[Cystic fibrosis: current therapy. Physical therapy and rehabilitation].
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Adolescent↗
Biomedical subjects
M Huber
Publications and source records attributed to M Huber.
Localization of endogenous Grb10 to the mitochondria and its interaction with the mitochondrial-associated Raf-1 pool.
Grb10 belongs to a small family of adapter proteins that are known to interact with a number of receptor tyrosine kinases and signaling molecules. We have recently demonstrated that the Grb10 SH2 domain interacts with both the Raf-1 and MEK1 kinases. Overexpression of Grb10 genes with mutations in their SH2 domains promotes apoptosis in cultured cells, a phenotype that is reversed by concomitant overexpression of the wild type gene. Using immunofluorescence microscopy and subcellular fractionation we now show that most of the Grb10 molecules are peripherally associated with mitochondria. Following insulin-like growth factor I or serum treatment, small pools of Grb10 can also be found at the plasma membrane and in actin-rich membrane ruffles, whereas overexpression of Grb10 leads to its mislocalization to the cytosol. Two-hybrid analysis shows that the Grb10-binding site on Raf-1 co-localizes with its Ras-binding domain. Finally, we show that the endogenous Grb10 and Raf-1 proteins can be co-immunoprecipitated from a partially purified mitochondrial extract, an interaction that is enhanced following the activation of Raf-1 by ultraviolet radiation. Thus, we infer that Grb10 may regulate signaling between plasma membrane receptors and the apoptosis-inducing machinery on the mitochondrial outer membrane by modulating the anti-apoptotic activity of mitochondrial Raf-1.
Animals↗
[Abdominal aortic aneurysms. Results of surgical treatment from 1987 to 1998].
Conventional open surgery for abdominal aortic aneurysm has recently been challenged by a closed transfemoral approach for repair (stent-graft). The presented data over the past eleven years after open surgery for graft implantation are intended to serve for comparison with future results after transfemoral graft placement. In addition, it is the purpose of this study to investigate the prognostic importance of treatment of concomitant coronary artery disease. Early mortality of all 195 consecutive patients with abdominal aortic aneurysm repair was 1.5%; it was 0.6% after elective repair for infrarenal aneurysm and not dependent on the presence of coronary artery disease if the latter was treated. Late outcome, however, related closely to coronary artery disease as a major risk factor. Late graft complications are extremely rare and occurred only once (graft thrombosis). Incisional hernias and impotence in male patients are non-lethal complications affecting quality of life. Open surgical repair of abdominal aneurysm is safe, and long-term, complication-free survival is good. Coronary artery disease is the most frequent concomitant disease and major risk factor requiring close observation and treatment. These results need to be matched by the new transfemoral graft implantation technique before broad application of the latter.
Aged↗
In vitro and in vivo studies investigating possible antioxidant actions of nicotine: relevance to Parkinson's and Alzheimer's diseases.
An inverse relationship appears to exist between cigarette smoking and the risk of Parkinson's and Alzheimer's diseases. Since both diseases are characterized by enhanced oxidative stress, we investigated the antioxidant potential of nicotine, a primary component of cigarette smoke. Initial chromatographic studies suggest that nicotine can affect the formation of the neurotoxin 6-hydroxydopamine resulting from the addition of dopamine to Fenton's reagent (i.e., Fe2+ and H2O2). Thus, under certain circumstances, nicotine can strongly affect the course of the Fenton reaction. In in vivo studies, adult male rats being treated with nicotine showed greater memory retention than controls in a water maze task. However, neurochemical analysis of neocortex, hippocampus, and neostriatum from these same animals revealed that nicotine treatment had no effect on the formation of reactive oxygen species or on lipid peroxidation for any brain region studied. In an in vitro study, addition of various concentrations of nicotine to rat neocortical homogenates had no effect on lipid peroxidation compared to saline controls. The results of these studies suggest that the beneficial/protective effects of nicotine in both Parkinson's disease and Alzheimer's disease may be, at least partly, due to antioxidant mechanisms.
