Did viruses play a part in the origin of the adaptive immune system?
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Biological Evolution↗
Biomedical subjects
J Klein
Publications and source records attributed to J Klein.
Insulin resistance-inducing cytokines differentially regulate SOCS mRNA expression via growth factor- and Jak/Stat-signaling pathways in 3T3-L1 adipocytes.
Various cytokines, including tumor necrosis factor (TNF) alpha, growth hormone (GH) and interleukin (IL)-6, induce insulin resistance. Recently, it was demonstrated that induction of suppressor of cytokine signaling (SOCS)-3 by TNFalpha and GH is an important mechanism by which these cytokines impair insulin sensitivity. The current study investigated in 3T3-L1 adipocytes whether TNFalpha and GH also upregulate SOCS-1 and SOCS-6, which have both been shown to inhibit insulin signaling potently, and whether IL-6 might alter synthesis of SOCS-1, -3 and -6. Interestingly, 10 ng/ml TNFalpha, 500 ng/ml GH and 30 ng/ml IL-6 induced SOCS-1 mRNA time-dependently with maximal stimulation detectable after 8 h of TNFalpha and 1 h of GH and IL-6 addition respectively. Furthermore, TNFalpha and GH caused sustained upregulation of SOCS-1 for up to 24 h, whereas stimulation by IL-6 was only transient, with SOCS-1 mRNA returning to basal levels 2 h after effector addition. Induction of SOCS-1 was dose-dependent, and significant stimulation was detectable at concentrations as low as 3 ng/ml TNFalpha, 50 ng/ml GH and 10 ng/ml IL-6. Furthermore, stimulation experiments and studies using pharmacologic inhibitors suggested that the positive effect of TNFalpha, GH and IL-6 on SOCS-1 mRNA is, at least in part, mediated by Janus kinase (Jak) 2. Finally, SOCS-3 expression was dose- and time-dependently induced by IL-6, at least in part via Jak2, but none of the cytokines affected SOCS-6 expression. Taken together, our results show a differential regulation of SOCS mRNA by insulin resistance-inducing hormones, and suggest that SOCS-1, as well as SOCS-3, may be an important intracellular mediator of insulin resistance in fat cells and a potential pharmacologic target for the treatment of impaired insulin sensitivity.
3T3 Cells↗
[Atypical portocaval anastomosis for hemorrhage in portal hypertension].
The success of endoscopy in treating esophageal varices and the later introduction of liver transplantation into the algorithm of therapy for liver failure shifted surgery of portal hypertension out of sight of hepatologists and surgeons. This decline from surgical treatment was further confirmed by introduction of TIPS into clinical practice. It is completely out of question that only liver transplantation is the causal solution of decompensated liver disease and a series of reliable and less invasive methods may be selected for acute treatment of bleeding from varices. However, even at the present time the portal-systemic shunt may be used in its own indication in repeatedly bleeding patients with a good liver capacity, where it can play a role by bridging the time to liver transplantation in a way similar to TIPS or even to provide a final solution, which makes it possible to live the life expectancy in adequate comfort without the risk of bleeding complications. However, it is not always possible to place a surgical shunt on some of the main branches of the portal vein. In such cases, devascularization is often successfully applied. Atypical shunts represent an exceptional alternative, because side feeder veins of the portal vein are rarely of sufficient caliber for placing a hemodynamically significant shunt. The authors describe two cases, in which stubborn anemia-causing bleeding events in portal hypertension were treated with left-side epiploic-renal shunt or anastomosis between the mesenteric and left-side iliac vein.
Aged↗
[Detection of the sentinel lymph nodes in lung carcinoma cases using patent blue and its clinical significance].
