Passage of irinotecan and its active metabolite, SN-38, into human milk.

WHAT IS KNOWN AND OBJECTIVE: We measured the levels of irinotecan and its active metabolite, SN-38, in human milk after the administration of irinotecan to assess the potential risks when women treated with irinotecan nurse their infants. CASE SUMMARY: Human milk was collected for 6 days starting on the day after irinotecan was administered. The levels of irinotecan and SN-38 in human milk were measured using liquid chromatography-mass spectrometry. Irinotecan was detected on Days 2 and 3 but not after Day 4. A strong signal indicating the presence of SN-38 was detected on Day 2 and the signal was readily detected until Day 7, indicating that SN-38 remained in human milk. WHAT IS NEW AND CONCLUSION: Intravenously administered CPT-11 continues to pass into human milk over a prolonged period in the form of its active metabolite, SN-38. The relationship between administration of CPT-11 and SN-38 exposure and toxicity is still not well defined, so patients should avoid nursing their infants while they are being treated with CPT-11.

Acupuncture for reducing pruritus induced by intrathecal morphine at elective cesarean delivery: a placebo-controlled, randomized, double-blind trial.

BACKGROUND: Intrathecal morphine is a standard postoperative analgesic administered after cesarean delivery, but frequently causes pruritus. Acupuncture reportedly resolves refractory pruritus in certain patients. The aim of the study was to investigate the effectiveness of acupuncture in preventing pruritus induced by intrathecal morphine. METHODS: Thirty parturients received intrathecal hyperbaric bupivacaine (12 mg), fentanyl (10 µg), and morphine (150 µg) for spinal anesthesia at elective cesarean delivery at term. Patients were randomly divided into the acupuncture group (n=15) and the control group (n=15). In the acupuncture and control groups, certified acupuncturists inserted either indwelling press needles or sham needles, into Hegu (LI4), Neiguan (PC6), Quchi (LI11), and Zhigou (SJ6) on both arms the day before surgery. Needles were removed 48 hours postoperatively. The primary outcome was the incidence of postoperative pruritus. Adverse effects including nausea and vomiting were also investigated. RESULTS: There were no significant differences between the acupuncture group and the control group in the incidence of pruritus (67% vs. 67%, P=1.000, RR 1.0 [95% CI 0.60 to 1.66]) or the requirement for antipruritic therapy (6.7% vs. 20.0%, P=0.283, RR 0.33 [95% CI 0.04 to 2.85]). The incidence of postoperative nausea in the acupuncture group versus control group was 40.0% vs. 13.3%, P=0.099, RR 3.0 [95% CI 0.72 to 12.6]). The postoperative analgesic effect was comparable. CONCLUSION: Preoperatively administered acupuncture using press needles did not decrease intrathecal morphine-induced pruritus or the requirement for treatment.

Physical association of the patient-specific GATA1 mutants with RUNX1 in acute megakaryoblastic leukemia accompanying Down syndrome.

Mutations of the GATA1 gene on chromosome X have been found in almost all cases of transient myeloproliferative disorder and acute megakaryoblastic leukemia (AMKL) accompanying Down syndrome (DS). Although most GATA1 mutations lead to the expression of GATA1s lacking the N-terminal activation domain, we recently found two novel GATA1 proteins with defects in another N-terminal region. It has been suggested that loss of the N-terminal portion of GATA1 might interfere with physiological interactions with the critical megakaryocytic transcription factor RUNX1, and this would imply that GATA1s is not able to interact properly with RUNX1. However, the interaction domain of GATA1 remains controversial. In this study, we show that GATA1 binds to RUNX1 through its zinc-finger domains, and that the C-finger is indispensable for synergy with RUNX1. All of the patient-specific GATA1 mutants interacted efficiently with RUNX1 and retained their ability to act synergistically with RUNX1 on the megakaryocytic GP1balpha promoter, whereas the levels of transcriptional activities were diverse among the mutants. Thus, our data indicate that physical interaction and synergy between GATA1 and RUNX1 are retained in DS-AMKL, although it is still possible that increased RUNX1 activity plays a role in the development of leukemia in DS.