Alzheimer Disease↗
The SH2-containing inositol-5'-phosphatase enhances LFA-1-mediated cell adhesion and defines two signaling pathways for LFA-1 activation.
The inside-out signaling involved in the activation of LFA-1-mediated cell adhesion is still poorly understood. Here we examined the role of the SH2-containing inositol phosphatase (SHIP), a major negative regulator of intracellular signaling, in this process. Wild-type SHIP and a phosphatase-deficient mutant SHIP were overexpressed in the murine myeloid cell line, DA-ER, and the effects on LFA-1-mediated cell adhesion to ICAM-1 (CD54) were tested. Overexpression of wild-type SHIP significantly enhanced cell adhesion to immobilized ICAM-1, and PMA, IL-3, or erythropoietin further augmented this adhesion. In contrast, phosphatase dead SHIP had no enhancing effects. Furthermore, PMA-induced activation of LFA-1 on DA-ER cells overexpressing wild-type SHIP was dependent on protein kinase C but independent of mitogen-activated protein kinase activation, whereas cytokine-induced activation was independent of protein kinase C and mitogen-activated protein kinase activation but required phosphatidylinositol-3 kinase activation. These results suggest that SHIP may regulate two distinct inside-out signaling pathways and that the phosphatase activity of SHIP is essential for both of them.
Animals↗
The carboxyl-terminal region of biliary glycoprotein controls its tyrosine phosphorylation and association with protein-tyrosine phosphatases SHP-1 and SHP-2 in epithelial cells.
Biliary glycoprotein (Bgp, C-CAM, or CD66a) is an immunoglobulin-like cell adhesion molecule and functions as a tumor suppressor protein. We have previously shown that the Bgp1 isoform responsible for inhibition of colonic, liver, prostate, and breast tumor cell growth contains within its cytoplasmic domain two tyrosine residues positioned in immunoreceptor tyrosine-based inhibition motif (ITIM) consensus sequences. Moreover, we determined that these residues, upon phosphorylation, associate with the protein-tyrosine phosphatase SHP-1. In this report, we have further evaluated the structural bases of the association of Bgp1 with Tyr phosphatases. First, we demonstrate that Bgp1 also associates with the SHP-2 Tyr phosphatase, but not with an unrelated Tyr phosphatase, PTP-PEST. Association of Bgp1 and SHP-2 involves the Tyr residues within the Bgp1 ITIM sequences, Val at position +3 relative to the second Tyr (Tyr-515), and the SHP-2 N-terminal SH2 domain. In addition, our results indicate that residues +4, +5, and +6 relative to Tyr-515 in the Bgp1 cytoplasmic domain play a significant role in these interactions, as their deletion reduced Bgp1 Tyr phosphorylation and association with SHP-1 and SHP-2 by as much as 80%. Together, these results indicate that both SHP-1 and SHP-2 interact with the Bgp1 cytoplasmic domain via ITIM-like sequences. Furthermore, they reveal that the C-terminal amino acids of Bgp1 are critical for these interactions.
Amino Acid Sequence↗
The role of relaxation times in monitoring proteoglycan depletion in articular cartilage.
Various proton relaxation times (T2, T1rho, and gadolinium-diethylene triamine pentaacetic acid [Gd-DTPA]-enhanced T1) were measured in articular cartilage in vitro at 3 T to assess their role in visualizing proteoglycan depletion. Cartilage-bone specimens were obtained from patients who underwent total joint replacement and got a double dose of Gd-DTPA 2 hours prior surgery. In these specimens, regions of mechanically undamaged cartilage having a decreased content of proteoglycans showed about 15% lower T1 values compared with apparently normal cartilaginous tissue. The expected increase of the T2 relaxation time was not observed in these regions. On the other hand, the T2 and, to a lower degree, T1 relaxation times were found to be increased in regions of cartilage fibrillation. The T1rho relaxation times obtained were slightly longer than the corresponding T2 values, but both parameters showed almost identical spatial distributions. J. Magn. Reson. Imaging 1999;10:497-502.
