CYP2D6 polymorphism in systemic lupus erythematosus patients

Objectives: To determine whether patients with idiopathic systemic lupus erythematosus (SLE) are associated with impaired CYP2D6 activity and to gain insight into whether there is an association between particular CYP2D6 genotypes and susceptibility to SLE, and whether CYP2D6 polymorphism is linked to any specific clinical features of SLE. Methods: Debrisoquine sulfate (10 mg p.o.) was given to 159 healthy volunteers and 39 idiopathic SLE patients. Genotypic assay was carried out in 80 healthy volunteers and 32 patients. A 10-ml blood sample was drawn for genotypic assay. Debrisoquine and 4-hydroxydebrisoquine were determined in 8-h urine samples. Blood samples were analysed for the presence of mutations in the CYP2D6 gene, by using polymerase chain reaction (PCR) specific for CYP2D6*3 and CYP2D6*4 alleles. Results: The metabolic ratio of debrisoquine to 4-hydroxydebrisoquine ranged from 0.01 to 86.98 in healthy subjects and from 0.02 to 96 in SLE patients. We observed the poor metabolizer(PM) debrisoquine phenotype in three of 39 patients with idiopathic SLE (7.6%) and five of 159 healthy subjects (3.1%). There was no significant difference in the frequency of PM phenotypes between idiopathic SLE and healthy subjects (Fisher's exact test, P = 0.19). No significant difference in the distribution of overall genotypes and allele frequencies were observed between the two groups. No significant relationships were found between specific clinical features and the overall genotype. Conclusion: The results of this study confirm that CYP2D6 activity is not impaired in SLE and that there is no association between SLE and phenotypic CYP2D6 status. The results also showed that there was no difference in the frequency of CYP2D6A and CYP2D6B alleles between controls and patients with SLE. Received: 14 May 1998 / Accepted in revised form: 19 October 1998     

Endothelium-dependent vasodilation in the isolated rabbit kidney following in vivo and in vitro ischaemia and reperfusion: effects of antagonizing platelet activating factor (PAF)

Renal ischaemia-reperfusion (I/R) is a pathological condition occurring frequently after transplantation and acute renal failure. A mediator thought to play a role in the disturbed haemodynamics of I/R is platelet activating factor (PAF). We studied endothelium-dependent (acetylcholine, ACh) and -independent (sodium nitroprusside, SNP) vasorelaxant responses and the effect of BN 52021, a PAF antagonist, in the isolated perfused rabbit kidney after in vivo and in vitro I/R. Anaesthetized rabbits underwent right nephrectomy and 1 h left renal artery clamping followed by 30min reperfusion with blood. In another group, kidneys were isolated and, after transferral to the perfusion system, the perfusion pump was turned off for 1 h, followed by 30min reperfusion with Krebs' solution. BN 52021 or its vehicle dimethylsulphoxide (DMSO) was administered 20min before left renal artery occlusion or turning off the pump. Although in vitro I/R did not influence ACh-induced responses, in vivo I/R caused a decrease which was prevented by BN 52021. SNP-induced responses did not change in in vitro I/R and decreased only at lower concentrations in in vivo I/R, whereby pretreatment with BN 52021 did not offer any protection. It is concluded that in vivo I/R diminishes ACh-induced endothelium-dependent vasodilation, possibly via PAF and blood components, whereas SNP-induced endothelium-independent vasodilation was not altered by in vivo and in vitro ischaemia in the isolated rabbit kidney.     

