws, a lung compression forceps and a fenestrated lung retractor to facilitate lung resections.
Interaction between Gab1 and the c-Met receptor tyrosine kinase is responsible for epithelial morphogenesis.
The proteins Gab1 and the related DOS (for 'daughter of sevenless') each bind to substrates of tyrosine kinases like Grb2 or Corkscrew, and act in signalling pathways downstream of tyrosine kinase receptors. Here we show that Gab1 interacts directly with the c-met-encoded receptor tyrosine kinase but not with a number of other tyrosine kinases from different subfamilies. A newly identified proline-rich domain of Gab1 is responsible for the binding of this protein to the tyrosine-phosphorylated bidentate docking site in c-Met. Expression of Gab1 in epithelial cells is sufficient to induce the c-Met-specific activities, including branching morphogenesis. Thus we have discovered a new phosphotyrosine interaction domain in Gab1 and shown that Gab1 is the substrate of the c-Met receptor tyrosine kinase that mediates epithelial morphogenesis.
Interaction between the phosphotyrosine binding domain of Shc and the insulin receptor is required for Shc phosphorylation by insulin in vivo.
Stimulation of the insulin receptor (IR) results in tyrosine phosphorylation of the intermediate molecules insulin receptor substrate-1 (IRS-1), IRS-2, and Shc, which then couple the IR to downstream signaling pathways by serving as binding sites for signaling molecules with SH2 domains. It has been proposed that direct binding of IRS-1, IRS-2, and Shc to an NPX-Tyr(P) motif in the juxtamembrane region of the IR is required for tyrosine phosphorylation of these molecules by the IR. In this regard, Shc and IRS-1 contain domains that are distinct from SH2 domains, referred to as the phosphotyrosine binding (PTB) or phosphotyrosine interaction (PI) domains, which bind phosphotyrosine in the context of an NPX-Tyr(P) motif. To further clarify the role of the Shc PTB/PI domain, we identified a mutation in this domain that abrogated binding of Shc to the IR in vitro. Interestingly, this mutation completely abolished Shc phosphorylation by the IR in vivo whereas mutation of the arginine in the FLVRES motif of the Shc SH2 domain did not affect Shc phosphorylation by insulin. In addition, we identified specific amino acids on the IR that are required for the IR to stimulate Shc but not IRS-1 phosphorylation in vivo. As with the PTB/PI domain Shc mutant, the ability of these mutant receptors to phosphorylate Shc correlates with the binding of the PTB/PI domain of Shc to similar sequences in vitro. These findings support a model in which binding of the PTB/PI domain of Shc directly to the NPX-Tyr(P) motif on the IR mediates Shc phosphorylation by insulin.
[A comparative study of intravenous opioid analgesia. Sufentanil and alfentanil for extracorporeal shock-wave lithotripsy in urologic patients].
UNLABELLED: Extracorporeal shock-wave lithotripsy (ESWL) is the method of choice for the treatment of solitary stones in the kidney or ureter. Early lithotripters required prolonged immobility of the patient and caused considerable pain, necessitating general or epidural anaesthesia during the procedure. Modern lithotripters are quicker, but still require analgesia. Intravenous opioids are currently the drugs in favour. The opioids most commonly used are fentanyl and its shorter-acting analogue, alfentanil. The latter has a more rapid onset and, because of its reduced lipid solubility, is less cumulative. Sufentanil is a new opioid that is also of the phenylpiperidone group and has been recently licensed and introduced in Germany. Its pharmacokinetic and pharmacodynamic properties suggest an intermediate duration of action, high analgesic potency, and cardiovascular stability with diminished respiratory depression. In this prospective double-blind study, the effects of alfentanil and sufentanil on cardiovascular and respiratory parameters, the quality of analgesia, degree of sedation and the number and type of side-effects were compared. PATIENTS AND METHODS: After giving informed consent and with the approval of the hospital ethics committee, 62 patients (ASA I or II) were investigated. They were randomly allocated to two groups, either receiving sufentanil (n = 32) or alfentanil (n = 30) during ESWL. No premedication was given. Excluded were patients with pain prior to treatment, patients treated with a spasmolytic or analgesic drug and those who had undergone ESWL within the last 6 months. The loading dose was given as a 5-min infusion to each group. The heart rate, systolic and diastolic blood pressure, percutaneous oxygen saturation (SpO2), and the transcutaneous capillary carbon dioxide tension (PicCO2) were recorded prior to the procedure (i.e. before administration of opioid), after 1000 and after 2000 shock waves and then 1 and 2 h after the end of lithotripsy. After 1000 and 2000 shock waves, and 1 an 2 h after the treatment, the patients were asked to express their degree of tiredness and pain on a visual analogue scale (VAS). The occurrence of side-effects such as nausea, vomiting, pruritus or other unpleasant sensations were noted by an anaesthesia nurse. Simultaneously, the anaesthetist recorded his/her impression of the patient's tiredness and degree of pain, both by using the VAS. He was not allowed to question the patient, nor was he aware of the patient's own scores. At the end of the observation period both the patient and the anaesthetist related their overall satisfaction with the anaesthetic procedure, again by using the VAS. Data were analysed with the Mann-Whitney-U for comparisons between groups and with the Wilcoxon test within each group. The side-effects were analysed with the Chi-square test. RESULTS: The systolic and diastolic blood pressure remained stable in both groups during and after treatment. The mean heart rate was different between the two groups at the beginning, and after the end of the treatment it dropped in both groups, but no significant difference was seen between groups. The PicCO2 rose from an initial mean of 36.8 mm Hg to a maximum of 44.6 mm Hg after 1000 shock waves in the sufentanil group, and from 37.8 mm Hg to 46.0 mm Hg after 2000 shock waves in the alfentanil group. The differences were significant within groups until 1 h after the end of the treatment, but there was no significant difference between groups. The oxygen saturation SpO2 dropped slightly in both groups. The differences were not significant between groups. In the alfentanil group, one patient had a maximum carbon dioxide tension of 83 mm Hg after 2000 shock waves, whereas in the sufentanil treated group the oxygen saturation fell to 72% in one case. (ABSTRACT TRUNCATED)
Motogenic and morphogenic activity of epithelial receptor tyrosine kinases.
Receptor tyrosine kinases play essential roles in morphogenesis and differentiation of epithelia. Here we examined various tyrosine kinase receptors, which are preferentially expressed in epithelia (c-met, c-ros, c-neu, and the keratin growth factor [KGF] receptor), for their capacity to induce cell motility and branching morphogenesis of epithelial cells. We exchanged the ligand-binding domain of these receptors by the ectodomain of trkA and could thus control signaling by the new ligand, NGF. We demonstrate here that the tyrosine kinases of c-met, c-ros, c-neu, the KGF receptor, and trkA, but not the insulin receptor, induced scattering and increased motility of kidney epithelial cells in tissue culture. Mutational analysis suggests that SHC binding is essential for scattering and increased cell motility induced by trkA. The induction of motility in epithelial cells is thus an important feature of various receptor tyrosine kinases, which in vivo play a role in embryogenesis and metastasis. In contrast, only the c-met receptor promoted branching morphogenesis of kidney epithelial cells in three-dimensional matrices, which resemble the formation of tubular epithelia in development. Interestingly, the ability of c-met to induce morphogenesis could be transferred to trkA, when in a novel receptor hybrid COOH-terminal sequences of c-met (including Y14 to Y16) were fused to the trkA kinase domain. These data demonstrate that tubulogenesis of epithelia is a restricted activity of tyrosine kinases, as yet only demonstrated for the c-met receptor. We predict the existence of specific substrates that mediate this morphogenesis signal.
Evaluation of caffeine as a test drug for CYP1A2, NAT2 and CYP2E1 phenotyping in man by in vivo versus in vitro correlations.