Cartilage, Articular↗
Platelet aggregation and platelet-derived growth factor inhibition for prevention of insufficiency of the transjugular intrahepatic portosystemic shunt: a randomized study comparing trapidil plus ticlopidine with heparin treatment.
Intimal proliferation at the interface between prosthetic material and tissue is an intrinsic phenomenon of stenting and the major cause of insufficiency of the transjugular intrahepatic portosystemic shunt (TIPS). For its prevention, a randomized study was performed comparing standard heparin treatment with a combination of trapidil, a drug with anti-platelet-derived growth factor (PDGF) activity, and ticlopidine, a platelet aggregation inhibitor. Ninety patients with cirrhosis who received a transjugular shunt were randomized, and 84 patients completed the trial. Group 1 (n = 42) received a bolus of heparin (12 to 24 U/kg) at shunt placement, followed by 1 week of intravenous and 4 weeks of subcutaneous heparin treatment. Group 2 (n = 42) received the same heparin bolus, followed by a 1-day intravenous heparin treatment and a 6-month treatment with trapidil (400 mg/d) and ticlopidine (250 mg/d). Shunt function was assessed by duplex-sonography and angiography. Stenoses were classified according to their location as type 1 (within the stent) and type 2 (in the draining hepatic vein). The estimated rate of overall stenoses (intention-to-treat analysis) at 1 year showed a significant reduction in patients receiving trapidil and ticlopidine (group 2) as compared with heparin (33 vs. 57%; P =.047). There was no difference in the estimated 1-year rate of type 1 stenoses between the two groups, but there was a significant reduction in type 2 stenoses (group 1: 58%, group 2: 19%; P =.016). The treatment effect continued after withdrawal of the drugs and was accompanied by a decreased incidence of rebleeding. The study demonstrates that the incidence of type 2 stenosis of the transjugular shunt can be reduced by combined inhibition of platelet aggregation and PDGF activity. The findings may be of relevance not only for the transjugular shunt, but also for other stent applications, e.g., vascular and biliary, as well as for bypass and shunt surgery.
Drug Therapy, Combination↗
Positive allosteric modulators of the GABA(A) receptor: differential interaction of benzodiazepines and neuroactive steroids with ethanol.
Endogenous pregnane steroids, such as allopregnanolone (3alpha-hydroxy-5alpha-pregnan-20-one; 3alpha, 5alpha-P) and pregnanolone (3alpha-hydroxy-5beta-pregnan-20-one; 3alpha,5beta-P), allosterically modulate GABA(A) receptor function and exhibit behavioral effects similar to benzodiazepines, though acting at a distinct recognition site. Inasmuch as some positive allosteric modulators of GABA(A) receptor function exhibit profound interactions with ethanol, the effects of 3alpha,5alpha-P and 3alpha,5beta-P were compared to those of two benzodiazepines, triazolam and diazepam, on the motor function of mice and rats when administered either alone or in combination with ethanol. All four test compounds exhibited dose-related impairment of motor function in the horizontal wire task in mice and the rotorod task in rats. Ethanol caused a marked enhancement of triazolamand diazepam-induced motor impairment. In contrast, ethanol enhanced to a lesser extent the motor impairment induced by both neurosteroids in mice and not at all in rats. All four compounds increased ethanol-induced behavioral sleep time in mice, although the benzodiazepines did so at a much smaller fraction of their ataxic doses as compared to the neurosteroids. As one of the undesired side-effects of therapeutic use of benzodiazepines is their interaction with ethanol, development of neuroactive steroids as drugs may offer therapeutic advantages.
Allosteric Regulation↗
Pharmacological evaluation of a modified conflict procedure: punished drinking in non-water-deprived rats.
