Modulation of Radioprotective Effects of Respiratory Hypoxia by Changing the Duration of Hypoxia before Irradiation and by Combining Hypoxia and Administration of Hemopoiesis-Stimulating Agents

Aim: Analysis of radioprotective effect of respiratory hypoxia on hemopoietic tissue and enhancement of this effect by heopoietic activation. Material and Methods: In mice breathing hypoxic gas mixture during total body gamma irradiation the recovery of pluripotent and committed granulocyte-macrophage progenitor cells and animal lethality were determined. Results: In mice forced to breathe 10% O₂ and 8% O₂ during irradiation, the oxygen tension in the spleen decreased to 40% and 20%, respectively, of control values. Hypoxia mitigated the lethal effect of gamma-rays and improved the recovery of hemopoiesis in compartments of pluripotent and committed progenitor cells. Enhancement of the proliferative activity in hemopoietic tissue by a cytokine (rmGM-CSF) or an immunomodulator (dextran sulfate) increased the effect of hypoxic radioprotection, while elimination of proliferative cells by hydroxyurea decreased the radioprotective effect. Adaptation of experimental animals to hypoxic conditions was found to reduce the radioprotective effect without influencing tissue partial oxygen pressure lowered by hypoxic conditions. Conclusion: The data presented confirm the radioprotective effect of 10% and 8% O₂ respiratory hypoxia on hemopoiesis. These findngs may represent a way out for further experimental and clinical research aimed at considering differential protection of various tissues by hypoxia. Ziel: Analyse von radioprotektiver Wirkung der respiratorischen Hypoxie auf das hämatopoetische Gewebe und Verstärkung dieses Effekts durch Aktivierung der Hämatopoese. Material und Methode: Es wurden bei Mäusen, die 10%igen und 8%igen Sauerstoff während der Bestrahlung geatmet haben, die Erholung von pluripotenten und unipotenten Progenitorzellen und das Überleben nach einer letalen Strahlendosis untersucht. Ergebnisse: Bei Mäusen, die 10% und 8% Sauerstoff während der Strahlentherapie geatmet haben, sank der Sauerstoffpartialdruck in der Milz auf 40% bzw. 20% in Bezug zu den Kontrollwerten ab. Die Hypoxie schwächte den letalen Effekt von Gammastrahlen ab und verbesserte die Erholung von Strahlenschädigungen in der Hämatopoese in den Kompartimenten von pluripotenten und unipotenten Progenitorzellen. Die Verstärkung der Proliferationsaktivität im hämatopoetischen Gewebe durch ein Zytokin (rmGM-CSF) oder durch einen Immunomodulator (Dextransulfat) verstärkte die hypoxische Radioprotektion, während die Elimination von proliferativen Zellen durch Hydroxyurea der radioprotektiven Effekt verringerte. Es wurde gefunden, dass die Adaption von experimentellen Tieren an die hypoxischen Bedingungen den radioprotektiven Effekt verringerte, ohne dass der durch die hypoxischen Bedingungen veränderte Sauerstoffpartialdruck im Gewebe weiter abgesenkt wurde. Schlussfolgerung: Die vorgestellten Daten bestätigen die radioprotektive Wirkung der respiratorischen Hypoxie (8% und 10% O₂) auf die Hämatopoese. Diese Entdeckungen können einen Weg für die weitere experimentelle und klinische Erforschung der unterschiedlichen Radioprotektion von verschiedenen Geweben durch respiratorische Hypoxie darstellen.     

Modulation of Radioprotective Effects of Respiratory Hypoxia by Changing the Duration of Hypoxia before Irradiation and by Combining Hypoxia and Administration of Hemopoiesis-Stimulating Agents

AIM: Analysis of radioprotective effect of respiratory hypoxia on hemopoietic tissue and enhancement of this effect by hemopoietic activation. MATERIAL AND METHODS: In mice breathing hypoxic gas mixture during total body gamma irradiation the recovery of pluripotent and committed granulocyte-macrophage progenitor cells and animal lethality were determined. RESULTS: In mice forced to breathe 10% O2 and 8% O2 during irradiation, the oxygen tension in the spleen decreased to 40% and 20%, respectively, of control values. Hypoxia mitigated the lethal effect of gamma-rays and improved the recovery of hemopoiesis in compartments of pluripotent and committed progenitor cells. Enhancement of the proliferative activity in hemopoietic tissue by a cytokine (rmGM-CSF) or an immunomodulator (dextran sulfate) increased the effect of hypoxic radioprotection, while elimination of proliferative cells by hydroxyurea decreased the radioprotective effect. Adaptation of experimental animals to hypoxic conditions was found to reduce the radioprotective effect without influencing tissue partial oxygen pressure lowered by hypoxic conditions. CONCLUSION: The data presented confirm the radioprotective effect of 10% and 8% O2 respiratory hypoxia on hemopoiesis. These findings may represent a way out for further experimental and clinical research aimed at considering differential protection of various tissues by hypoxia.     

