Biomedical subjects
A Hellman
Publications and source records attributed to A Hellman.
Replication delay along FRA7H, a common fragile site on human chromosome 7, leads to chromosomal instability.
Common fragile sites are specific chromosomal loci that show gaps, breaks, or rearrangements in metaphase chromosomes under conditions that interfere with DNA replication. The mechanism underlying the chromosomal instability at fragile sites was hypothesized to associate with late replication time. Here, we aimed to investigate the replication pattern of the common fragile site FRA7H, encompassing 160 kb on the long arm of human chromosome 7. Using in situ hybridization on interphase nuclei, we revealed that the replication of this region is initiated relatively early, before 30% of S phase is completed. However, a high fraction ( approximately 35%) of S-phase nuclei showed allelic asynchrony, indicating that the replication of FRA7H is accomplished at different times in S phase. This allelic asynchrony is not the result of a specific replication time of each FRA7H allele. Analysis of the replication pattern of adjacent clones along FRA7H by using cell population and two-color fluorescent in situ hybridization analyses showed significant differences in the replication of adjacent clones, under normal growth condition and upon aphidicolin treatment. This pattern significantly differed from that of two nonfragile regions which showed a coordinated replication under both conditions. These results indicate that aphidicolin is enhancing an already existing difference in the replication time along the FRA7H region. Based on our replication analysis of FRA7H and on previous analysis of the common fragile site FRA3B, we suggest that delayed replication is underlying the fragility at aphidicolin-induced common fragile sites.
The effect of a heat and moisture exchanger on humidity in a low-flow anaesthesia system.
The heat and humidity in a low-flow breathing system was measured in order to study the inherent humidifying properties of the system at low fresh gas flows (< 1 and 21.min-1) and whether a heat and moisture exchanger could compensate for the loss of heat and humidification occurring at higher fresh gas flows (51.min-1) in these systems. Sixty patients were randomly divided into three groups (< 1, 2 and 51.min-1 fresh gas flows) with a heat and moisture exchanger and three groups without a heat and moisture exchanger in the breathing system. Thirty minutes after the start of anaesthesia a control measurement was performed, after which a heat and moisture exchanger was inserted into the breathing system of the three groups randomly allocated to have one. Three more measurements were performed at 10, 30 and 60 min after control. At low fresh gas flows the humidifying properties of the low-flow breathing system are adequate (i.e. provide an absolute humidity > 20 mg.l-1) but at a fresh gas flow of 51.min-1 there is a need for a heat and moisture exchanger for adequate humidification of the inspired gas.
[Evaluation of bone marrow grafts and hemopoietic chimerism using PCR hypervariable sequencing with variable number tandem repeat sequences].
PCR amplification of highly polymorphic variable number of tandem repeat (VNTR) sequences could be particularly useful in documentation of engraftment and characterization of chimerism following allogeneic bone marrow transplantation (BMT). We have monitored a 31-year old male patient treated with allogeneic BMT for chronic myeloid leukaemia. The recipient's DNA samples were obtained before the transplant and on day 28, 100 and 150 after BMT. The donor's DNA (patient's sister) was also obtained as a reference. ACT B2 locus on chromosome 6 was chosen for the analysis. In addition a deletion polymorphism locus within the pseudoautosomal region of chromosome X and Y (amelogenin gene) was also analysed. On day 28 after BMT both donor and recipient specific alleles were detected in the recipient's sample. However, on day 100 and 150 the recipient specific alleles were no longer detectable. The aforementioned pattern was observed for both markers analysed. The disappearance of recipient specific alleles correlated with clinical symptoms of chronic graft-versus host disease.
Diclofenac versus pethidine in the treatment of pain after hysterectomy.
A double-blind study was performed in 63 patients to compare diclofenac (a non-steroidal anti-inflammatory drug), pethidine and placebo with regard to efficacy and tolerability in the treatment of pain after abdominal hysterectomy. The compounds were injected post-operatively and the duration of pain relief was chosen as the parameter of efficacy. Pain intensity was measured on a visual analogue scale by the patient and according to a six-point scale by the investigator. Diclofenac gave significantly longer pain relief than pethidine or placebo. Few side-effects were reported after diclofenac and placebo, and post-operative bowel paralysis tended to be shorter with diclofenac.
Hemodynamic effects of high doses of corticosteroids.