RATIONALE: Conflict procedures used to detect anxiolytic-like activity of drugs often rely on maintaining strict schedules of water or food availability. It is ethically and practically desirable to reduce such states of deprivation in animal testing. OBJECTIVE: The purpose of the present experiment was to develop and pharmacologically characterize a conflict drinking procedure that did not require the use of water-deprived animals. METHODS: Rats were tested during daily sessions with alternating unpunished drinking (no tone: lick = sucrose solution) and signaled punished drinking (tone: lick = sucrose + shock) components, and developed individual steady baselines over a brief training period (approximately 3-4 weeks). The drugs tested i.p. were the positive allosteric modulators of gamma-amino butyric acidA (GABA)A receptors, diazepam (0.03-30 mg/kg), chlordiazepoxide (0.03-30 mg/kg), lorazepam (0.03-10 mg/kg), zolpidem (0.3-10 mg/kg), pentobarbital (1-30 mg/kg), pregnanolone (1-30 mg/kg), and bretazenil (0.03-10 mg/kg); the 5-hydroxy tryptamine1A (HT)1A-mediated anxiolytics, buspirone (1-10 mg/kg) and ipsapirone (1-17 mg/kg); and the negative controls D-amphetamine (0.3-3 mg/kg), haloperidol (0.01-0.3 mg/kg), morphine (0.3-17 mg/kg), and imipramine (0.3-30 mg/kg). RESULTS: The experimental procedure was sensitive to increases in punished drinking by the GABAA-positive modulators, consistent with their known or putative anxiolytic activity. Further, the 5-HT1A-mediated anxiolytics increased punished drinking, although to a lesser extent and over a more narrow dose range than did the GABAergic drugs. In contrast, D-amphetamine, haloperidol, morphine, and imipramine failed to increase punished drinking up to doses that decreased unpunished drinking. CONCLUSIONS: The present results indicate that water deprivation is not a necessary condition to engender drinking conflict behavior or to obtain pharmacological effects similar to those obtained with other classical conflict procedures.
Animals↗
The role of SHIP in growth factor induced signalling.
The recently cloned, hemopoietic-specific, src homology 2 (SH2)-containing inositol phosphatase, SHIP, is rapidly gaining prominence as a potential regulator of all phosphatidylinositol (PI)-3 kinase mediated events since it has been shown both in vitro and in vivo to hydrolyze the 5' phosphate from phosphatidylinositol-3,4,5-trisphosphate (PI-3,4,5-P3). Thus SHIP, and its more widely expressed counterpart, SHIP2, could play a central role in determining PI-3,4,5-P3 and PI-3,4-P2 levels in many cell types. To explore the in vivo function of SHIP further we recently generated a SHIP knock out mouse and in this review we discuss experiments carried out with bone marrow derived mast cells (BMMCs) from these animals.
Animals↗
Multiple endometrial stromal nodules with sparse cysts and glands in the lung--a nodular variation of endometriosis that may mimic metastases of sarcoma.
We report an unusual case of a nodular variation of pulmonary endometriosis. To our knowledge, there is no previous report on a morphological investigation of this entity. The etiology of this rare condition is still a matter of discussion. The well-circumscribed nodular mass is composed of cells identical to, or closely resembling, those of endometrial stroma containing sparse cysts and glands. Immunohistochemically, the cells showed an extensive co-expression of cytokeratin AE1/AE3 and vimentin and were highly positive for progesterone receptor (PRICA) and estrogen receptor (ERICA). Cells lining the cysts and glands as a monolayer were reactive for Ber-Ep4, cytokeratin Pan and cytokeratin AE1/AE3 and negative to all other markers used including PRICA and ERICA. The differential diagnosis of this entity included fibrous tumor of the pleura and metastatic low-grade-endometrial-stromal-sarcoma. The morphological findings are correlated with immunohistochemical studies and results of cell image analysis. This study details the clinicopathological features of the nodular variation of pulmonary endometriosis.