INTRODUCTION: Views on significance and the most appropriate approach to lymphadenectomy in the non-small-cell lung carcinoma cases, have not been consistent. The method of the sentinel lymphonode identification and biopsy, which has been verified for other tumor types, may become a promising alternative or, at least, a supplement to currently applied procedures in cases of the lung carcinoma. STUDY GROUP AND RESULTS: This prospective, non-randomized study was conducted in the Faculty Hospital in Olomouc between the years 2000-2003. The sentinel lymphonode identification was conducted in the group of 48 patients suffering from the non-small cell lung carcinoma, using the patent blue lymphatic mapping method. The sentinel lymphonode was identified in 40 patients (83.3%), a false negativity of the sentinel lymphonode was detected in 3 cases (7.5%). CONCLUSION: The study proved the clinical benefit of the sentinel lymphonode identification and biopsy method in cases of the non-small cell lung carcinoma using the patent blue dye. Under the circumstance of certain experience with the technology, the reliability of the detection approaches that of the radionuclide sentinel lymphonode detection method. However, the clinical significance of the above method must be further tested on larger patient groups.
Aged↗
[Complications of extended lung resection procedures following the neoadjuvant therapy].
UNLABELLED: Local tumor expansion in the sense of the tumor invasion into the extrapulmonary structures, which must be removed in one step, preferably en-bloc, together with the primary tumor, is the reason for extending the lung resection procedure. Although verified lymphogenic metastasing into either unilateral, eventually into contralateral mediastinal lymphonodes (stage N2 resp. N3, according to the TNM), remains the commonest indication for the induction therapy in cases of the lung carcinoma, application of the neoadjuvant therapy in cases when extended resections may be expected, is indicated in case the tumor expands into the surrounding structures, which signifies opening of new, unnatural routes of possible lymphogenic and haematogenic dissemination, and thus, a significantly higher risk of the surgical therapy failure. During the period 1995-2002, our team conducted 15 extended lung resection procedures following the preceding induction therapy in patients suffering from the IIB-IIIB stage of the non-small cellular lung carcinoma (NSCLC). The 30-day lethality rate equalled zero. We recorded two rare complications and the postoperative morbidity was acceptable. CONCLUSION: Exhausting staging, the best possible prediction of the tumor behaviour following the surgical procedure and minimal surgical complications remain the prerequisite for good long-term results following the extended lung resections for the lung carcinoma. Application of the neoadjuvant therapy prior to the resection procedure need not increase the risk of surgical complications and, furthermore, may positively affect the disease prognosis.
Carcinoma, Non-Small-Cell Lung↗
[What to expect from the neoadjuvant therapy of the oesophageal carcinoma?].
AIM: The aim of this study was to assess the neoadjuvant therapy of the oesophageal carcinoma firstly from the perspective of the immediate effect on the resection procedure itself and, secondly, from the perspective of the long-term results. METHODOLOGY: Prior to the resection of the oesophagus, the patients were administered the neoadjuvant therapy. The patients were allocated to three groups with the following branches of the cytostatic treatment: CDDP+FU, TAX+FU a CDDP. A smaller group with a less advanced disorder was treated only surgically, with the oesophageal resection. Furthermore, the study aimed at assessing chemoresistance of the tumors according to the MTT test and at correcting the individual branches appropriately. RESULTS: The total of 70 patients were operated from 2001 to V/2004. Out of this number, 15 oesophgeal resections without the neoadjuvant therapy were conducted. None of the patients exited, and fistules were the commonest complications. CONCLUSION: No differences in postoperative complications were reported between the groups with or without the neodjuvant therapy. Therefore, this therapy has no positive effect on the resection results themselves. The MTT test proved to be of low significance in the neodjuvant therapy assessment. Chemoresistance can be assessed only retrospectively and, furthermore, the results are likely to be affected by a relatively high sensitivity to the neodjuvant therapy itself. The pCR rate reaches 20%. Long-term results had not been assessed due to a short follow-up period.
Antineoplastic Combined Chemotherapy Protocols↗
[Reoperations following laparoscopic fundoplication].
During an eight-year-period, 623 laparoscopic fundoplications were conducted in the Surgical Clinic in Olomouc. Out of the total number, 14 of them were reoperations and 4 reoperations were conducted on patients, primarily operated in other clinics. 9 patients were reoperated for dislocations of the rim transhiatally into the mediastinum, respectively aborally to the gastric fundus. 4 patients were operated for oesophageal constricions in the hiatus region and 2 patients for haemoperitoneum caused by haemorrhaging from a wound after the port removal. The remaining 3 patients had the reoperation indicated for a biliary reflux in the oesophageus, the rim loosening or for a non-standard primary procedure, conducted to treat the oesophageal reflux disorder in another clinic. This study discusses causes of individual complications and their treatment alternatives. The authors point-out prevention of complications based on following certain principles during the laparoscopic fundoplication procedures.