Caffeine is used to phenotype subjects in vivo for the cytochrome P450 isoforms CYP1A2 and CYP2E1, and for N-acetyltransferase type 2 (NAT2). However, how much of the variation in phenotyping parameters may be attributed to variations in CYP1A2 and CYP2E1 activities has not been determined. Therefore, this study intraindividually compared enzyme activities and/or content in liver samples with pharmacokinetic parameters of caffeine in vivo after administration of a test dose in 25 patients undergoing hepatectomy. Parameters measured in vitro were the high affinity components of caffeine 3-demethylation and phenacetin 0-deethylation, microsomal CYP1A2 and CYP2E1 immunoreactivity, and cytosolic sulfamethazine N-acetylation. Caffeine parameters in vivo included caffeine clearance from plasma and/or saliva, paraxanthine/caffeine ratios in plasma and saliva, plasma theophylline/caffeine ratio, and several metabolite ratios from spot urine sampled 6 h postdose. Correlations between parameters were determined using weighted linear regression analyses. Caffeine clearance and paraxanthine/caffeine ratios correlated most highly to intrinsic clearance of caffeine 3-demethylation and to CYP1A2 immunoreactivity (r= 0.584-0.82), whereas urinary CYP1A2 ratios correlated less strongly with CYP1A2 parameters in vitro. Assignment of acetylator phenotype by urinary NAT2 ratios was concordant with sulfamethazine-N-acetylation in vitro. In contrast to CYP1A2 parameters in vitro, CYP2E1 immunoreactivity was not related to the theophylline/caffeine plasma ratio. CYP1A2 activity, thus, is the major determinant of caffeine clearance and the paraxanthine/caffeine ratios in vivo, of which the saliva ratio 6 h postdose appears as the most advantageous parameter. The results confirm that phenotyping using caffeine provides valid estimates of CYP1A2 and NAT2 activity.
[History of surgical instruments: 4. The Deschamp ligation needle for the Overholt forceps: development of instruments for blood-saving tissue preparation].
The development of effective ligature carrying forceps is described, which are useful in dissection. The ligature needle, which has been developed by the French surgeon J.F.L. Deschamp (1740-1824), is presented on the basis of his original publication from 1793. Today many surgeons use a ligature forceps, which has been developed in 1938 by R.H. Overholt (b. 1901) in Boston and was modified by R. Geissendörfer (1902-1976) in the 1950s.
[Ludwig Rehn (1849-1930) and his importance in the development of modern surgery].
The unusual course of Ludwig Rehn's professional development directed him from a general practitioner close to Frankfurt am Main to his convocation as first Professor in ordinary for surgery to the Frankfurt University, which was newly established in 1914. Among his numerous publications, especially the following contributed immensely to the development of modern surgery: in 1884, he already described the healing of patients with Graves' disease by subtotal resection of the goiter; in 1885 he first described the high prevalence of bladder tumors in workers of an aniline factory; in 1886, he managed the first successful heart-suture after a stab-incision of the right ventricle; in 1897, he already performed an operation at the thoracal oesophagus, with an access via the posterior mediastinum; in 1920, he established the operative treatment (pericardectomy) of patients with a calcified pericarditis (armour heart).
[History of surgical instruments: 5. The development of tangentially closing vascular clamps].
We demonstrate the historical development of tangential occlusion clamps, which by partially clamping the vessels and by partially maintaining the blood flow, allow to reconstruct or to anastomose large vessels in the side-by-side-technique. The first tangential occlusion clamp was developed by Friedrich Trendelenburg (1844-1924) in 1908, when he performed the operative treatment of embolism of the pulmonary artery. This clamp was modified later by A.W. Meyer [1927] and V.P. Satinsky [ca. 1950].
Identification of a transactivation function in the progesterone receptor that interacts with the TAFII110 subunit of the TFIID complex.
Transcriptional activation of target genes by the human progesterone receptor is thought to involve direct or indirect protein-protein interactions between the progesterone receptor and general transcription factors. A key role in transcription plays the general factors. A key role in transcription plays the general transcription factor TFIID, a multiprotein complex consisting of the TATA-binding protein and several tightly associated factors (TAFs). TAFs have been shown to be required for activated transcription and are, thus, potential targets of activator proteins. Using in vitro interaction assays, we could identify specific interactions between the progesterone receptor and the TATA-binding protein-associated factor dTAFII110. The dTAFII110 domain responsible for the interaction is distinct from that reported to suffice for binding to Sp1. Somewhat surprisingly, deletion analysis indicated that the previously identified activation functions 1 and 2 of the progesterone receptor are not required for this interaction but pointed to an important role of the DNA binding domain. In cotransfection experiments and an in vitro transcription assay, the DNA binding domain of the progesterone receptor displayed significant activation potential. These findings, taken together, suggest that an interaction between the progesterone receptor and TAFII110 may represent an important step in the mechanism of activation.
Mutation of juxtamembrane tyrosine residue 1001 suppresses loss-of-function mutations of the met receptor in epithelial cells.