A case of thyrotropin-producing pituitary adenoma, accompanied by an increase in anti-thyrotropin receptor antibody after tumor resection.

We describe a rare, but interesting, case of TSH-producing adenoma (TSHoma), accompanied by increases in both anti-TSH receptor antibody (TRAb) and thyroid-stimulating antibody (TSAb) after tumor resection. A 21-yr-old woman was referred to our department for further evaluation of pituitary tumor. In a nearby hospital, she had been diagnosed as having pituitary tumor. Her serum free T4, free T3, and TSH levels were all elevated concomitantly. On the basis of a diagnosis of pituitary adenoma with TSH production, transsphenoidal resection of the pituitary adenoma was performed. Two weeks after the operation, the blood concentrations of TSH were undetectable, whereas both TRAb and TSAb levels were elevated. TSAb levels gradually increased further from 2 weeks to 3 months after the operation, accompanied by an increase in TSH and free T4 levels. TSH is an important hormone in maintaining physiology and regulating immunomodulators in thyrocytes, as it can influence a variety of immune-regulating cytokine-like activities and inhibit expressions of Fas antigen, intracellular adhesion molecule-1, and class II trans-activator. Changes in TSH would modulate the immune circumstances in the thyroid, and then induce TRAb and TSAb. Autoimmune parameters with thyroid function should be observed carefully when managing patients with TSHoma.

Risk stratification for congenital diaphragmatic hernia by factors within 24 h after birth.

OBJECTIVE: To establish a simple risk stratification system for patients with congenital diaphragmatic hernia (CDH) based on postnatal information within 24 h after birth. STUDY DESIGN: A multi-institutional retrospective cohort study was conducted including 348 neonates who had isolated CDH born between 2006 and 2010. Based on the two most powerful variables for 90-day survival selected by multivariate analyses, a risk stratification system was established. RESULTS: Multiple logistic regression analysis identified two adverse prognostic factors: an Apgar score at 1 min (Ap1) of 0-4 (odds ratio (OR) 3.3, P=0.004), and a best oxygenation index (OI) ⩾8.0 (OR 11.4, P<0.001). Based on a combinations of these two factors, patients were classified into three risk categories. The 90-day survival rates in categories 1-3 were 100, 88 and 52%, respectively (P<0.001). CONCLUSION: Our simple risk stratification system based on Ap1 and best OI was capable of predicting mortality well.

A novel mutation of the thiazide-sensitive sodium chloride cotransporter gene in a Japanese family with Gitelman syndrome.

Gitelman syndrome is an inherited renal disorder characterized by impaired NaCl reabsorption in the distal convoluted tubule leading to hypokalemia, hypomagnesemia and normocalcemic hypocalciuria. It has been shown that this syndrome results from mutations in the gene encoding the thiazide-sensitive sodium chloride cotransporter (TSC). We performed the mutational analysis in the TSC gene of a 30-year-old Japanese woman with Gitelman syndrome and found two mutations at adjacent spots in both alleles. One was a frame shift mutation which generated stop codon at position 671, the other was a single nucleotide mutation, which resulted in an aminoacid substitution at position 672, Met to Ile. Her 52-year-old mother and two daughters had neither hypokalemia nor hypomagnesemia. However, her mother and her 8-year-old daughter had the Met672Ile mutation as heterozygotes. Her 4-year-old daughter had the same frame shift mutation as her mother, a heterozygotic mutation. These results suggest that Gitelman syndrome requires 2 compound heterozygotic mutations and the coexistence of the large deletion in the C-terminal domain with Met672Ile substitution of the TSC could impair the transporter activity underling the hypokalemia and hypomagnesemia in this patient.

Gene analysis of the calcium channel 1 subunit and clinical studies for two patients with hypokalemic periodic paralysis.