Fundoplication↗
[Extent of lymphadenectomy in lung resection for carcinoma].
Dissemination of the bronchogenic carcinoma into the lung and mediastinal lymphonodes is considered one of the basic prognostic factors. Correct evaluation of the lymphonodes involvement remains the principal pre-requisite for the choice of the most appropriate procedure and makes a forecast of a particular patient's perspective possible. The preoperative diagnostics of malignant lymphadenopathy is based on a CT examination. Once enlarged lymphonodes are detected, invasive exploration is indicated--either via mediastinoscopy, eventually via thoracoscopy. The final picture of the extent of the tumor dissemination via lymphatics is provided by the final histopathological examination of the lymphonodes removed during the surgical procedure. The minimal extent of lymphadenectomy is still being discussed. Some clinics do not conduct it at all. On the other hand, there are some clinics, where the en-bloc mediastinal lymphonodes dissection remains a common procedure during all lung carcinoma surgical procedures. On the group of 226 patients operated between 1996-1999, the authors assess surgical aspects and complications of the lymphadenectomic procedure within the radical lung resection for the non-spinocellular lung carcinoma. In the subgroup of 73 patients with a confirmed malignancy of the lung lymphonodes, the authors have found no statistical difference in the five-year survival rate which would be connected to lymphadenectomy. Mediastinal lymphadenectomy, with respect to its sound diagnostic and prognostic benefits, remains a necessary part of any curative resection. It proved to improve local control of the tumor, however, it has no clear influence on the survival rate. In small peripheral tumors (T1, T2), its extent may be restricted to systematic sampling of the interlobium, lung hilus and medistinum lymphonodes. On the other hand, in case of advanced tumors after the induction therapy, no other than en-block resection procedures are suitable or even possible.
Carcinoma, Bronchogenic↗
Subharmonic and ultraharmonic emissions for emboli detection and characterization.
Emboli detection and characterization is of importance for different patients, such as those undergoing carotid or cardiac surgery. The emboli occur as particulate or gaseous matters. To select the appropriate treatment and reduce the risk of embolism, it is essential to first detect and then classify and, ultimately, size the emboli. We propose, in this study, an approach to characterize and size the emboli based on the nonlinear properties of the emboli. Gaseous emboli were produced by generating single and uniform air bubbles. These bubbles had diameters ranging from 40 microm to 120 microm. Acoustic measurements were carried out and special attention was devoted to the generation of subharmonic and first ultraharmonic components for gas bubbles of different sizes and at different acoustic pressures. For the scanning frequency and the applied acoustic pressures used in this study, only bubbles ranging from 58 microm up to 110 microm are capable of generating a subharmonic and an ultraharmonic frequency component. However, gas emboli outside this range behave differently. In conclusion, such an approach can be used to provide information needed to classify and size emboli.
Acoustics↗
Cardiac complications after elective major vascular surgery.
Cardiac complications are the major cause of perioperative and late mortality and morbidity in patients undergoing elective major vascular surgery. This review focuses on the pathophysiology of perioperative complications, risk assessment and risk reduction strategies, all related to cardiovascular disease. Patients without cardiac risk factors are considered to be at low risk and no additional evaluation for coronary artery disease is recommended; beta-adrenergic blockers may reduce perioperative cardiac events; patients with one or more risk factors represent an intermediate to high-risk population. beta-Adrenergic blockers should be prescribed to all patients and coronary revascularization should be reserved for patients who have a clearly defined need for revascularization independent of the need for vascular surgery.
Anesthesia↗
Effects of cerebral air embolism on brain metabolism in pigs.
