Allogeneic bone marrow transplantation versus chemotherapy in high-risk childhood acute lymphoblastic leukaemia in first remission

We compared the outcome of children with high-risk acute lymphoblastic leukaemia (HR-ALL) in first complete remission (first CR) treated with chemotherapy (CHEMO) or with allogeneic bone marrow transplantation (BMT) in a multicentre study.   All children treated by the Italian Paediatric Haematology Oncology Association for HR-ALL in first CR between 1986 and 1994 were eligible for the study. 30 children were given BMT at a median of 4 months from first CR, with preparative regimens including total-body irradiation ( n  =25/30). 130 matched controls for BMT patients were identified among 397 HR-ALL CHEMO patients. Matching on main prognostic factors and duration of first CR was adopted to control the selection and time-to-transplant biases. The comparative analysis was based on the results of a stratified Cox model. The estimated hazard ratios of BMT versus CHEMO at 6 months, 1 year and 2 years after CR were 1.38 (CI 0.59–3.24), 0.69 (CI 0.27–1.77) and 0.35 (CI 0.06–1{\raise 5mu ..91), with an overall non-significant difference between the two groups ( P  = 0.34). With a median follow-up of 4 years, the disease-free survival was 58.5% (SE 9.3) in the BMT group and 47.7% (SE 4.8) in the CHEMO group, at 4 years from CR. Non-leukaemic death occurred in 4% of CHEMO and 10% of BMT patients. In the BMT group the estimated cumulative incidence of relapse at 1.5 years from CR was 31.5% (SE 8.8) and did not change thereafter, whereas in the CHEMO group the corresponding figure was 29.2% (SE 4.1) and the incidence continued to increase thereafter (48.2% (SE 4.8) at 4 years from CR).   The results of this study suggest that, with respect to the CHEMO group, the higher risk of early failure in the BMT group is outweighed by the lower risk of relapse after 1 year. Results prompt the need for a prospective study, in order to demonstrate the likely advantage of BMT in HR childhood ALL in first CR.     

Hormonal and metabolic characteristics of geneticall obese Zucker and dietar obese Sprague-Dawle rats

Abstract. The endocrine-metabolic plasma pattern and the capacit of isolated perfused livers to produce triglcerides and ketone bodies have been studied in geneticall and diet-acquired obese rats (Zucker and Sprague-Dawle obese rats), and in control groups of the same strains.
An increased plasma insulin/glucagon molar ratio with hperinsulinaemia and hpoglucagonaemia was associated with hpertriglceridaemia, normal ketonaemia, elevated free fatt acids and normal or slight hperglcaemia in obese rats.
During oleate perfusion, the livers of Zucker and Sprague-Dawle obese rats showed an increase in triglceride output and liver triglceride content. The ketone bod output as well as the mitochondrial carnitine palmitol transferase activit were normal or slightl decreased.
In our rat population, a positive correlation between the insulin/glucagon molar ratio and triglceride output has been found.     

Reversible Inhibition of Cholinesterases by Opioids: Possible Pharmacological Consequences

The inhibitory potency of opioids belonging to different structural categories on electric eel and rat brain acetylcholinesterase (AChE) and horse serum butyrylcholinesterase (BuChE) was investigated. The phenylazepine meptazinol, the pyrrolo-[2,3-b]-indole derivative eseroline and the benzomorphan normetazocine were the most potent inhibitors of AChE among the compounds tested. These were followed by (-)-metazocine, N-allylnorcyclazocine, 3-(1,3-dimethyl-3-pyrrodinyl)-phenol, levallorphan, levorphanol and pentazocine. The opioids which inhibited horse serum BuChE were in order of potency: meptazinol, methadone, profadol, levallorphan and 1,2,3-trimethyl-3-(3-hydroxyphenyl)-piperidine. The results of this work appear consistent with the fact that the anticholinesterase activity of the opioids is not confined to specific structural categories, although conformationally constrained molecules, like those of morphinans, benzomorphans or pyrrolo-[2,3-b]-indoles, appear to favour affinity for AChE, whereas highly flexible molecules, like those of acyclic opioids, inhibit BuChE in a rather selective way. In all cases, the inhibitory action of opioids markedly differed from that of carbamates or organophosphorous compounds, in that it was time-independent and immediately reversible on dilution. In general the anticholinesterase action of opioids does not seem to influence appreciably the pharmacological properties of the drugs since it is evidenced at drug doses higher than those which are analgesic. However, in the case of mixed agonist/antagonist opioids with rather weak analgesic activity, the enzyme inhibition caused by the levels of circulating drugs can be so marked as to exert also a cholinergic component of action.     

