Autoantibodies against glutamate receptor δ2 after allogenic stem cell transplantation.

OBJECTIVE: To report on a Caucasian patient who developed steroid-responsive transverse myelitis, graft vs host disease of the gut, and anti-GluRδ2 after allogenic stem cell transplantation. METHODS: Histoimmunoprecipitation (HIP) with the patient's serum and cryosections of rat and porcine cerebellum followed by mass spectrometry was used to identify the autoantigen. Correct identification was verified by indirect immunofluorescence using recombinant GluRδ2 expressed in HEK293 cells. RESULTS: The patient's serum produced a granular staining of the cerebellar molecular layer (immunoglobulin G1 and immunoglobulin G3; endpoint titer: 1:1,000) but did not react with other CNS tissues or 28 established recombinant neural autoantigens. HIP revealed a unique protein band at ∼110 kDa that was identified as GluRδ2. The patient's serum also stained GluRδ2 transfected but not mock-transfected HEK293 cells. Control sera from 38 patients with multiple sclerosis, 85 patients with other neural autoantibodies, and 205 healthy blood donors were negative for anti-GluRδ2. Preadsorption with lysate from HEK293-GluRδ2 neutralized the patient's tissue reaction whereas control lysate had no effect. In addition to anti-GluRδ2, the patient's serum contained immunoglobulin G autoantibodies against the pancreatic glycoprotein CUZD1, which are known to be markers of Crohn disease. CONCLUSIONS: In the present case, the development of anti-GluRδ2 was associated with transverse myelitis, which was supposedly triggered by the stem cell transplantation. Similar to encephalitis in conjunction with anti-GluRδ2 reported in a few Japanese patients, the patient's neurologic symptoms ameliorated after steroid therapy.

Evaluation of 5-fluorouracil pharmacokinetics in cancer patients with a c.1905+1G>A mutation in DPYD by means of a Bayesian limited sampling strategy.

BACKGROUND AND OBJECTIVE: Dihydropyrimidine dehydrogenase (DPD) is the initial enzyme in the catabolism of 5-fluorouracil (5FU) and DPD deficiency is an important pharmacogenetic syndrome. So far, only very limited information is available regarding the pharmacokinetics of 5FU in patients with a (partial) DPD deficiency and no limited sampling models have been developed taking into account the non-linear pharmacokinetic behaviour of 5FU. The aim of this study was to evaluate the pharmacokinetics of 5FU and to develop a limited sampling strategy to detect decreased 5FU elimination in patients with a c.1905+1G>A-related DPD deficiency. METHODS: Thirty patients, heterozygous for the c.1905+1G>A mutation in DPYD, and 18 control patients received a dose of 5FU 300 mg/m2 and/or 5FU 450 mg/m2, followed by pharmacokinetic analysis of the 5FU plasma levels. A population pharmacokinetic analysis was performed in order to develop a compartmental pharmacokinetic model suitable for a limited sampling strategy. Clinical aspects of treating DPD-deficient patients with 5FU-based chemotherapy were assessed from the retrospectively collected clinical data. RESULTS: In a two-compartment model with Michaelis-Menten elimination, the mean maximum enzymatic conversion capacity (V(max)) value was 40% lower in DPD-deficient patients compared with controls (p < 0.001). Using a limited sampling strategy, with V(max) values calculated from 5FU concentrations at 30 or 60 minutes, significant differences were observed between DPD-deficient patients and controls at both dose levels (p < 0.001). The positive predictive value and negative predictive value for V(max), calculated from 5FU levels at 60 minutes, were 96% and 88%, respectively, in patients treated with a single dose of 5FU 300 mg/m2. All seven DPD-deficient patients (two males and five females) who had been genotyped prior to initiation of standard 5FU-containing chemotherapy developed grade 3-4 toxicity, with one case of lethal toxicity in a female patient. No grade 4 toxicity or lethal outcome was observed in 13 DPD-deficient patients treated with reduced doses of 5FU. The average dose of 5FU in DPD-deficient patients with mild toxicity (grade ≤2) was 61 ± 16% of the normal 5FU dose (n = 10). CONCLUSIONS: Profound differences in the elimination of 5FU could be detected between DPD-deficient patients and control patients. Pharmacokinetic 5FU profiling, using a single 5FU concentration at 60 minutes, may be useful for identification of DPD-deficient patients in order to reduce severe toxicity. Furthermore, treatment of DPD-deficient patients with standard 5FU-containing chemotherapy was associated with severe (lethal) toxicity.

Incidence and risk factors for medical complications after carotid artery stenting.

OBJECTIVE: Carotid angioplasty and stenting (CAS) is being evaluated as an alternative to carotid endarterectomy for the treatment of carotid artery stenosis; however, to date little is known about the incidence of medical complications after CAS. The goal of this study was to determine the frequency of, and to identify potential clinical risk factors for, the development of medical complications after CAS. METHODS: Medical complications that occurred < or = 30 days after CAS in 327 consecutive patients (241 men, 86 women; mean age, 69 +/- 9 years; range, 45 to 90 years) treated for symptomatic (n = 182, 56%) or asymptomatic (n = 145, 44%) carotid artery stenosis were recorded. The effect of clinical characteristics on the subsequent development of medical complications was analyzed by logistic regression. RESULTS: Fifty-one patients (15%) had 62 medical complications: 3 (0.9%) myocardial infarctions, 3 (0.9%) cardiac arrhythmias, 4 (1.2%) episodes of angina pectoris, 3 (0.9%) episodes of symptomatic hypertension, 16 (4.9%) episodes of symptomatic hypotension, 10 (3.1%) chest infections, 9 (2.7%) had periods of confusion, 5 (1.5%) had urinary retention, and 9 (2.7%) urinary tract infections. One chest infection was fatal and 16 complications prolonged the intensive care unit monitoring period > 24 hours. Advanced age (odds ratio [OR], 1.1; 95% confidence interval [CI], 1.05 to 1.14) and a symptomatic carotid stenosis (OR, 2.1; 95% CI, 1.07 to 4.1) independently predicted the occurrence of medical complications. CONCLUSION: Although life-threatening or fatal non-neurologic events were uncommon in this series, the overall incidence of medical complications after CAS might be higher than currently anticipated. Older and symptomatic patients are at the highest risk, and these subgroups should be monitored closely.