Comparison of the pharmacokinetics of diazepam after single and subchronic doses

Summary In seven healthy male volunteers the effects of the pattern of dosing on the pharmacokinetics of diazepam have been studied. A cross-over design was employed that consisted of three parts: a single intravenous dose (0.1 mg/kg), and oral dosing (10 mg/day) for six days followed by an intravenous bolus (0.1 mg/kg) on the seventh day, followed by re-examination of a single intravenous dose after diazepam (D) and its major metabolite desmethyldiazepam (DD) had been completely eliminated. Plasma levels of D and DD were monitored by a specific, sensitive GLC-method. In younger patients (n=5, age 29 – 35 years) the elimination half-life, T_{1/2 ()}, of D was 33.9±10.6 h (mean±S.D.) after the single dose. The control study gave an almost identical result (35.7±12.1). After subchronic dosage in all patients T_{1/2 ()} showed a modest but significant prolongation (paired t-test p<0.01) to 52.9±17.4 h. It was caused by a significant decrease (p=0.016) in total plasma clearance ( ), from 26.0±10.8 ml/min to 18.2±7.0 ml/min. Older patients (age 43–60 years) showed the same phenomenon. Blood/plasma ratios remained constant indicating no change in protein binding. Biliary excretion of D was measured in five patients with a T-tube. Only negligible amounts (0.3–0.4%) of administered D were excreted within 3 days after subchronic dosage, which demonstrates a lack of enterohepatic cycling of D. After multiple administration of D, there was accumulation of DD to levels approximately five times higher than after a single dose. The possibility that the slower elimination of D after subchronic treatment might be caused by DD was also supported by experiments in dogs and rabbits. After pretreating rabbits with DD and maintaining a high DD plasma level, there was prolongation of T_{1/2 ()} from 2.7 h to 5.2 h, with a corresponding decrease of from 101.6 ml/min to 23.4 ml/min. Similar results were obtained in dogs. It is concluded that the disposition of D is altered by subchronic use and may be regulated by the plasma DD concentration.The results were presented in part at the 6th International Congress of Pharmacology, Helsinki, 1975     

Different ocular abnormalities in individuals of a three-generation family caused by a new nonsense mutation in the PST domain of the PAX6 gene

PAX6 is a candidate gene for familial aniridia. We have carried out a mutational analysis of the PAX6 gene in a three-generation family from Germany, containing 5 individuals affected with ocular abnormalities. In all affected individuals, a heterozygous mutation was detected in the PAX6 gene, exchanging tyrosine 369 by a stop codon. The mutation is located in the 3′ moiety of the PST domain, at the C terminus of the PAX6 protein. In the affected family members, the same heterozygous mutation leads to distinct phenotypes of varying severity. Most notably, s of varying severity. Most notably, no aniridia was observed in one of the family members carrying the mutation, although other ocular abnormalities (underdeveloped iris and cataracts) were present. We discuss the possibility that small C terminal truncations of the PAX6 protein might lead to less severe or more divergent phenotypes than truncations at internal positions. © 1998 Wiley-Liss, Inc.     

Laparoscopic myomectomy with lateral dissection of the uterine artery.

BACKGROUND: We assessed the results and impact of lateral uterine artery dissection on clinical outcome following laparoscopic myomectomy. METHODS: We retrospectively analyzed the clinical data for 27 laparoscopic myomectomy cases (Group I) and 54 laparoscopic myomectomy cases combined with lateral uterine artery dissection (Group II) between January 2001 and August 2004 in one center. Only 81 patients who had dominant fibroids between 4 cm and 10 cm in diameter were included in the study. We assessed the clinical outcomes: perioperative blood loss, operating time, hospital stay, complications, hemoglobin decrease, inflammatory response, and tissue markers (C-reactive protein, white blood cells, creatinine kinase) changes. RESULTS: The mean operating time was 70.37 minutes in group I and 78.61 minutes in group II. The mean length of hospital stay was 2.7 days versus 2.2 days, respectively (P>0.05). The difference in intraoperative blood loss was 70.1 mL (147.7 mL vs 77.3 mL, Group I) and 33.9 mL (105 mL vs 71.1 mL, Group II); estimated postoperative blood loss was statistically significant (P<0.001, P<0.05, respectively). Group 2 demonstrated a less intense stress response in C-reactive protein (P<0.001) and white blood cell count (P<0.05). CONCLUSION: The dissection of the uterine artery in laparoscopic myomectomy is a feasible operative procedure with a low rate of complications. The procedure reduced perioperative blood loss and resulted in significant improvement in fibroid-related symptoms.     

Laparoscopic pelvic lymphadenectomy in the surgical treatment of endometrial cancer: results of a multicenter study.