Hypokalemic periodic paralysis (HypoPP) is a skeletal muscle disorder in which episodic attacks of muscle weakness occur; they are associated with decreased serum potassium (K+) levels. Recent molecular approaches have clarified that the condition is caused by mutations in the skeletal muscle voltage-gated calcium channel 1 subunit (CACNA1S). We describe two unrelated patients with HypoPP, followed by their relevant clinical studies and gene analysis. Clinical studies included an oral glucose tolerance test (OGTT), food-loading and insulin tolerance tests (ITT). For Case 1, serum K+ levels were extremely decreased following insulin tolerance testing compared with levels for controls. These results support the hypothesis that no efflux of K+ ion occurs in patients because of low activity of adenosine triphosphate (ATP)-sensitive K+ channel (KATP) channels. Mutational analysis of the CACNA1S gene showed a duplicate insertion of 14 base pairs (bp) from 52 to 65 in intron 26, present in the heterozygous state in both patients. No other mutations were detected in the CACNA1S gene, the muscle sodium channel gene (SCN4A) or the voltage-gated K+ channel gene (KCN3) of either patient. Further analysis showed that this duplicate insertion of 14 bp in intron 26 of the CACNA1S gene was found in 23.7% of healthy subjects. K+ dynamics studies are useful for confirming this syndrome, while further gene analysis for various ion channels using amplification and direct sequencing are required to evaluate the molecular basis of the disorder in the individual patient.

Anesthetic management for cesarean section in moyamoya disease: a report of five consecutive cases and a mini-review.

We report five consecutive cases of neuraxial anesthesia for cesarean section in women with moyamoya disease. Either epidural or combined spinal-epidural anesthesia was provided, with adequate sedation using intravenous diazepam and/or opioid(s). Hemodynamic stability and normocapnia were well maintained, except in one patient who exhibited transient hypertension and hypocapnia due to anxiety. None of the parturients suffered from neurological deficit in the intra- or postoperative period, although one patient complained of numbness in her fingers at the end of surgery, but she was not hypotensive or hypocapneic. The neonates were all in good health. The literature is reviewed on the anesthetic management for cesarean section in patients with moyamoya disease.

Functional characterization of the two alternative promoters of human p45 NF-E2 gene.

OBJECTIVE: The transcription factor NF-E2, a heterodimeric protein complex composed of p45 and small Maf family proteins, is considered crucial for the proper differentiation of erythrocytes and megakaryocytes in vivo. We report the results of studies aimed at understanding the regulatory mechanisms controlling p45 gene expression in erythroid cells. MATERIALS AND METHODS: Human p45 mRNAs have two alternative isoforms, aNF-E2 and fNF-E2, and these isoforms are transcribed from the alternative promoters. We investigated lineage-specific expression of both isomers in human erythroid and megakaryocytic cells by reverse transcriptase polymerase chain reaction or Northern blot analysis. For functional characterization of both promoters, plasmids in which reporter genes were placed under the control of a series of truncated or mutated promoter fragments were transfected to human hematopoietic cell lines. RESULTS: When CD34(+) cells isolated from human cord blood were induced to unilineage erythroid or megakaryocytic differentiation in liquid suspension culture, both transcripts, although barely detected at day 0, were induced in both erythroid and megakaryocytic cultures. fNF-E2 mRNA was found to be more abundant in erythroid cells than megakaryocytic cells at day 7 of culture. Although both isomers were expressed in human erythroid-megakaryocytic cell lines, megakaryocytic maturation with loss of erythroid phenotype induced by phorbol 12-myristate 13-acetate (PMA) resulted in exclusive downregulation of fNF-E2, suggesting that fNF-E2 promoter is more erythroid specific. Functional analysis of fNF-E2 promoter showed that the promoter is active only in erythroid-megakaryocytic cells and that the double GATA site in the proximal region is necessary for its efficient activity. CONCLUSION: These results suggest that GATA proteins, which govern the differentiation of erythroid lineage cells, are required for full promoter activity of the p45 gene.

Electroencephalographic responses to the formalin test in rats.