Signals transduced by the met tyrosine kinase, which is the receptor for scatter factor/hepatocyte growth factor, are of major importance for the regulation of epithelial cell motility, morphogenesis, and proliferation. We report here that different sets of tyrosine residues in the cytoplasmic domain of the met receptor affect signal transduction in epithelial cells in a positive or negative fashion: mutation of the C-terminal tyrosine residues 13-16 (Y1311, Y1347, Y1354, and Y1363) reduced or abolished ligand-induced cell motility and branching morphogenesis. In contrast, mutation of the juxtamembrane tyrosine residue 2 (Y1001) produced constitutively mobile, fibroblastoid cells. Furthermore, the gain-of-function mutation of tyrosine residue 2 suppressed the loss-of-function mutations of tyrosine residue 15 or 16. The opposite roles of the juxtamembrane and C-terminal tyrosine residues may explain the suggested dual function of the met receptor in both epithelial-mesenchymal interactions and tumor progression.
Sequential requirement of hepatocyte growth factor and neuregulin in the morphogenesis and differentiation of the mammary gland.
We have examined the role of two mesenchymal ligands of epithelial tyrosine kinase receptors in mouse mammary gland morphogenesis. In organ cultures of mammary glands, hepatocyte growth factor (HGF, scatter factor) promoted branching of the ductal trees but inhibited the production of secretory proteins. Neuregulin (NRG, neu differentiation factor) stimulated lobulo-alveolar budding and the production of milk proteins. These functional effects are paralleled by the expression of the two factors in vivo: HGF is produced in mesenchymal cells during ductal branching in the virgin animal; NRG is expressed in the mesenchyme during lobulo-alveolar development at pregnancy. The receptors of HGF and NRG (c-met, c-erbB3, and c-erbB4), which are expressed in the epithelial cells, are not regulated. In organ culture, branching morphogenesis and lobulo-alveolar differentiation of the mammary gland could be abolished by blocking expression of endogenous HGF and NRG by the respective antisense oligonucleotides; in antisense oligonucleotide-treated glands, morphogenesis could again be induced by the addition of recombinant HGF and NRG. We thus show that two major postnatal morphogenic periods of mammary gland development are dependent on sequential mesenchymal-epithelial interactions mediated by HGF and NRG.
Hepatocyte growth factor/scatter factor induces a variety of tissue-specific morphogenic programs in epithelial cells.
Hepatocyte growth factor/scatter factor (HGF/SF) is the mesenchymal ligand of the epithelial tyrosine kinase receptor c-Met. In vitro, HGF/SF has morphogenic properties, e.g., induces kidney epithelial cells to form branching ducts in collagen gels. Mutation of the HGF/SF gene in mice results in embryonic lethality due to severe liver and placenta defects. Here, we have evaluated the morphogenic activity of HGF/SF with a large variety of epithelial cells grown in three-dimensional collagen matrices. We found that HGF/SF induces SW 1222 colon carcinoma cells to form crypt-like structures. In these organoids, cells exhibit apical/basolateral polarity and build a well-developed brush border towards the lumen. Capan 2 pancreas carcinoma cells, upon addition of HGF/SF, develop large hollow spheroids lined with a tight layer of polarized cells. Collagen inside the cysts is digested and the cells show features of pancreatic ducts. HGF/SF induces EpH4 mammary epithelial cells to form long branches with end-buds that resemble developing mammary ducts. pRNS-1-1 prostate epithelial cells in the presence of HGF/SF develop long ducts with distal branching as found in the prostate. Finally, HGF/SF simulates alveolar differentiation in LX-1 lung carcinoma cells. Expression of transfected HGF/SF cDNA in LX-1 lung carcinoma and EpH4 mammary epithelial cells induce morphogenesis in an autocrine manner. In the cell lines tested, HGF/SF activated the Met receptor by phosphorylation of tyrosine residues. These data show that HGF/SF induces intrinsic, tissue-specific morphogenic activities in a wide variety of epithelial cells. Apparently, HGF/SF triggers respective endogenous programs and is thus an inductive, not an instructive, mesenchymal effector for epithelial morphogenesis.
[History of surgical instruments: 2. The first atraumatic vascular clamp by E. Höpfner (1903)].
The author describes one of the first atraumatic vascular clamps specifically developed for vascular surgery in 1903, and used for temporary arterial occlusion. This forceps was about 15 cm long, and its spring steel jaws were separated in the middle, but approximated toward the ends. This clamp was developed by Edmund Höpfner (b. 1873) in 1903, at the Berlin University Hospital, department of Surgery, when he performed end-to-end anastomoses of divided arteries in dogs as part of his doctoral thesis. The Höpfner clamp was in common use in Germany until the 1960s.