It is somewhat difficult to reconcile the contrasting findings regarding the hemodynamic actions of high doses of corticosteroids in shock. The studies differ according to type of shock (hypovolemic, septic or cardiogenic), animal species, shock model, type of corticosteroid, etc. Beneficial hemodynamic effects (e.g. myocardial improvement, vasodilation) of steroids given alone are not consistently observed and when so often mild and transient. This might indicate that the hemodynamic changes of corticosteroids are not due to primary actions on the cardiovascular system but rather represent the hemodynamic consequences of the metabolic response to corticosteroid therapy. If, however, the corticosteroid therapy is combined with an alpha-adrenoreceptor blocker the nutritive tissue blood flow is distinctly increased.
High doses of corticosteroids in the treatment of septic shock.
High doses of corticosteroids are reported to be beneficial in the treatment of septic shock in many animal species, e.g. dog, rat and rabbit. Recent findings in baboons subjected to E. coli shock indicate that early treatment with a combination of antibiotics and steroids strongly enhance survival rate. In clinical studies the protective effects of steroids are more ambiguous, however. In part this may be explained by variations in the amount of steroids used or by the fact that in some studies the steroid is administered late in shock. The dose recommended, 30 mg/kg bw of methylprednisolone or an equivalent amount of another glucocorticoid given once or twice, is based on animal as well as clinical documentation.
Failure of an increased dose of ATP-MgCl2 to improve protein synthesis and transmembrane potential in the postischemic liver.
To study the effects of ATP-MgCl2 on impaired protein synthesis and hepatic cell membrane potential (HCMP) in the postischemic liver, ATP-MgCl2 (50 or 150 mumole/kg) or saline was administered intravenously following 90 min of liver ischemia in rats. Protein synthesis was measured by determining rate of leucine incorporation into proteins in incubated liver slices. HCMP was registered in vivo with glass microelectrodes. No effects of the two doses of ATP-MgCl2 on protein synthesis or HCMP in the postischemic liver were found. The results indicate that beneficial effects of ATP-MgCl2 previously reported following liver ischemia are not primarily caused by direct energy provision to hepatocytes.
Effects of methylprednisolone on protein synthesis and blood flow in the postischemic liver.
The effects of methylprednisolone (MP) on hepatic protein synthesis and blood flow following liver ischemia were studied in rats. Ischemia was induced by occluding all blood vessels to the left and median liver lobes during 1 hr and the experiments were continued for 2 hr following reperfusion. Protein synthesis was studied by determining rate of leucine incorporation into proteins in incubated liver slices. Hepatic blood flow was measured by xenon washout technique. One group of animals received MP intravenously (30 mg/kg) before induction of liver ischemia; one group was given the same dose of MP after ischemia; control rats received saline. Protein synthesis was reduced to the same extent at the end of the ischemic period in rats pretreated with MP as in control animals. During reperfusion, however, protein synthesis was restored faster and more completely both in animals receiving MP before and after ischemia than in control rats. No effects of MP on blood flow or adenine nucleotides in liver tissue were found. This study confirms previous reports on beneficial effects of glucocorticoids in liver ischemia and demonstrates improvement of one important hepatocellular function in the postischemic liver following administration of MP.
Intensive care treatment in septic shock.
Deaths in septic shock continue to occur at a high frequency despite current treatment programs. However, the mortality can be substantially decreased with a close bedside attendance of patients at risk and if the patient is transferred to an intensive care unit for intensive treatment and monitoring as soon as shock is suspected or established. The treatment program consists of adequate antibiotic administration in combination with massive doses of steroids and aggressive infusion therapy supplemented with cardiovascular drugs according to the hemodynamic response to the initial treatment.
Increasing incidence of stab wounds.
During the four-year period 1978-1981 74 patients were hospitalized due to stab wounds obtained in criminal trauma. 84% of the patients were submitted to different kinds of surgery. The incidence of stab wounded patients increased each year during the period studied and was doubled the last year as compared to the first year. During the last two years of the study all patients admitted to the emergency unit with stab wounds were registered. Almost 50% of the patients had injuries of a magnitude which did not allow treatment on an out-patient basis. This study showed an increasing trend in the incidence of patients with stab wounds and a need of large resources in the care of these patients.
Expression of oncornaviral RNA in mouse uterus during pregnancy.
The expression of oncornaviral-specific RNA was studied in the NIH Swiss mouse uterus during gestation using hybridization with complementary DNAs synthesized from type C viral high molecular weight RNAs. Following conception there was a marked decrease in the relative concentration of viral RNA below the levels in nonpregnant uteri. Thereafter, the level of viral RNA remained low (less than 30% of prepregnancy levels) until Day 14. Following Day 14 there was a progressive increase in levels of viral RNA and peak levels (greater than or equal to pregestation) were reached just before parturition (Day 18). One day after parturition viral RNA levels were still elevated. A similar profile was observed for p30, a viral-coded protein. We suggest that oncornaviral gene expression is under transcriptional control, most likely by ovarian steroid hormones, and that oncornaviruses can be useful tools to study gene expression in the mammalian uterus.