Adult↗
MRI visualization of proteoglycan depletion in articular cartilage via intravenous administration of Gd-DTPA.
The effect of intravenous administration of gadolinium diethylenetriamine-pentaacetic acid (Gd-DTPA) on MR images was studied in vitro, using pathologic osteochondral specimens removed during surgery for total endoprosthesis, and in vivo, on a group of volunteers. In ex vivo specimens, lesions of different shape having lower T1 were detected which corresponded to areas with depleted proteoglycans found histologically. In vivo experiments on young volunteers showed that the time course of cartilage enhancement was different for different anatomies. The time for maximum enhancement ranged from 45 min for the ventral femoral condyle to 270 min for patellar cartilage.
Adult↗
Closure of bronchopleural fistula after pneumonectomy with a pedicled intercostal muscle flap.
OBJECTIVES: The value of the pedicled intercostal muscle flap for the closure of postpneumonectomy bronchopleural fistulas was studied retrospectively. METHODS: Bronchopleural fistula was suspected in case of fever, cough, putrid or haemorrhagic expectoration, in combination with a rise of WBC and CRP. Fistula diagnosis was established bronchoscopically. Two patients underwent an initial trial of bronchoscopic sealing, the rest were reoperated immediately after fistula diagnosis. Immediately after operation antibiotic irrigation according to culture sensitivity was started via a single chest tube drainage twice a day. After instillation of antibiotics the drain was kept clamped for 3 h. Culture samples were obtained twice a week. Empyema was considered eradicated, if three subsequent cultures showed no bacterial growth. After drain removal the patients were kept in hospital for another week and observed for clinical signs of infection, WBC and CRP were controlled. Age, side, sex, histology, TNM-stage, duration of hospital stay after fistula diagnosis (days), duration of treatment (defined as the duration of chest tube drainage in days after operation), total hospital stay (including the initial hospital stay for primary resection and the hospital stay for fistula treatment in case of readmission), fistula size (mm), interval (days) between primary operation and fistula formation, and bacteriology were recorded. RESULTS: Eight patients (seven male) were treated. Age ranged from 46 to 70 years (mean 57.86). Six fistulas were located on the right side. All patients had non small cell lung cancer. Interval ranged from 2 to 72 days (mean 26.9 days). Fistula size ranged from 1 to 7 mm (mean 3.43). Seven fistulas were successfully closed. Duration of treatment lasted from 15 to 28 days in those patients treated successfully (mean 17). Hospital stay ranged from 15 to 31 days (mean 24.4). In one patient the flap became necrotic, he was successfully treated with total thoracoplasty. One patient died on the 38th day after rethoracotomy due to aspiration pneumonia. At postmortem examination the bronchial stump was closed. CONCLUSION: The use of the pedicled intercostal muscular flap is an efficient method for the closure of bronchopleural fistula after pneumonectomy.
Aged↗
SHIPs ahoy.
In 1996 three groups independently cloned a hemopoietic specific, src homology 2-containing inositol 5'-phosphatase which, based on its structure, was called SHIP. More recently, a second more widely expressed SHIP-like protein has been cloned and called SHIP2. Both specifically hydrolyze phosphatidylinositol-3,4,5-trisphosphate and inositol 1,3,4,5-tetrakisphosphate in vitro. Moreover, SHIP has been shown in vivo to be the primary enzyme responsible for breaking down phosphatidylinositol-3,4,5-trisphosphate to phosphatidylinositol-3,4-bisphosphate in normal mast cells and, as a result, limits normal and prevents inappropriate mast cell degranulation. Because of their ability to break down phosphatidylinositol-3,4,5-trisphosphate, the SHIPs have the potential to regulate many, if not all, phosphatidylinositol-3-kinase induced events including, proliferation, differentiation, apoptosis, end cell activation, cell movement and adhesion and will thus likely be the subject of intensive research over the next few years.
