Low-dose acyclovir prophylaxis for the prevention of herpes simplex virus disease after allogeneic hematopoietic stem cell transplantation.

BACKGROUND: Currently, acyclovir (ACV) at 1000 mg/day is widely used as prophylaxis in the early phase of hematopoietic stem cell transplant (HSCT) in Japan. However, low-dose ACV (200 mg/day) has been shown to prevent varicella zoster virus reactivation in the middle and late phases of HSCT. METHODS: Therefore, in this study, we decreased the dose of ACV to 200 mg/day in the early phase after HSCT. We analyzed 93 consecutive herpes simplex virus (HSV)-seropositive patients who underwent allogeneic HSCT for the first time in our center between June 2007 and December 2011. RESULTS: Before August 2009, 38 patients received oral ACV at 1000 mg/day (ACV1000) until day 35 after HSCT, whereas 55 patients received oral ACV at 200 mg/day (ACV200) after September 2009. We compared the cumulative incidence of HSV infection in the 2 groups. Oral ACV was changed to intravenous administration because of intolerance in 66% and 45% of the patients in the ACV1000 and ACV200 groups, respectively (P = 0.060). The probability of severe stomatitis (Bearman grade II-III) was 76% and 60% in the ACV1000 and ACV200 groups, respectively (P = 0.12). The number of patients who developed HSV disease before day 100 after HSCT was 0 in the ACV1000 group and 2 in the ACV200 group, with a cumulative incidence of 3.6% (P = 0.43). HSV disease in the latter 2 patients was limited to the lips and tongue and was successfully treated with ACV or valacyclovir at a treatment dose. CONCLUSION: ACV at 200 mg/day appeared to be effective for preventing HSV disease in the early phase after HSCT.

Varicella zoster virus meningoencephalitis after allogeneic hematopoietic stem cell transplantation.

Although the reactivation of varicella zoster virus (VZV) is a common complication after allogeneic hematopoietic stem cell transplantation (HSCT), VZV meningoencephalitis is a rare life-threatening infectious disease after HSCT. We describe here a patient who developed VZV meningoencephalitis 2 years after human leukocyte antigen-matched unrelated HSCT for acute myeloblastic leukemia. She developed chronic graft-versus-host disease, and cyclosporine (CSA) was continued until 17 months after HSCT. Low-dose acyclovir (ACV) at 200 mg/day was administered to prevent the reactivation of VZV from day -7 to the termination of CSA. At 22 months, she suddenly developed fever, loss of consciousness, and seizure, with generalized skin rash. A high level of VZV DNA was detected in her cerebrospinal fluid (CSF). She was diagnosed to have VZV meningoencephalitis. Intravenous ACV at 30 mg/kg/day was given for 2 months. Although loss of consciousness was quickly resolved, some neurologic symptoms persisted. She did not have any known risk factors for VZV reactivation. Therefore, we should keep in mind that any HSCT recipient may develop VZV meningoencephalitis, and examination of CSF for VZV infection with an empiric administration of ACV may be recommended for HSCT recipients with central nervous system symptoms, even in the absence of skin manifestations.

L-index as a novel index to evaluate both the intensity and duration of lymphopenia after allogeneic hematopoietic stem cell transplantation.

We retrospectively investigated L-index, which evaluates both the intensity and duration of lymphopenia after allogeneic hematopoietic stem cell transplantation (HSCT) (n = 50). L-index was defined as the area over the lymphocyte curve during lymphopenia (absolute lymphocyte count < 700/µL). We calculated the L-index from the start of conditioning to day 30 - L-index(30) - and to day 100 - L-index(100) - after HSCT. Multivariate analysis revealed that human leukocyte antigen mismatched donor, female gender, and non-lymphoid disease were significantly associated with high L-index(30). Grade III-IV acute graft-versus-host disease, alemtuzumab-containing regimen, and non-lymphoid disease were identified as independent significant factors for high L-index(100). Cytomegalovirus (CMV) antigenemia was detected > 3 cells/2 slides by C10/11 method in 30 patients (CMV-AG ≥ 3 group) and was not detected in 20 patients (CMV-AG < 3 group). Although no significant difference was seen in absolute lymphocyte count on day 30 between the 2 groups, the L-index(30) was significantly higher in the CMV-AG ≥ 3 group than in the CMV-AG < 3 group (P = 0.050). L-index(30) was identified as an independent factor on CMV reactivation in multivariate analysis, when it was treated as a dichotomous variable with a cut-off value of 22,318, determined by receiver operating characteristic curve analysis. In conclusion, both the intensity and duration of lymphopenia in early phase after HSCT evaluated on the basis of L-index(30) showed significant association with CMV reactivation.

Identification of the amino acid residues involved in selective agonist binding in the first extracellular loop of the delta- and mu-opioid receptors.

Effects of amino acid substitutions in the first extracellular loop region of the delta- and mu-opioid receptors were examined. Substitution of lysine-108 of the delta-receptor (delta K108) with asparagine improved affinity to [D-Ala2,MePhe4,Gly-ol5]enk ephalin (DAGO), a mu-selective peptide agonist, to be comparable with that of the mu-receptor. On the other hand, replacement of mN127 with lysine decreased the affinity to DAGO by approximately 15-fold. These results suggest that dK108 and mN127, which correspond to each other in the aligned amino acid sequences, mainly determine the difference in DAGO binding affinity between the delta- and mu-receptors.

