Protection of murine bone marrow by dexamethasone during cytotoxic chemotherapy

Corticosteroids have the ability to suppress the production of growth factors and cytokines and are thus implicated in the negative regulation of hematopoiesis. We have shown that the corticosteroids, prednisolone and dexamethasone, were able to effectively protect progenitor cells in four strains of mice against cell-cycle-specific antimetabolic chemotherapy agents. The highest levels of protection against 5-fluorouracil (FU; 200 mg/kg) were achieved when two or three intraperitoneal injections of dexamethasone were administered between - 7 and +3 hours at a dose of 7.5 mg/kg/injection (optimal dose) or by continuous infusion between -4 and +20 hours. This protective effect is manifested as an increase in the number of high proliferative potential colony-forming cells that survive in the bone marrow 3 days after treatment with FU from between 0.5% and 11% to between 10% and 34% of normal. The bone marrow progenitors and blood cell numbers return to normal from 3 to 5 days and 1 to 2 days earlier, respectively. Less dexamethasone than prednisolone is required to give an equivalent protective effect, which is consistent with their anti-inflammatory potency. These findings are further evidence of the negative regulatory role played by corticosteroids, and indicate that the treatment schedules of corticosteroids during cancer therapy need to be reexamined to obtain the maximum benefit from their use.     

Conjugated dihydroxy bile salt inhibition of glucose influx in rat jejunumin vitro

Effects of bile salts on intestinal glucose transfer differ in diverse animal preparations exposed to various bile acids. Radiolabeled glucose influx into rat jejunum in vitro was studied in buffer and compared to taurodeoxycholate, taurochenodeoxycholate, taurocholate, and deoxycholate. Jejunum was obtained from intact, bile-diverted, and colestipoltreated rats and in similar categories after abdominal x-irradiation. Taurodeoxycholate but not taurocholate inhibited glucose influx only in bile-fistula and colestipol-treated rats. Bile diversion increased and colestipol decreased glucose uptake from buffer. Added inhibitory effects of irradiation and bile salts were seen in bile-fistula animals. These data suggest that normal exposure to bile is chronically inhibiting jejunal glucose transport and that dihydroxy bile salts are responsible for this effect. They do not provide an explanation for the role of bile in the intestinal radiation syndrome.This work was supported in part by contract No. AT-(40-1) 3882 from the U.S. Atomic Energy Commission.These data were presented in part at the annual meeting of the Southern Society for Clinical Investigation, New Orleans, La. February, 1975.     

Increasing sexually transmitted infection rates in young men having sex with men in the Netherlands, 2006–2012

Background

Men having sex with men (MSM) remain the largest high-risk group involved in on-going transmission of sexually transmitted infections (STI), including HIV, in the Netherlands. As risk behaviour may change with age, it is important to explore potential heterogeneity in risks by age. To improve our understanding of this epidemic, we analysed the prevalence of and risk factors for selected STI in MSM attending STI clinics in the Netherlands by age group.

Methods

Analysis of data from the national STI surveillance system for the period 2006–2012. Selected STI were chlamydia, gonorrhoea, infectious syphilis and/or a new HIV infection. Logistic regression was used to identify factors associated with these selected STI and with overall STI positivity. Analyses were done separately for MSM aged younger than 25 years and MSM aged 25 years and older.

Results

In young MSM a significant increase in positivity rate was seen over time (p?<?0.01), mainly driven by increasing gonorrhoea diagnoses, while in MSM aged 25 and older a significant decrease was observed (p?<?0.01). In multivariate analyses for young MSM, those who were involved in commercial sex were at higher risk (OR: 1.5, 95% CI: 1.2-1.9). For MSM aged 25 years and older this was not the case. Having a previous negative HIV test was protective among older MSM compared to those not tested for HIV before (OR: 0.8, 95% CI: 0.8-0.8), but not among younger MSM.

Conclusions

MSM visiting STI clinics remain a high-risk group for STI infections and transmission, but are not a homogenous group. While in MSM aged older than 25 years, STI positivity rate is decreasing, positivity rate in young MSM increased over time. Therefore specific attention needs to be paid towards targeted counselling and reaching particular MSM sub-groups, taken into account different behavioural profiles.