Animals↗
[Short-term follow-up of a series of 21 uncemented total ankle prostheses].
GOALS OF THE STUDY: To analyse the short term results of 21 non cemented meniscal-bearing total ankle arthroplasties. MATERIAL AND METHODS: [corrected] 21 ankle arthroplaties were performed in 21 patients with a mean age of 63.5 years. Diagnoses include primary and post-traumatic osteoarthritis. Our mean follow-up is 21 months. RESULTS: We evaluated the patients with the Koefod ankle score. We present only the results of the patients whose follow-up exceed one year. Eleven patients had an excellent result, seven a good and two a medium result. One case was a failure and needed an arthrodesus. DISCUSSION: The non-cemented meniscal-bearing ankle prosthesis leads to good relieve of pain and good function but fair improvement of the mobility. These first results are encouraging but definitive conclusions cannot be drawn yet.
Adult↗
A novel substitution in keratin 10 in epidermolytic hyperkeratosis.
Epidermolytic hyperkeratosis is characterized by tonofilament clumping, cytolysis, and blister formation in suprabasal keratinocytes. It has been shown that the tonofilament aggregates in these areas are composed of keratin 1 (K1) and keratin 10 (K10), and several K1 and K10 point mutations have been identified as the molecular basis of epidermolytic hyperkeratosis. In this report we identify a novel, single base pair substitution resulting in an amino acid exchange from tyrosine to serine at residue 14 within the conserved 1A region of K10 (Y14S). This A to C transversion in codon 160 was only present in the affected individual and was associated with a very severe disease phenotype. Our observations are in agreement with previous reports documenting that this tyrosine residue, located at the beginning of the rod domain of type I keratins, is particularly sensitive to amino acid substitutions, and that alterations in this residue can have deleterious effects on filament assembly and stability.
Child, Preschool↗
Modulation of palmitate-induced cardiomyocyte cell death by interventions that alter intracellular calcium.
The objective of this study was to investigate whether palmitate-induced cell death in cardiomyocytes was dependent on alterations of intracellular calcium ([Ca2+)I). Specifically, we sought to determine whether palmitate might produce a cellular calcium overload by increasing calcium influx into the cell or by altering sarcoplasmic reticulum (SR) calcium transport. We also determined whether palmitate's effects might be modulated by agents that alter [Ca2+]l. Treatment of chick embryonic cardiomyocytes in culture with palmitate (100 uM) produced a significant (P < 0.05) and 42.9 +/- 5.3% reduction in cell survival or increase in cell death. As determined by FURA-2 measurement of [Ca2+]I, the cytotoxicity of palmitate on cardiomyocytes did not appear to be mediated through acute increases in [Ca2+]l. In contrast, the unsaturated fatty acid, arachidonic acid increased [Ca2+]l. The calcium ionophore ionomycin significantly (P < 0.05) increased palmitate-induced cardiomyocyte cell death. The effects of ionomycin and palmitate, however, were additive, suggesting palmitate and ionomycin acted in an independent manner to induce cell death. Furthermore, in contrast to palmitate, an ionomycin-induced increase in [Ca2+]l was demonstrated in these cells. Inhibition of SR calcium reuptake by thapsigargin, which acutely increases [Ca2+]I, also significantly (P < 0.05) increased palmitate-induced cardiomyocyte death. Again, these two agents most likely acted in an independent manner because of the additive nature of the effect of palmitate and thapsigargin on cell viability. Palmitate-induced cardiotoxicity was not mediated through release of [Ca2+]I from SR or through voltage-operated channels on plasma membranes, as neither SR calcium depletion by low concentrations of ryanodine nor blockade of the voltage-operated calcium channel with nifedipine significantly altered palmitate-induced cardiomyocyte death. These data suggest that palmitate-induced cardiac cell death is enhanced by increases in [Ca2+]I and highlights the potential adverse effect of a combination of palmitate with conditions that increase [Ca2+]I in cardiomyocytes.
Animals↗