The effect of polycythemic hyperviscosity on ischemic bowel necrosis

It is known that polycythemia decreases the fluidity of the blood and impairs tissue perfusion due to red-cell sludging in the microcirculation. In this study, the effect of polycythemic hyperviscosity (PH) on bowel necrosis was evaluated in an experimental model of intestinal ischemia. Twenty-eight Wistar albino rats (90–170 g) were divided into two groups: group 1 was transfused to create hyperviscosity and then intestinal ischemia was produced (n = 16); in group 2 ischemia was produced without transfusion (n = 12). Intestinal ischemia was produced by clamping the superior mesenteric artery and the collateral arcades of the right colic artery for 30 min. Gross and histopathologic evaluations were performed by either immediate necropsy or relaparotomy 24 h later. Microscopic findings were graded from 0 to 3 according to the degree of ischemic changes. In group 1, 2 animals (12.5%) died before 24 h postoperatively; coagulation necrosis with grade 2 or 3 ischemic changes was observed in 10 animals (62.5%). In group 2 only a few hypertrophied Peyer's patches and capillary dilation were found, and all histopathologic changes were between grades 0 and 1. The difference between the histopathologic gradings of the two groups was significant (P < 0.001). It appears that in addition to reduced splanchnic blood flow, a secondary effect of PH is needed to induce ischemic coagulation necrosis. PH of the newborn must be considered a risk factor for necrotizing enterocolitis, so-called spontaneous intestinal perforations, and even intestinal atresia.Presented at the 1st European Congress of Pediatric Surgery, Graz/Austria, May 4–6, 1995     

Granulocyte colony-stimulating factor in neutropenic, pediatric solid tumor patients following chemotherapy

Granulocyte colony-stimulating factor (G-CSF) has been used to reduce the duration and/or degree of neutropenia of different etiologies in recent years. In this study, experience with the use of G-CSF (Neupogen, Roche) after 123 courses of highly myelosuppressive chemotherapy administered to 31 (20 female, 11 male) patients with pediatric solid tumors is reported. G-CSF was initialed at a white blood cell (WBC) count of 918 ± 452/μL (100-2000), at a dose of 7.6 ± 2.3 μg/kgl/d (5-14) subcutaneously for 5.2 ± 2.4 days (2-18). G-CSF was given for afebrile neutropenia after 82 and for febrile neutropenia after 41 courses. Only in two episodes where G-CSF was given for afebrile neutropenia, fever developed. The average hospitalization period for febrile neutropenia was 9.8 ± 3.3 days (5-20). Chemotherapy could be given on scheduled time and dosage in 90% of the courses in which G-CSF was used for afebrile neutropenia. G-CSF was well tolerated. Bone pain was observed in two patients and urticaria in one patient. In conclusion, G-CSF increased the WBC count effectively, there were only two febrile episodes in 82 courses in children receiving G-CSF for afebrile neutropenia, it was well tolerated, and it was found to be feasible for use in a developing country.     

Hypozincaemia in febrile convulsion

To understand further the role of trace elements in the pathogenesis of febrile convulsions, serum zinc (Zn), copper (Cu), magnesium (Mg) and CSF Zn, Cu, Mg and protein levels were measured by spectrometry in patients with febrile convulsion (n=19), bacterial meningitis (n=9), viral CNS infection (n=16) and in the control groupn=10) which consisted of children with signs of meningeal irritation due to upper respiratory tract infection but normal CSF findings. Samples were obtained within 6 h after admission to hospital. Mean serum and CSF Zn levels in the febrile convulsion group were significantly lower than in the other groups (for serum Zn: 0.66±0.03 mg/l vs 0.98±0.07 mg/l, 1.06±0.08 mg/l, 1.05±0.09 mg/lP<0.05; for CSF Zn: 22.96±1.62 g/l vs 75.47 ±6.9 g/l, 50.32±5.235 g/l, 39.85 ±2.81 g/lP<0.05). A linear relationship was established between serum Zn and CSF Zn levels (P<0.001). Mean CSF Zn, Cu and protein levels in the bacterial meningitis group were significantly higher than in the other groups (for CSF Cu 63.94±6.33 g/l vs 38.77±2.70 g/l, 35.84±3.48 g/l, 33.86±2.88 g/lP<0.05; for CSF protein 0.80 ± 0.12 g/l vs 0.22±0.02 g/l, 0.53±0.08 g/l, 0.19±0.01 g/lP<0.05). In children with meningitis, the elevation of the mean CSF Zn and Cu levels may result from the breakdown of the blood-brain barrier and subsequent leakage of trace elements and protein from serum to CSF. There was no significant difference between the four groups in terms of mean serum Mg and mean CSF Mg levels.Conclusion Serum and CSF Zn levels are decreased in children with febrile seizures. Zinc deprivation may play a role in the pathogenesis of febrile seizures.     