The formalin test is an animal model of persistent pain. Although biphasic behavioral responses to formalin injection have been well described, the significance of the biphasic time course of the pain behaviors has not been established. To explore the significance of the behavioral responses to the formalin injection, we measured and analyzed cortical electroencephalogram (EEG) during the formalin tests in rats. Formalin was injected subcutaneously in the hindpaw of freely moving rats, and behavioral responses were visually counted and recorded. Results were compared with a control group which received saline injection. Neocortical EEG was recorded from implanted dural surface electrodes and analyzed using a Fast Fourier Transformation. Formalin produced biphasic pain behaviors with a transient pause between two phases. Cortical EEG recordings showed a biphasic change; a vigilant pattern (a low amplitude high frequency activity) followed by a non-vigilant pattern (a high amplitude low frequency activity), showing a good correlation with apparent arousal states of rats. Observed discrepancies between pain behaviors and EEG-measured vigilance stages included (1) a vigilant EEG pattern persisted during the transient pause of pain behavior, and (2) pain behaviors persisted even after non-vigilant EEG pattern became dominant. The results of the current study showed that there are temporal discrepancies between the pain behaviors and EEG-measured vigilance during the formalin test in rats. The temporal relationship between the 'pain' behaviors and nociception per se may not be as solid as believed.

Coronary vasodilation and positive inotropism by urocortin in the isolated rat heart.

Corticotropin-releasing factor (CRF) has a coronary vasodilator effect and a positive inotropic effect on the isolated rat heart. Recently, expression of CRF receptor type 2 (CRF-R2) has been demonstrated in the heart. In addition, urocortin (Ucn), a new member of the CRF family, has been reported to have much greater affinity for CRF-R2 than CRF. It is suggested that the cardiac effects of Ucn may be more potent than those of CRF. We compared the effect of Ucn with that of CRF on isolated rat heart. The effects of Ucn were then analyzed to determine whether these effects were mediated by CRF receptors and/or any other mediators under the following conditions: perfusion buffer containing (1) alpha-helical CRF 9-41, (2) indomethacin, (3) N(G)-nitro-l -arginine methylester and (4) propranolol. Ucn exhibited a greater effect with a longer duration of action than CRF. Indomethacin significantly attenuated the vasodilator effects of Ucn (P<0.05). CRF receptor antagonist diminished both coronary vasodilation and the positive inotropic effects of Ucn (P<0.05). These results suggest that the cardiac effects of Ucn may be mediated by a CRF receptor, and prostaglandins may be involved in the vasodilator effect.

Lack of clinical utility of minimal residual disease detection in allogeneic stem cell recipients with childhood acute lymphoblastic leukemia: multi-institutional collaborative study in Japan.

The clinical utility of minimal residual disease (MRD) measurements following allogeneic stem cell transplantation (SCT) in childhood ALL is controversial. We therefore performed a multi-institutional study of MRD in bone marrow samples taken before SCT and at 1, 3, 6 and 12 months after SCT. Case-specific clonal rearrangements of IgH and TCR genes and expression levels of Wilms' tumor 1 (WT1) mRNA were determined by PCR or RT-PCR methods. In total, 95 cases met all criteria for analysis of informative IgH/TCR markers and quantitative WT1 mRNA expression levels. During the 2-year (median 414 days) study period, 20 patients relapsed. Although the proportion of patients with a positive IgH/TCR result before SCT was significantly reduced at 1 month after treatment (P<0.001), attesting the efficacy of SCT, serial measurements of IgH/TCR rearrangements did not correlate with leukemic relapse. Clonal switch was demonstrated in 11 of the 14 patients with bone marrow relapse, indicating that the poor predictive power of the MRD assay most likely reflected the loss of PCR targets. WT1 expression was not related to either MRD detection by IgH/TCR assays or to clinical leukemic relapse. The clinical value of serial MRD monitoring would be limited in ALL patients undergoing SCT.

Effect of xenon on autonomic cardiovascular control--comparison with isoflurane and nitrous oxide.