OBJECTIVES: Cerebral air embolism was induced in pigs and changes in intracranial pressure (ICP), brain oxygen (PbrO2), brain carbon dioxide (PbrCO2), brain pH (brpH) and glucose, lactate and pyruvate levels were used to characterize this model. METHODS: In seven anesthetized pigs, ICP, PbrO2, PbrCO2 and brpH were measured continuously with multiparameter sensors and brain glucose metabolism by microdialysis. After injection of air into the internal carotid artery, these parameters were recorded for 2 h. RESULTS: ICP increased (433%) from 12 +/- 1 to 52 +/- 8 mmHg (P < 0.05). PbrO2 decreased from 25.7 +/- 6.2 to 11.9 +/- 5.2 mmHg. PbrCO2 increased (109%) from 57.7 +/- 2.7 to 120.4 +/- 21.5 mmHg (P < 0.05). Brain glucose decreased (38%) from 3.05 +/- 0.91 to 1.91 +/- 0.55 mmol, while brain lactate increased (384%) from 1.36 +/- 0.15 to 5.22 +/- 0.53 mmol/l (P < 0.05). CONCLUSIONS: Cerebral air embolism has a deleterious effect on ICP and brain metabolism. Therefore, this model may be suitable for testing therapeutic regimens in cerebral air embolism.
Animals↗
Providing assisted reproductive care to male haemophiliacs infected with human immunodeficiency virus: preliminary experience.
Outlined is our experience with couples in whom the male was both human immunodeficiency virus (HIV) seropositive and a haemophiliac who underwent assisted reproductive technologies (ART) in order to attain family goals while minimizing the risk of HIV transmission. We report their demographics, attitudes towards assisted reproduction, and ART performance and outcomes. The study included HIV serodiscordant couples (n = 11) who underwent ART at a university-based infertility practice from August 1997 to May 2002. Prior to treatment, couples prospectively completed a survey regarding their demographics and attitudes towards assisted reproduction. All couples underwent ART and pregnancy outcomes were analysed. The majority of the patients were fully employed, college-educated, in good health, married and motivated to have a child while minimizing the risk of HIV transmission. Eleven couples underwent 25 cycles of ART [19 in vitro fertilization (IVF) cycles; five frozen embryo transfer cycles; and one oocyte donation cycle] resulting in nine successful pregnancies. The ongoing/delivered pregnancy rate per initiated IVF cycle was 42.1% per embryo transfer. Eight of 11 (72.7%) couples achieved a successful pregnancy. More than half (six of 11; 54.5%) the couples conceived during their initial attempt. Four of nine (44.4%) pregnancies were multiple gestations, including three sets of triplets. All female recipients tested seronegative for HIV at 3 and 6 months post-embryo transfer. All delivered babies (n = 8) tested seronegative for HIV at birth and 3 months postpartum. Four pregnancies are currently ongoing. ART should be considered for HIV serodiscordant couples with haemophilia who desire to have children in order to minimize the risk of viral infection.
Adult↗
Phylogeny of antigen-processing enzymes: cathepsins of a cephalochordate, an agnathan and a bony fish.
Cathepsins are enzymes that have been cleaving peptide bonds of lysosomal proteins probably since lysosomes appeared in early eucaryotes. When the adaptive system emerged in gnathostomes, cathepsins were recruited to produce peptides for loading onto the major histocompatibility complex class II molecules and for degrading the class II-associated invariant chain just before the loading. The circumstances under which this recruitment took place are unclear because the knowledge about vertebrate cathepsins is limited largely to mammals. To shed light on the recruitment, 10 amphioxus, one lamprey and one cichlid fish cathepsin cDNA clone were characterized and analysed phylogenetically. Disregarding cathepsin O, whose phylogenetic position is uncertain, the analysis confirms the existence of two old lines of descent, the B and the L lineages of cathepsins, which diverged from each other early in the evolution of eucaryotes. The B lineage encompasses cathepsins B, C and Z (X). The L lineage splits off sublineages encompassing cathepsins F and W before the plant-animal separation and cathepsin H early in the evolution of the metazoa. The remaining cathepsins belonging to the L lineage diverged from one another during the evolution of vertebrates: S, K and L before the emergence of bony fishes, and the group of rodent placentally expressed cathepsins [J (P), M, Q, R, 3, 6, 7 and 8] as well as the testis/ova-expressed cathepsins (testins) probably after the divergence of rodents from primates. The part possibly played by the adaptive immune system in some of these divergences is discussed.