Hemodynamic effects of massive doses of dexamethasone in controlled hypovolemic shock in the dog.
The hemodynamic effects of massive doses of dexamethasone in combination with the alpha-adrenergic blocking agent phenoxybenzamine were studied in dogs subjected to hemorrhagic hypotension. Previously it has been shown that the glucocorticoid methylprednisolone, but not the glucocorticoid betamethasone, induces a pronounced vasodilation in combination with phenoxybenzamine. In the present study it was found that also dexamethasone (a stereoisomer of betamethasone) is unable to increase the peripheral blood flow after phenoxybenzamine. Since equivalent doses were used in relation to glucocorticoid activity, it seems reasonable to conclude that the different hemodynamic patterns are unrelated to the glucocorticoid ability of the drugs. Furthermore, it is unlikely that possible beneficial effects of dexamethasone in hypovolemic shock are due to a direct vascular influence.
No beneficial effect of ATP-MgCl2 on impaired transmembrane potential and protein synthesis in liver ischemia.
Hepatic cell membrane potential (HCMP) and protein synthesis were studied in rats during and after a period (60 min) of liver ischemia. ATP-MgCl2 (5 mumol . 100 g bw-1) or saline was administered slowly intravenously before or after the period of liver ischemia. No beneficial effect of ATP-MgCl2 on the impaired HCMP or protein synthesis was observed. On the contrary, the post-ischemic restitution of these cellular metabolic variables was slower in animals receiving ATP-MgCl2 after the period of liver ischemia as compared with saline-treated rats. At the end of the ischemic period, ATP, glucose and lactate in liver tissue were the same in animals receiving ATP-MgCl2 or saline before ischemia. These results suggest that the beneficial effects previously reported after administration of ATP-MgCl2 in conditions with reduced hepatic blood flow are not primarily due to an improved metabolic situation in the liver.
[Current review. Massive doses of corticosteroids in hypovolemic shock].
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Induction of type-C retrovirus by the tumor promotor TPA.
The tumor promotor 12-0-tetradecanoyl-phorbol-13-acetate (TPA) induced endogenous murine xenotropic type-C retrovirus from A1-2 cells, derived from the BALB/c mouse, as determined by infectious center focus-forming assay on permissive normal rat kidney (NRK) cells. Kinetic dose-response studies showed that the number of cells induced to release virus was dependent on TPA concentration and the time of assay following TPA exposure. Maximal induction occurred when cells were treated with 80 ng/ml of TPA for 24 h and assayed at 24 or 48 h. A 30-min pulsed TPA exposure and 200 ng/ml induced virus levels approximating those observed after a continuous 24-h exposure to 80 ng/ml. The combination of TPA at concentrations of 10 and 20 ng/ml and a suboptimal level of 5-iodo-2-deoxyuridine (IdUrd) enhanced retrovirus induction threefold above that seen by the optimum IdUrd concentration alone. The protease inhibitors, antipain and leupeptin, decreased virus induction by TPA, a protease inducer. The capacity of TPA to induce type-C retrovirus complements results demonstrating the enhancement of Epstein-Barr virus (EBV) and murine mammary tumor virus (MMTV) synthesis by TPA.
[Toxic shock syndrome with severely impaired circulation].
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Vascular and metabolic effects of methylprednisolone and phenoxybenzamine during controlled hypotension in the dog.
The relationship between central haemodynamics and vascular and metabolic parameters in skeletal muscle was studied in dogs subjected to controlled haemorrhagic hypotension and treated with cumulative doses of methylprednisolone (4-32 mg x kg-1), (or saline in the control group), followed by phenoxybenzamine. There were no significant haemodynamic or metabolic changes between the groups during the injections of steroid or saline. The alpha-adrenergic receptor blockade caused, as found earlier, a pronounced vasodilation in the steroid group, which was parallelled by an increase in muscle blood flow in the same order of magnitude. There was no clearcut relationship between metabolic and vascular effects in the groups. Despite the significant difference in blood flow between the groups after phenoxybenzamine, only small and insignificant differences were seen in muscle metabolites, with the exception of muscle lactate which showed higher values in the steroid group. The study provides further evidence in support of the hypothesis that the haemodynamic effects of the combination of methylprednisolone and phenoxybenzamine are of neurogenic origin.