STUDY OBJECTIVES: To clarify the effect of xenon on the autonomic nervous system by comparing similar effects of isoflurane and nitrous oxide. DESIGN: Prospective, randomized study. SETTING: Operating room at a university hospital. PATIENTS: 39 ASA physical status I and II patients scheduled for general anesthesia. INTERVENTIONS: Patients were randomly allocated into one of three groups and received one of the following inhalational anesthetics: 56% of xenon (Group X), 0.94% of isoflurane (Group I), or 70% of nitrous oxide and 0.15% of isoflurane (Group N). Phenylephrine (pressor test) and nicardipine (depressor test) were given to assess baroreflex sensitivity. MEASUREMENTS AND MAIN RESULTS: Continuous blood pressure (BP) and electrocardiogram (ECG) were recorded before and during anesthesia to analyze heart rate (HR) variability and baroreflex sensitivity. Power spectrum of HR variability was calculated by fast Fourier transformation and power spectrum densities at low frequency (LF: 0.04-0.15Hz) and high frequency (HF: 0.15-0.40 Hz) were compared. Baroreflex sensitivity was calculated from the slope of regression for BP changes versus associated changes in R-R intervals. For HR variability, Group X showed lower power spectrum densities (ms(2).Hz(-1)) in LF and HF than did Group I (LF: 0.09 +/- 0.06 vs. 0.35 +/- 0.53; p < 0.05; HF: 0.40 +/- 0.34 vs. 0.98 +/- 0.68, p < 0.01). Group X had the lowest baroreflex sensitivity (ms.mmHg(-1)) via pressor test of the three study groups (Group X: 2.00 +/- 0.87, Group I: 3.53 +/- 2.14, Group N: 3.78 +/- 2. 17, p < 0.05). CONCLUSIONS: Xenon depressed both sympathetic and parasympathetic transmission more than isoflurane at 0.8 MAC. Xenon was also suggested to be relatively vagotonic.

Effect of xenon on endotracheal tube cuff.

STUDY DESIGN: To investigate the effect of xenon on the endotracheal tube cuff in comparison to that of nitrous oxide. DESIGN: Prospective, randomized study. SETTING: Laboratory in vitro testing of endotracheal tubes. INTERVENTIONS: Exposure of air-filled endotracheal tube cuffs to xenon or nitrous oxide (79 vol%) mixed with a balance of oxygen (21 vol%) for 3 hours. MEASUREMENTS: The intra-cuff pressure and gas volume in the cuff were measured for 3 hours. MAIN RESULTS AND CONCLUSION: Increase in pressure and gas volume was significantly less and slower with xenon than with nitrous oxide. More nitrous oxide passes into the cuff than xenon.

Preoperative pulse wave velocity fails to predict hemodynamic responses to anesthesia and to surgical stimulation.

STUDY OBJECTIVE: To determine whether pulse wave velocity (PWV), which is a useful indicator of cardiovascular disease, can predict the hemodynamic responses to anesthesia and surgical stimulation in surgical patients. DESIGN: Prospective, randomized study. SETTING: Operating rooms at a university hospital. PATIENTS: 30 ASA physical status I and II female patients presenting for elective gynecologic surgery. INTERVENTION: Patients who received one of the following anesthesia techniques were studied; isoflurane, sevoflurane and sevoflurane with nitrous oxide (N2O). MEASUREMENTS AND MAIN RESULTS: Patients underwent preoperative PWV measurements using an automatic PWV measurement device. Systolic blood pressure and heart rate levels were recorded at baseline, during anesthesia, and at skin incision. PWV had no significant correlation with percent changes of systolic blood pressure or heart rate, even after controlling the choice of anesthetic drugs. CONCLUSIONS: Preoperative PWV fails to predict hemodynamic responses to anesthesia and to surgical stimulation.

Xenon suppresses the hypnotic arousal in response to surgical stimulation.