Short-term effect of cigarette smoking on CO(2)-induced vasomotor reactivity in man: a study with near-infrared spectroscopy and tanscranial Doppler sonography.

Cigarette smoking is a major risk factor for stroke, and quitting reduces the stroke risk within a few years. The aim of our study was to clarify whether CO(2)-induced vasomotor reactivity (VMR) is impaired in smokers after smoking a cigarette as a possible factor of an increased stroke risk. We compared VMR of 23 healthy smokers assessed at baseline, immediately, and 30 min after smoking a cigarette (1.2 mg nicotine) with values from nonsmoking, age-matched controls (n=24), obtained at identical time intervals. Cerebral blood flow velocities (CBFV) of both middle cerebral arteries (transcranial Doppler sonography), changes in concentration of cerebral oxygenated, deoxygenated, and total hemoglobin (HbO(2), Hb, and HbT, near-infrared spectroscopy), mean arterial blood pressure (MAP), and skin blood flow were recorded during normo- and hypercapnia. VMR was calculated as percentage change in CBFV and as micromolar change in concentration of HbO(2), Hb, and HbT per 1% increase in endtidal CO(2). CBFV in smokers was increased at baseline (left, p<0.05; right, p=0.05), immediately (p<0.01), and 30 min after smoking (p<0.05) as compared with nonsmokers. MAP rose immediately after smoking (p<0.01) and declined after 30 min. VMR in smokers at baseline did not differ from controls, decreased immediately after smoking (p<0.05), and normalized after 30 min (p>0.05). Increased baseline CBFV in smokers after smoking might be due to arteriolar dilation, increased MAP, and possibly constriction of basal cerebral arteries. Impaired VMR for about 30 min after smoking reflects endothelial dysfunction. This might contribute to the enhanced stroke risk in smokers.

Acute effects of cigarette smoking on cerebral oxygenation and hemodynamics: a combined study with near-infrared spectroscopy and transcranial Doppler sonography.

Cigarette smoking has been shown to increase cerebral blood flow velocity (CBFV) and reduce vasomotor reactivity temporarily. The aim of our study was to clarify whether this results from dilation of resistance vessels alone with subsequent increase in regional cerebral blood flow (rCBF), or an additional constriction of basal cerebral arteries. In 24 healthy smokers (mean age+/-S.D., 32.7+/-10.5 years), cerebral oxygenation and hemodynamics were monitored by transcranial Doppler sonography and near-infrared spectroscopy before, during, and after smoking a cigarette (nicotine 0.9 mg). We simultaneously recorded CBFV of both middle cerebral arteries, mean arterial blood pressure, skin blood flow, end-tidal CO(2), changes in concentration of cerebral oxyhemoglobin, deoxyhemoglobin, and total hemoglobin (micromol/l), and a cerebral tissue oxygenation index. Smoking increased CBFV (p<0.01), oxyhemoglobin (p<0.01), and total hemoglobin (p<0.01). After smoking, the increase in CBFV and total hemoglobin persisted (p<0.01), while oxyhemoglobin returned to baseline. Deoxyhemoglobin and cerebral tissue oxygenation index did not change during the whole procedure. During, but not after smoking, CBFV increase was correlated to ipsilateral changes in oxyhemoglobin and total hemoglobin (p<0.05). The increase in oxyhemoglobin only during smoking and the lack of changes in deoxyhemoglobin and cerebral tissue oxygenation index indicate that smoking did not substantially increase rCBF. The smoking-induced elevation in CBFV might therefore be due to an additional constriction of the middle cerebral artery. The combined effects of smoking on basal cerebral arteries and arterioles might contribute to the increased stroke risk in smokers.

Preserved CO(2) reactivity and increase in middle cerebral arterial blood flow velocity during laparoscopic surgery in children.

UNLABELLED: In adult patients, the creation of pneumoperitoneum (PP) by means of carbon dioxide (CO(2)) insufflation leads to an increase in cerebral blood flow velocity (CBFV), which is thought to be caused by hypercapnia. We evaluated whether PP leads to an increase of CBFV in children, and whether this increase is directly related to PP. The effects of PP on middle cerebral artery blood flow velocity were investigated in 12 children (mean age 3 yr, range 15-63 mo) undergoing laparoscopic herniorrhaphy under general anesthesia with sevoflurane and nitrous oxide/oxygen. CBFV was measured by using transcranial Doppler ultrasonography. During CO(2) insufflation, the end-tidal CO(2) concentration was kept constant by adjustment of ventilation by increasing minute volume. The CBFV increased significantly at an intraabdominal pressure of 12 mm Hg compared with baseline from 68 +/- 11 cm/s to 81 +/- 12 cm/s (P < 0.05). CO(2) reactivity remained in the normal range (4.0% +/- 1.9%/mm Hg) during PP. We conclude that the induction of PP leads to an increase in middle cerebral artery blood flow velocity in young children independent from hypercapnia, whereas CO(2) reactivity remains normal. IMPLICATIONS: Laparoscopic surgery is performed frequently in pediatric patients. Cerebral blood flow velocities increase during insufflation of the intraperitoneal cavity for minimally invasive surgery in children. The vasoreactivity as part of the cerebral autoregulation remains unaffected.