Contrasting effects of recombinant human granulocyte-macrophage colony- stimulating factor (CSF) and granulocyte CSF treatment on the cycling of blood elements in childhood-onset cyclic neutropenia

Recombinant human granulocyte colony-stimulating factor (G-CSF) treatment has been shown to increase average neutrophil counts substantially in patients with childhood-onset cyclic neutropenia (or "cyclic hematopoiesis"), but not to eliminate the cyclic oscillations of neutrophil counts or those of other blood elements (monocytes, platelets, eosinophils, and reticulocytes) that are characteristic of this hematopoietic disorder. Indeed, oscillations of neutrophil counts are amplified during G-CSF treatment. We have compared the effects of recombinant granulocyte-macrophage-CSF (GM-CSF) with those of G-CSF in three patients with this disease (2 men and 1 woman, 17, 30, and 32 years of age). These patients were treated with GM-CSF (2.1 micrograms/kg/day, subcutaneously) for 6 weeks, preceded and followed by 6 to 13 weeks of detailed observation to document changes in the cyclic oscillations of blood neutrophils and other blood elements; two of the patients were subsequently treated with G-CSF (5.0 micrograms/kg/d, subcutaneously) and observed for comparable periods of time. Unlike G-CSF treatment, which increased average neutrophil counts more than 20-fold, GM-CSF increased neutrophil counts only modestly, from 1.6- to 3.9-fold, although eosinophilia of varying prominence was induced in each patient. However, at the same time, GM-CSF treatment dampened or eliminated the multilineage oscillations of circulating blood elements (neutrophils, monocytes, platelets, and/or reticulocytes) in each of the patients. In contrast, G-CSF treatment of the same patients markedly amplified the oscillations of neutrophil counts and caused the cycling of other blood elements (monocytes in particular) to become more distinct. These findings support the conclusion that the distinctive cycling of blood cell production in childhood-onset cyclic neutropenia results from abnormalities in the coordinate regulation of both GM-CSF-responsive, multipotential progenitor cells and G-CSF-responsive, lineage-restricted, neutrophil progenitors.     

Increased CKMB (mass concentration) in patients without traditional evidence of acute myocardial infarction. A risk indicator of coronary death.

A study of 102 patients consecutively admitted to a coronary care unit (CCU) investigated the clinical usefulness of three different immunoenzymometrical CKMB methods: NovoClone CK-MB, ICON QSR CKMB and IMx CK-MB. Blood samples were drawn on admission and then every 6 h for 48 h. The three different methods correlated very well (r = 0.93-0.96). With discrimination levels of 10 micrograms.l-1 for NovoClone CK-MB and 5 micrograms.l-1 for the other two methods, a sensitivity of 1.0 and a still acceptable specificity (> 0.81) were achieved. In the group of patients (n = 53) with suspicion of acute myocardial infarction (AMI) but with no standard criteria for AMI, 14 patients were identified with small but significant increase of serum CKMB (mass concentration) and an increased CKMB (mass concentration)/CK ratio. During a 4 year follow-up nine out of these 14 patients died within 2 years, the majority being coronary deaths, as compared to only two out of the remaining 39 non-AMI patients with suspicion of AMI but with normal CKMB values (chi 2 = 18.47, P < 0.001). The finding of such a high mortality rate among patients with increased CKMB (mass concentration) has an important prognostic value even in patients without standard criteria for AMI.     

Anti-HERG activity and the risk of drug-induced arrhythmias and sudden death.

AIMS: Drug-induced QTc-prolongation, resulting from inhibition of HERG potassium channels may lead to serious ventricular arrhythmias and sudden death. We studied the quantitative anti-HERG activity of pro-arrhythmic drugs as a risk factor for this outcome in day-to-day practice. METHODS AND RESULTS: All 284,426 case reports of suspected adverse drug reactions of drugs with known anti-HERG activity received by the International Drug Monitoring Program of the World Health Organization (WHO-UMC) up to the first quarter of 2003, were used to calculate reporting odds ratios (RORs). Cases were defined as reports of cardiac arrest, sudden death, torsade de pointes, ventricular fibrillation, and ventricular tachycardia (n = 5591), and compared with non-cases regarding the anti-HERG activity, defined as the effective therapeutic plasma concentration (ETCPunbound) divided by the HERG IC50 value, of suspected drugs. We identified a significant association of 1.93 (95% CI: 1.89-1.98) between the anti-HERG activity of drugs, measured as log10 (ETCPunbound/IC50), and reporting of serious ventricular arrhythmias and sudden death to the WHO-UMC database. CONCLUSION: Anti-HERG activity is associated with the risk of reports of serious ventricular arrhythmias and sudden death in the WHO-UMC database. These findings are in support of the value of pre-clinical HERG testing to predict pro-arrhythmic effects of medicines.     