Amino Acid Sequence↗
Interleukin (IL)-6 mRNA expression is stimulated by insulin, isoproterenol, tumour necrosis factor alpha, growth hormone, and IL-6 in 3T3-L1 adipocytes.
Interleukin (IL)-6 has recently been shown to be an adipocyte-expressed cytokine. Its serum concentrations are elevated in insulin resistance and obesity. For further evaluation of IL-6 gene expression regulation, fully differentiated 3T3-L1 adipocytes were treated with various hormones known to induce insulin resistance. IL-6 mRNA content was measured by quantitative real-time reverse transcription-polymerase chain reaction. Interestingly, treatment of adipocytes with 100 nM insulin, 10 micro M isoproterenol, 10 ng/ml tumour necrosis factor alpha (TNFalpha), and 500 ng/ml growth hormone (GH) for 16 h stimulated IL-6 mRNA expression 2.3-fold, 47-fold, 74-fold, and 1.4-fold, respectively (p < 0.01). In contrast, treatment with 100 nM dexamethasone significantly decreased IL-6 expression to 32 % of control levels (p < 0.01), whereas triiodothyronine and angiotensin 2 did not have any effect. Furthermore, stimulation of IL-6 expression was time-dependent with maximal stimulatory effects detectable after 1 h of insulin, isoproterenol, and GH addition and 12 h of TNFalpha, respectively. Moreover, isoproterenol's effect could be almost completely reversed by pretreatment of 3T3-L1 cells with the beta-adrenergic antagonist propranolol and mimicked by stimulation of G S -proteins with cholera toxin and adenylyl cyclase with forskolin and dibutyryl cAMP, respectively. Finally, IL-6 strongly induced its own expression in a time-dependent fashion. Taken together, our results demonstrate that IL-6 expression in adipocytes is governed by an autocrine positive feedback loop and upregulated by insulin, isoproterenol, TNFalpha, and GH. In concert with this adipocytokine's upregulation in states of decreased insulin sensitivity such as obesity and diabetes, the data support a possible role of IL-6 as a selectively regulated mediator of insulin resistance.
3T3-L1 Cells↗
Suppression of aquaporin adipose gene expression by isoproterenol, TNFalpha, and dexamethasone.
Aquaporin adipose (AQPap) is a putative glycerol channel in adipocytes. It has recently been shown to be upregulated in insulin resistance stimulated by thiazolidinediones and inhibited by insulin. To further clarify regulation of AQPap gene expression, 3T3-L1 adipocytes were chronically treated with various hormones known to influence insulin sensitivity and adipocyte metabolism, and AQPap mRNA was measured by quantitative real-time reverse transcription-polymerase chain reaction. Interestingly, treatment of 3T3-Ll adipocytes with 10 micro M isoproterenol, 10 ng/ml TNFalpha, and 100 nM dexamethasone for 16 h inhibited AQPap gene expression by 62 %, 60 %, and 39 %, respectively; angiotensin 2, growth hormone, and triiodothyronine did not have any effect. The inhibitory effects were dose-dependent with significant suppression detectable at concentrations as low as 1 nM isoproterenol, 1 ng/ml TNFalpha, and 10 nM dexamethasone. Furthermore, inhibition of AQPap gene expression could be almost completely reversed by pretreating 3T3-L1 adipocytes with the beta-adrenoceptor antagonist propranolol. Moreover, stimulation of Gs-proteins with cholera toxin and adenylyl cyclase with forskolin and dibutyryl-cAMP dramatically downregulated AQPap mRNA. Taken together, our results suggest that AQPap is an adipocyte-expressed glycerol channel selectively regulated and profoundly downregulated by hormones implicated in the pathogenesis of insulin resistance and dyslipidemia.
3T3-L1 Cells↗
Excitotoxic hippocampal membrane breakdown and its inhibition by bilobalide: role of chloride fluxes.