     

Autoantibody against erythrocyte protein 4.1 in a patient with autoimmune hemolytic anemia

We observed the presence of a new autoantibody, anti-erythrocyte protein 4.1, in a patient with autoimmune hemolytic anemia (AIHA). Western blotting analysis revealed that IgG from the patient's plasma reacted with erythrocyte protein 4.1. However, among other patients with hemolytic diseases (six having AIHA and three each having either hereditary spherocytosis, elliptocytosis, or lead poisoning) as well as among control subjects, no antibody activity to protein 4.1 was observed. In addition to the anti-protein 4.1 antibody, two different kinds of anti-erythrocyte antibodies were detected by conventional serological studies in this patient. One of them was an anti-Ena-like antibody in the eluate from the patient's erythrocytes, while another was the anti-S-specific antibody in the plasma. An elution study and an absorption study using S antigen-positive erythrocytes demonstrated that the anti-protein 4.1 antibody differed from both the anti-Ena-like antibody and the anti-S antibody. Familial analysis of the patient revealed the same antibody in her brother, who did not have hemolytic anemia. These results demonstrate that anti-protein 4.1 antibody is considered to be included in the spectrum of anti-cytoskeleton autoantibodies, which have been observed in patients having increased cell lysis as well as in healthy subjects.     

Unstable angina pectoris: the first half century: natural history, pathophysiology, and treatment

Unstable angina pectoris as a distinct syndrome intermediate between chronic stable angina and acute myocardial infarction was first described about a half century ago. The incidence of death or myocardial infarction rises in the first few months after destabilization of angina. Hemodynamic, scintigraphic, and arteriographic studies in the last 15 years have shown that unstable angina is chiefly due to "dynamic" coronary stenoses, transient reversible limitations in coronary blood flow caused by a complex interaction between coronary vasoconstriction, transient platelet plugging, and transient thrombosis. The trigger for the onset of dynamic coronary stenoses is probably acute changes in coronary arterial morphology in or near atherosclerotic plaques making those areas more thrombogenic. A large fraction of patients with unstable angina restabilize initially with medical management. The role of beta blockers is unclear, but they may protect against development of coronary events for patients with unstable angina similar to that reported for patients with myocardial infarction. Nitrates and calcium blockers are probably superior to beta blockers in restabilization of angina, but protection against coronary events has not yet been demonstrated clearly. Further investigation is needed to distinguish the relative benefits of a two-drug (heart rate-limiting calcium blocker plus nitrates) regimen vs. a three-drug regimen including beta blocker. There is no basis for emergency coronary bypass surgery to prevent myocardial infarction or death. Urgent surgery should be limited to patients who do not stabilize readily with medical therapy. One third or more of the patients who initially restabilize with medical therapy will require coronary revascularization in the year after unstable angina because of severe angina. An antithrombotic regimen of aspirin (or possibly heparin) reduces the incidence of progression to death or myocardial infarction. Two important future directions for research should be promising: development of better antithrombotic regimens other than aspirin alone for protection against coronary events; and improved ability to distinguish the patients who initially respond to medical therapy who are at low risk for later severe angina from those at higher risk.     

Genetic marking shows that Ph+ cells present in autologous transplants of chronic myelogenous leukemia (CML) contribute to relapse after autologous bone marrow in CML

Relapse after autologous bone marrow transplantation for chronic myelogenous leukemia (CML) can be due either to the persistence of leukemia cells in systemic tissues following preparative therapy, or due to the persistence of leukemia cells in the autologous marrow used to restore marrow function after intensive therapy. To help distinguish between these two possible causes of relapse, we used safety-modified retroviruses, which contain the bacterial resistance gene NEO, to mark autologous marrow cells that had been collected from patients early in the phase of hematopoietic recovery after in vivo chemotherapy. The cells were then subjected to ex vivo CD34 selection following collection and 30% of the bone marrow were exposed to a safety-modified virus. This marrow was infused after delivery of systemic therapy, which consisted of total body irradiation (1,020 cGy), cyclophosphamide (120 mg/kg), and VP-16 (750 mg/m2). RT PCR assays specific for the bacterial NEO mRNA, which was coded for by the virus, and the bcr-abl mRNA showed that in two evaluable CML patients transplanted with marked cells, sufficient numbers of leukemia cells remained in the infused marrow to contribute to systemic relapse. In addition, both normal and leukemic cells positive for the retroviral transgenome persisted in the systemic circulation of the patients for at least 280 days posttransplant showing that the infused marrow was responsible for the return of hematopoiesis following the preparative therapy. This observation shows that it is possible to use a replication-incompetent safety-modified retrovirus in order to introduce DNA sequences into the hematopoietic cells of patients undergoing autologous bone marrow transplantation. Moreover, this data suggested that additional fractionation procedures will be necessary to reduce the probability of relapse after bone marrow transplantation in at least the advanced stages of the disease in CML patients undergoing autologous bone marrow transplantation procedures.