Second primary cancer after treatment of invasive carcinoma of the uterine cervix, compared with those arising after treatment for in situ carcinomas. An effect of irradiation? A cancer registry study

A cancer registry cohort of 16,704 cases of invasive carcinoma of the uterine cervix and 56,116 cases of in situ carcinomas of the uterine cervix was followed up and second new primary cancers were recorded. The invasive carcinomas contributed 127,118 woman-years at risk and the in situ carcinomas contributed 453,362 woman-years at risk. The main treatment for the invasive carcinomas had been radiotherapy and for the in situ carcinomas, conization and other types of surgical intervention. 767 new primaries occurred after treatment of invasive carcinoma of the uterine cervix, compared with 644.5 expected. O/E is 1.19. After the in situ carcinomas, 1,421 malignant tumors were observed, vs. 1,188.0 expected (O/E 1.19). If, however, cases of invasive carcinoma of the uterine cervix after in situ carcinomas are excluded, the ratio observed/expected is 1.10. For some sites the increased observed/expected ratios were found after both invasive and in situ carcinomas, which speaks for some common carcinogenic effect other than irradiation (for instance, in bronchus and trachea, pharynx, nose, sinus and larynx, but also in rectum, urinary bladder, other female genital organs, pancreas, lymphosarcoma, as well as acute and non-lymphatic leukemia). A lower risk than expected--after both in situ and invasive carcinoma of the uterine cervix--is observed for breast cancer, cancer of the corpus uteri and for multiple myeloma. However, analyses based on time since treatment provide evidence of a carcinogenic effect of irradiation, especially in intensively irradiated organs such as bladder, rectum, corpus uteri and ovary, and also for acute and non-lymphatic leukemia.     

Parity and risk of thyroid cancer: a nested case-control study of a nationwide Swedish cohort

The association between parity and risk of thyroid cancer was examined in a case-control study nested within a cohort of Swedish women born 1925–60. A total of 1,409 cases of thyroid cancer were compared with 7,019 agematched controls. Odds ratios (OR) and 95 percent confidence intervals (CI) were calculated as estimates of relative risk. A weak association was found between parity and risk of thyroid cancer (OR for ever-parous women cf nulliparous was 1.1, CI=1.0–1.3). For the subset of papillary cancers, there was a significantly increased risk (OR for ever-parous cf nulliparous = 1.3, CI=1.0–1.6), and among women diagnosed at the age of 50 or older, there was a positive linear trend with increasing number of livebirths. Women during the first year after a livebirth had an increased risk of thyroid cancer compared with women who delivered 10 or more years before; this association was most prominent among uniparous women (OR=2.5, CI=1.1–5.9). An increased risk was also apparent for age over 20 years at livebirth (among uniparous women) and age over 25 years at last livebirth (among multiparous women). A negligible effect of parity on thyroid cancer risk was seen, but each livebirth may have a short-term and age-dependent promoting effect.Authors are with the Department of Cancer Epidemiology, University Hospital, Uppsala, Sweden (M.R. Galanti, M. Lambe, A. Ebbora, R. Sparda B. Pettersson): Department of Social Medicine, University Hospital, Uppsala, Sweden (M. Lambe); Department of Epidemiology, Harvard School of Public Health, Boston, USA (A. Ekbom). Address correspondence to Dr M. Rosaria Galanti, Department of Cancer Epidemiology, University Hospital, S-751 85 Uppsala, Sweden. This work was supported in part by grant n. 3136-B92-02XBB from the Swedish Cancer Society.     