STUDY OBJECTIVE: To evaluate the suppressive effects of xenon (Xe) on hypnotic arousal at skin incision. DESIGN: Prospective, randomized study. SETTING: Operating rooms at a university hospital. PATIENTS: 35 ASA physical status I and II patients presenting for elective lower abdominal surgery. INTERVENTIONS: Patients were randomly assigned to receive one of the following regimens: 1.3 minimum alveolar concentration (MAC) isoflurane, 1.3 MAC sevoflurane, 0.7 MAC Xe with 0.6 MAC sevoflurane, 1 MAC Xe with 0.3 MAC sevoflurane, or 0.7 MAC nitrous oxide (N2O) with 0.6 MAC sevoflurane (n = 7 each group). MEASUREMENTS AND MAIN RESULTS: The bispectral index (BIS) was measured at baseline, during anesthesia, and after skin incision. BIS increased significantly at skin incision from the values noted during anesthesia in the sevoflurane and N2O groups, whereas it remained stable at incision in the other three groups (mean change in BIS: 0 +/- 9 for isoflurane, 15 +/- 8 for sevoflurane, 5 +/- 6 for 0.7 MAC Xe, 4 +/- 11 for 1 MAC Xe, and 9 +/- 5 for N2O). CONCLUSIONS: Unlike N2O, Xe was able to suppress hypnotic arousal in response to surgical stimulation when administered with sevoflurane.

[Retardation of platelet recovery after autologous stem cell transplantation in a patient with acute lymphoblastic leukemia: possible role of decreased thrombopoietin production by bone marrow stromal cells].

A 16-year-old boy was diagnosed as having acute lymphoblastic leukemia and underwent autologous stem cell transplantation at the time of his second complete remission. Retardation of platelet recovery was evident at day 90 (< 5 x 10(4)/microliter), and at day 660 after transplantation the platelet count was 8.5 x 10(4)/microliter. Neutrophils and RBCs showed only slightly retarded recovery. Bone marrow stromal cells, which are thought to play an integral role in megakaryopoiesis, were examined. Although TPO mRNA expression per cell was normal, CFU-F was significantly decreased, resulting in a decrease of total TPO mRNA expression. In contrast, expression of G-CSF mRNA per cell was increased. It was thought that chemotherapy before bone marrow transplantation may have reduced the number of stromal cells, leading to retardation of platelet recovery because of low TPO expression.

[Acute megakaryoblastic leukemia with complex chromosomal aberrations].

A case of acute megakaryoblastic leukemia with complex chromosomal aberrations is reported. A 63-year-old man was admitted to our hospital because of pancytopenia. Bone marrow aspiration resulted in a dry tap and biopsy showed hypoplastic marrow with fibrosis. Blast cells in the peripheral blood were identified as megakaryoblasts because they were positive for electron microscopic platelet peroxidase (PPO). In addition, monoclonal antibody, TP80, to platelet glycoprotein II b-III a reacted with in about 26% of the blast cells. Chromosomal analysis of the peripheral blood revealed a mosaic pattern of a normal karyotype and abnormal ones, including 44, XY, -5, -7, -18, 10q-, +marker.

[Respiratory arrest after a ventriculoscopic surgery in infants: two case reports].

Case-1: A 4 month old, 7120 g, girl with hydrocephalus underwent endoscopic fenestration of the septum pellucidum. Her development had been normal without signs or symptoms of intracranial hypertension. She had no history of convulsion or apnea. Ventriculoscopic diagnosis was complete obstruction of the right foramen of Monro and partial defect of right ependyma. Intraoperative course was uneventful under general anesthesia. She had two episodes of respiratory arrest accompanied with myoclonus and the left conjugate deviation 15 min after extubation. Postoperative CT scan showed no abnormal findings such as intracranial hemorrhage. The respiratory arrest and conjugate deviation disappeared after phenobarbital administration. She had no further respiratory arrest. Case-2: A 1-month old boy with congenital hydrocephalus underwent endoscopic third ventriculostomy. He had no signs or symptoms of intracranial hypertension. CT scan showed enlargement of lateral ventricle and third ventricle due to aqueductal stenosis. Respiratory arrest was noted 10 min after extubation in the recovery room. His anterior fontanel sank abnormally and rigidity of the extremities was observed. His trachea was reintubated and he was transferred to ICU. After 24 h of respiratory care in the ICU he was extubated and discharged to the ward. He had no further episodes of respiratory arrest. We believe that postanesthetic apnea monitoring is mandatory in young infants who undergo ventriculoscopic surgery.