Seizure outcome after extratemporal epilepsy surgery in childhood

Aim The aim of the study was to describe seizure outcome following surgery for focal extratemporal epilepsy and identify factors associated with prolonged postsurgical freedom from seizures. Method In this retrospective cohort study, children with drug‐resistant focal extratemporal epilepsy were treated surgically and followed up in a single tertiary care centre between 1997 and 2008. Results Eighty children were identified for inclusion in the study (42 males, 38 females; median age 9y 1mo, range 3mo–18y 7mo). The aetiology was identified as focal cortical dysplasia (n=37), low‐grade tumour (n=22), tuberous sclerosis (n=9), or non‐specific (n=12). Children were followed for a median of 3 years 1 month (range 8mo–10y 7mo) after surgery. Overall, at last follow‐up, 50% of the children had been completely seizure free since surgery (Engel class Ia); of these 40 individuals, 15 had discontinued all antiepileptic drugs. Several presurgical factors were associated with a favourable outcome. However, after controlling for confounding factors, aetiology appeared to be the only determinant of long‐term seizure outcome as non‐specific lesion pathology was associated with seizure recurrence (hazard ratio 10.43; 95% confidence interval 3.26–33.39). Interpretation In 50% of cases, children with surgically treated drug‐resistant extratemporal epilepsies have an excellent long‐term outcome. The aetiology of the epileptogenic lesion appears to be the only significant determinant of surgical outcome in this population of children. It is difficult to correctly identify non‐specific pathology on presurgical magnetic resonance imaging.     

24-Hour Heart Rate Variability in Patients with Vasovagal Syncope

Since alterations in the autonomic nervous system are thought to play a major role in the pathogenesis of vasovagal syncope, we characterized the chronic autonomic profile of 44 patients with syncope and 20 healthy subjects by means of heart rate variability using 24-hour Holter recordings (time- and frequency-domain indexes), and evaluated whether the different types of responses to tilting (vasodepressive versus cardioinhibitory) could be associated with different cardiac autonomic patterns. Twenty-three patients exhibited a positive response to tilting, which was vasodepressive in 11 patients and cardioinhibitory in 12 patients. All vasodepressive patients had a standard deviation of the averages of NN (SDANN) intervals in all 5-minute segments lower than 100 ms. Patients with vasodepressive syncope also had significantly lower values of RMSSD (the 24-hour square root of the mean of the sum of the squares of differences between adjacent normal RR intervals) than those with cardioinhibitory response, and lacked the day-night rhythm of the low frequency/high frequency ratio. However, only SDANN values correctly identified patients with vasodepressive response to tilting. We conclude that (1) the population of patients with vasovagal syncope is heterogeneous, (2) patients with vasodepressive syncope have a peculiar chronic autonomic profile as assessed by 24-hour heart rate variability analysis, and (3) the evaluation of the autonomic profile in 24-hour Holter recordings could be of value in the diagnosis of patients with syncope.     

IMMUNE ACTIVATION AS EFFECT MODIFIER OF ATHEROGENESIS IN CHRONIC INFECTION

Although no study has proven that infections cause atherosclerotic disease, findings suggest that exposure to infections such as Chlamydia pneumoniae, Helicobacter pylori, and bacterial infections related to periodontal disease or smoking might influence the development of heart, carotid, and peripheral vascular disease. Epidemiological data convincingly demonstrate risk for atherosclerotic disease associated with bacterial infection and endotoxemia; however, the independent contributions to disease and pathogenic mechanisms of endotoxin remained elusive. Investigation into this relation tested the correlation between endotoxin and neopterin. Data indicated that neopterin, which reflects immune activation of monocytes/macrophages, functions as atherogenic effect modifying factor on the effects of endotoxin. We hypothesize that immune activation via induction of endotoxin hyperresponsiveness determines the atherogenic potential of Gram-negative infections.