Bilateral traumatic abducens nerve paralysis with cervical spine flexion injury

Bilateral traumatic abducens nerve palsy is a rare condition. We report a case associated with cervical spine flexion injury. This may be the first such case report, as no similar case was found in our review of the literature. The mechanisms of injury in this case are relevant to theories that explain hyperextension injuries.     

Germline mutations of the p53 gene in children with malignant solid tumors

Although somatic mutations of p53 are the most common genetic changes observed to date, the frequency of germline p53 mutations is found to be very low in sporadic malignant tumors. It has been postulated that de novo germline p53 mutations may occur in a substantial population of patients in pediatric age group, who die of their disease and do not propagate the mutation. To determine the frequency and type of p53 germline mutations in pediatric patients, we screened 65 children who were consecutively admitted with primary malignant solid tumors.     

Plasma protein binding of prednisolone in normal volunteers and arthritic patients

Summary The plasma binding of prednisolone was studied in twenty normal volunteers and twenty rheumatoid arthritis patients. An in vitro assessment of the binding following the addition of prednisolone, prednisone, and hydrocortisone to the plasmas obtained from the subjects showed significant differences in the percentage of prednisolone bound. However, the differences observed were regarded as clinically insignificant. The plasma protein binding was determined by an in vitro equilibrium dialysis of the individual plasma samples at 37° C. Prednisolone levels on both sides of the dialysis membrane were determined using radioactivity and HPLC analytical methodologies. The percentages of prednisolone bound calculated from the analytical results of either the radiochemical or HPLC method were not significantly different. The change in the percentage of prednisolone bound to plasma proteins was studied as a function of the total prednisolone plasma concentration in a normal volunteer and in a systemic lupus erythematosis patient. As a result of prednisolone binding to both transcortin and albumin, the binding of prednisolone changes as a function of prednisolone concentration. The binding data were fitted using nonlinear least squares regression, and the affinity constants for the binding of prednisolone to transcortin and albumin were estimated.     

Is there significance of the choice of prone versus supine position in the treatment of proximal ureter stones with extracorporeal shock wave lithotripsy?

OBJECTIVE: To determine whether there is a significance of the choice of prone versus supine position in the treatment of proximal ureter stones with extracorporeal shock wave lithothripsy (ESWL). METHODS: Ninety-six patients with proximal ureter stones underwent ESWL. The procedure was performed in the supine position in 48 of them (group 1) and in the prone position in the other 48 patients (group 2). Stone-free rates, repeat ESWL rates, shocks per patient and shocks per session were compared in both groups. RESULTS: The mean session number per patients was 1.64+/-0.75 in group 1 and 1. 33+/-0.59 in group 2 (p = 0.224). The stone-free rates 3 months after ESWL were 88.3% in group 1 and 90.6% in group 2. The difference between the results was statistically insignificant (p<0.05). Therefore, these two parameters were similar in both groups. On the other hand, the number of shocks per session was 4,863.54+/-2, 114.85 in group 1 and 3,704.16+/-1,726.75 in group 2. This difference was statistically significant (p = 0.011). The patients tolerated the supine position better in general. Patients in the prone position experienced discomfort on inspiration and expiration and pain localized to the lumbar vertebrae. CONCLUSION: These results suggest that the supine position decreases the number of shocks per session in the treatment of proximal ureter stones with ESWL and this will be cost-effective.