OBJECTIVE: To analyze the results and determine the contribution of laparoscopic pelvic lymphadenectomy in the surgical treatment of women with endometrial cancer and compare with the open technique. METHODS: A prospective multicenter study was carried out on 120 women who underwent laparoscopic surgery (96 women) and open procedures (24 women) for endometrial cancer between April 1996 and March 2000. RESULTS: Four patients whose laparoscopic surgery was completed by laparotomy were excluded from the study. The other 92 laparoscopic procedures were successfully completed. Laparoscopically assisted surgical staging (LASS) was performed based on the grade of the tumor and the depth of myometrial invasion. Sixty-seven of the patients underwent hysterectomy, bilateral salpingooophorectomy (BSO), and pelvic lymphadenectomy, and 25 women also had para-aortic lymph node sampling dissection. Eleven of these patients had positive pelvic or para-aortic nodes. The mean operating time for the laparoscopic procedure was significantly longer (173.8 min, P < 0.0001) than the time for the open procedure (135.0 min). The rate of complications was similar in both groups. The recovery time was significantly reduced (P < 0.0001). CONCLUSION: The laparoscopic approach to hysterectomy and lymphadenectomy for early stage endometrial carcinoma is an attractive alternative to the abdominal surgical approach. The advantages of laparoscopically assisted surgical staging are patient related. Because the abdominal incision is avoided, the recovery time is reduced. Laparoscopic pelvic lymph node dissection is a procedure that is appropriate, when applicable.     

Analysis of the interleukin-6 gene promoter polymorphisms in Czech patients with chronic periodontitis

BACKGROUND: Chronic periodontitis is an inflammatory disease, which is a major cause of tooth loss. The proinflammatory cytokines interleukin-1 (IL-1) and interleukin-6 (IL-6) are key regulators of the host response to microbial infection and major modulators of extracellular matrix catabolism and bone resorption. The purpose of this study was to investigate the associations of chronic periodontitis with IL-6 gene polymorphisms (at positions -597 [G/A], -572 [G/C], and -174 [G/C]). METHODS: We analyzed allele, genotype, and haplotype distributions of the IL-6 promoter variants in a case-control study involving 148 patients with chronic periodontitis and 107 unrelated controls. RESULTS: Our results showed significant differences in the distributions of alleles and genotypes of the IL-6 (-572 G/C) polymorphism between patients and the control population (chi2 = 10.393, P= 0.001, P(corr) < 0.01). The difference was due to the underrepresentation of the -572 G/C heterozygotes in patients (6.1%) compared to controls (19.6%). Although no variant "CC" homozygotes were detected in our cases and controls, heterozygosity protected against chronic periodontitis, representing a 73% reduction of risk (odds ratio [OR] = 0.27, 95% confidence interval: 0.12-0.61) compared to wild-type homozygotes. However, there were no significant differences in genotype or allele frequencies between both groups for IL-6 -597 G/A and -174 G/C polymorphisms. CONCLUSION: This study is the first, to our knowledge, suggesting that the -572 G/C polymorphism of the IL-6 gene may be one of the protective factors associated with lower susceptibility to chronic periodontitis.     

Laparoscopic management of bleeding after laparoscopic or vaginal hysterectomy.

OBJECTIVE: To assess the results and contributions of laparoscopy in the management of postoperative bleeding following laparoscopic (LH) or vaginal hysterectomy (VH). METHODS: A retrospective study of a 5-year period was carried out on 1167 women who underwent laparoscopic or vaginal hysterectomy. Ten women with postoperative bleeding following laparoscopic or vaginal hysterectomy were identified. RESULTS: The overall incidence of bleeding after laparoscopic or vaginal hysterectomy was 0.85% (10 of 1167). Over the 5-year study period, the incidence fluctuated between 1.1% and 0.4%. Surgical revision was primarily vaginal in 1 woman, followed by laparoscopic control. In 6 patients, laparoscopy was performed immediately. The patients profited from the prompt laparoscopic treatment, because intraabdominal hemorrhage was found and stopped. Of 6 cases of intraperitoneal bleeding, 1 resulted from a blood disorder. The collagen-fibrin agent TachoComb was applied locally, and the patient was postoperatively treated with blood products and coagulation factors. Only bipolar coagulation, TachoComb, and Foley catheter were used to achieve local hemostasis during laparoscopy. The remaining 3 cases where the vaginal cuff was bleeding were managed by vaginal repair and packing without laparoscopy. CONCLUSION: The laparoscopic approach to postoperative bleeding following laparoscopic or vaginal hysterectomy is an attractive alternative to the abdominal surgical approach. Bleeding following laparoscopic or vaginal hysterectomy can be managed by laparoscopy in the majority of patients. Because the abdominal incision is avoided, the recovery time is reduced.