We have previously shown that hypoxia and N-methyl-D-aspartate (NMDA) receptor activation induce breakdown of choline-containing phospholipids in rat hippocampus, a process which is mediated by calcium influx and phospholipase A (2) activation. Bilobalide, a constituent of Ginkgo biloba, inhibited this process in a potent manner (Weichel et al., Naunyn-Schmiedeberg's Arch. Pharmacol. 360, 609-615, 1999). In this study, we used fluorescence microscopy and radioactive flux measurements to show that bilobalide does not interfere with NMDA-induced calcium influx. Instead, bilobalide seems to inhibit NMDA-induced fluxes of chloride ions through ligand-operated chloride channels. In our experiments, substitution of chloride in the superfusion medium fully blocked the effect of NMDA on choline release from hippocampal slices, while the presence of chloride transport inhibitors (furosemide, DIDS) was partially antagonistic. The inhibitory effect of bilobalide and of HA-966, a glycine B receptor antagonist, on NMDA-induced choline release was attenuated in the presence of glycine. The inhibitory effect of bilobalide, but not that of HA-966, was also antagonized by GABA. The inhibitory effect of MK-801, an NMDA channel blocker, on choline release was insensitive to glycine. We conclude from our findings that bilobalide inhibits an NMDA-induced chloride flux through glycine/GABA-operated channels, thereby preventing NMDA-induced breakdown of membrane phospholipids. This effect is expected to contribute to the neuroprotective effects of ginkgo biloba extracts.
4,4'-Diisothiocyanostilbene-2,2'-Disulfonic Acid↗
Development and characterization of a long-acting recombinant hFSH agonist.
BACKGROUND: Fusion of the carboxyterminal peptide (CTP) of hCG to FSH results in a follitropin agonist with an extended half-life, presumably due to the four O-oligosaccharides on the CTP. Alternatively, an rhFSH analogue containing additional N-linked carbohydrate is described in this report. METHODS: A DNA sequence containing two N-oligosaccharide signal sequences was ligated into a vector containing hFSHbeta- and alpha-subunit encoding cDNA, and expressed in CHO-K1 cells. In-vitro bioactivity of the single-chain hormone was assessed in CHO cells expressing the hFSH receptor. Pharmacokinetic values were derived from serial serum assays of the analogue in immature female rats following a single i.v. injection. In-vivo bioactivity was assessed by measuring ovarian weight gain 3 days post-injection. RESULTS: rhFSH-N2 and native rhFSH induced comparable levels of cAMP in vitro. t(1/2) for native rhFSH, rhFSH-CTP and rhFSH-N2 were 3.7, 7.1 and 7.3 h respectively. Rats receiving rhFSH-N2 had a mean +/- SD ovarian weight 3 days post-i.v. injection (22 +/- 3.6 mg) significantly greater than rats receiving rhFSH and saline (16.7 +/- 1.5 and 15.3 +/- 0.47 mg respectively, P < 0.05). CONCLUSIONS: rhFSH-N2 has prolonged half-life and increased bioactivity compared with native rhFSH. This rhFSH agonist, and other analogues containing additional N-oligosaccharides may have important clinical applications.
Animals↗
Comparison of meconium and neonatal hair analysis for detection of gestational exposure to drugs of abuse.
BACKGROUND: Meconium and hair are two biological markers of in utero exposure to illicit drugs. OBJECTIVE: To compare the sensitivity of the two tests for different drugs. SETTING: Motherisk laboratory which tests in utero drug exposure in Toronto. METHODS: Cocaine, benzoylecgonine, opiates, cannabis, benzodiazepines, methadone, and barbiturates were measured in pairs of hair and meconium samples from the same neonates. RESULTS: Meconium was marginally more sensitive than neonatal hair for detection of cocaine and cannabis, possibly because it may detect second trimester exposure whereas hair grows only during the third trimester of pregnancy. There was a significant correlation between hair and meconium concentrations of cocaine, cannabis, and opiates. CONCLUSION: In cases of clinical suspicion and a negative neonatal urine test, both meconium and hair are effective biological markers of in utero illicit drug exposure. Meconium may be more sensitive, but neonatal hair is available for three months whereas meconium is available for only one or two days. In contrast, the use of meconium, being a discarded material, is more acceptable to some parents than hair testing, which entails cutting scalp hair from the newborn.
Cannabis↗