Environmental Monitoring of the Kafue River, Located in the Copperbelt, Zambia

Zambia is a country with an extensive mining industry with the majority of mines located in the Copperbelt province. Through this region of the country, the Kafue River drains and receives effluent water from mining activities as well as from other industrial point sources. In addition, production of agricultural products and pest control requires use of different pesticides in the area. Information on industrial and agricultural pollution has not been clearly identified in Zambia, and little attention has been paid to pollution control and possible impact of metals, pesticides, and other persistent compounds in the environment. The objective of this study was to introduce and to evaluate a few methodologies based on in situ bioassays for environmental assessment to promote sustainable and environmentally sound water resource management of the Kafue River. The results show that caged threespot tilapia exposed downstream of industrial points sources rapidly bioaccumulate several trace elements, i.e., Cd, Co, Cu, Cr, Ni. These elements also occurred in much higher concentrations in water samples downstream of the industrial area compared with a locality upstream. Furthermore, the use of a semipermeable membrane device (SPMD) for passive absorption of lipophilic pollutants in the water showed relatively high concentration of several pesticides, i.e., DDT with major metabolites, PCB, and dieldrin. The present study shows that only 2 weeks of in situ studies in waters contaminated by pollutants affects in situ exposed fish and that the correlation between water and tissue concentrations was relatively good. Both trace elements and persistent organic pollutants occurred in such high concentrations that they must be considered from ecotoxicological aspects and may affect aquatic animal health. Received: 31 January 1999/Accepted: 20 September 1999     

Instrumental perforation of the oesophagus. A ten year study from two ENT clinics

During the 10-year period 1972-1981, 3,688 and 867 oesophagoscopies were performed at two ENT clinics of a university hospital and of a county hospital with an incidence of oesophageal perforation of 0.8 per cent and 1.1 per cent respectively. Rigid instruments were used in all cases, most often in combination with dilatation of a benign stricture.     

A comparative study of size and function of the remnant kidney in patients nephrectomized in childhood for Wilms' tumor and hydronephrosis

To obtain more information about the natural history of compensatory renal hypertrophy beginning in childhood we traced those who were nephrectomized in childhood for Wilm's tumor (W) and hydronephrosis (Hn) between 1950 and 1978 at one department of surgery in Stockholm. All W patients had received treatment that suppresses cellular division. None of the patients were in renal failure or treated with antihypertensive drugs. All the patients in the follow-up study (22 W, 15 Hn) had a normal contralateral kidney at nephrectomy. Five healthy adults served as controls. The kidney was enlarged in both Hn (142%) and W (125%), but significantly larger in Hn than in W. Renal compensatory growth in W was retarded during the first two years after nephrectomy. The glomerular filtration rate (GFR) was 92% of control in Hn and 82% of control in W. The GFR did not seem to decline with a longer follow-up time in any of the groups. PAH clearance was the same in Hn and W. Albumin excretion was significantly higher in Hn than in W, but not significantly higher in W than in controls. The highest albumin excretion rates were found among the Hn patients with long follow-up time. The results suggest that the large increases in size and function that follow childhood nephrectomy can be blunted by antimitotic agents.     

The use of biodegradable PGA stents to judge the risk of post-TURP incontinence in patients with combined bladder outlet obstruction and overactive bladder

OBJECTIVE: For patients with the combination of severe bladder outlet obstruction (BOO) and severe overactive bladder (OB), no straightforward and safe treatment exists due to the risk of urge incontinence after TURP. In this study we have used a biodegradable polyglycolic stent to simulate the status after TURP and register the risk for urge incontinence. METHODS: A total of 37 patients with severe OB, combined with moderate to severe BOO, were asked if they wanted to participate. Under cystoscopic vision a polyglycolic biodegradable stent was inserted in the prostatic urethra. RESULTS: Twenty-five of the patients noticed no or only minor leakage and 19 of these have been subjected to TURP with good results. Three patients are on the waiting-list for TURP. Twelve of 37 patients were found to have major leakage after stent insertion. During the stent period, we noted five cases of complications, due to UTI, stent crash and irritation. All of these patients recovered within three weeks. CONCLUSIONS: A biodegradable PGA stent seems to be a new and unique tool to test the risk for post-TURP incontinence in patients with combined BOO and severe OB.     

Styrene emissions from the spray-up and vacuum injection processes--a quantitative comparison

Styrene emissions were studied during manufacturing of two identical glass-fiber reinforced plastic boats by two different manufacturing methods. The manufacturing methods were spray-up, which is an open method, and vacuum injection, which is a closed method. Changing the manufacturing process from an open method to a closed method decreased the styrene evaporation dramatically in this particular case. By using vacuum injection, the styrene emission during the laminate application was reduced by 98% compared with the styrene emission during laminate application by spray-up. Gel coat application by spraying will remain a major source for styrene emissions. The greatest environmental benefit is achieved with closed manufacturing methods when products without gel coat are made. The whole manufacturing process can then be performed in a closed system virtually free from emissions.