[Low dose dibutylic cyclic AMP administration during coronary artery bypass graft surgery].

To evaluate the effectiveness of low dose dibutylic cyclic AMP (DBcAMP) during coronary artery bypass graft surgery, we compared circulatory and endocrine-metabolic parameters among the three different doses: (1) DBcAMP 10 microg.kg-1.min-1 (A-10 group), (2) DBcAMP 20 microg.kg-1.min-1 (A-20 group), and (3) control (A-0 group). In the A-10 group, perfusion pressure was significantly higher than in the A-0 group at the point of maximum cooling and at the start of warming during cardiopulmonary bypass (CPB), while peripheral vascular resistance was significantly lower than in the A-0 group at the closing of CPB. On the contrary, in the A-20 group, perfusion pressure was significantly lower than in the A-0 group at the point of maximum cooling and the start of warming during CPB, while peripheral vascular resistance was significantly lower than in the A-0 group at the start of warming and the closing of CPB. Among these groups, the hourly urine volume during CPB was significantly largest in A-10 group. Endocrine-metabolic parameters showed no statistic difference among these groups. These results suggest that the administration of DBcAMP 10 microg.kg-1.min-1 during CPB might improve the cardiac performance and maintain the tissue perfusion without the endocrine-metabolic deterioration.

Single-cell T-cell receptor-ß analysis of HLA-A*2402-restricted CMV- pp65-specific cytotoxic T-cells in allogeneic hematopoietic SCT.

Cellular immunity is important for the control of CMV infection after allogeneic hematopoietic cell transplantation (Allo-HCT). However, the actual in vivo dynamics of CMV-specific cytotoxic T cell (CMV-CTL) clones are still unclear. We conducted clone monitoring of tetramer(+) CMV-CTLs in HLA-A*2402-positive donor-patient pairs, using a direct single-cell analysis that enabled the simultaneous identification and quantification of CTL clones. Clone dynamics were assessed in three cases with or without CMV reactivation. In Case-1 without CMV reactivation, despite the long-term use of systemic steroid, dominant clones of Donor-1 persisted and remained dominant. The CMV-CTLs at 1 year after Allo-HCT included a high proportion of CD45RA(+)CCR7(-) effector and CD27(-)CD57(+)mature T cells. On the other hand, in Cases-2 and -3 with CMV reactivation, novel clones appeared and became dominant during the follow-up. Their CMV-CTLs included more CD27(+) immature T cells at 1 year after Allo-HCT. With regard to clonotypes, HLA-A*2402-restricted CMV-CTLs tended to select BV7 and BJ1-1 genes for complementarity-determining region 3 (CDR3) of T-cell receptor (TCR)-ß. Specific amino-acid sequences of CDR3 of TCR-ß were found in each case. Patterns of clone reconstitution and phenotype would be different according to CMV reactivation. In vivo clone monitoring of CMV-CTLs could provide insight into the mechanism of immunological reconstitution following Allo-HCT.

Hyperbilirubinemia in the early phase after allogeneic HSCT: prognostic significance of the alkaline phosphatase/total bilirubin ratio.

Hyperbilirubinemia in the early phase after allogeneic hematopoietic SCT (HSCT) is due to various causes. One of the most important causes of hyperbilirubinemia is veno-occlusive disease/sinusoidal obstructive syndrome (VOD/SOS). However, the prognosis of patients who are clinically diagnosed as SOS varies. We retrospectively evaluated 82 patients who underwent their first allogeneic HSCT. GVHD prophylaxis was a combination of short-term MTX and CsA (n=77) or tacrolimus (n=5). Thirty-three patients developed hyperbilirubinemia, with a bilirubin level of at least 2 mg/dL, within 20 days after HSCT. Of these patients, 24 were diagnosed as VOD/SOS using the modified Seattle criteria. Twenty-six recovered to a bilirubin level of <2 mg/dL. We focused on the serum alkaline phosphatase/total bilirubin ratio (ALP/TB) at the onset of hyperbilirubinemia and found that it significantly predicted the recovery from hyperbilirubinemia. OS was significantly higher in patients with a lower ALP/TB ratio (P=0.00056). In addition, a lower ALP/TB ratio was associated with better survival even in patients who were clinically diagnosed as SOS (P<0.001). The ALP/TB ratio at the onset of hyperbilirubinemia may be a useful predictor for the prognosis of hyperbilirubinemia and SOS early after HSCT.

Prediction of transplant-related complications by C-reactive protein levels before hematopoietic SCT.

Various biomarkers have been investigated with regard to their ability to predict the outcome of allogeneic hematopoietic SCT (HSCT). In this study, we retrospectively reviewed 90 recipients who received HSCT between 2007 and 2011 in our institution, and evaluated the predictive value of the baseline serum C-reactive protein (CRP) levels just before the initiation of conditioning for transplant-related complications after allogeneic HSCT. A receiver-operating characteristic curve revealed that the baseline serum CRP levels had an excellent predictive value for non-relapse mortality (NRM), with an area under the curve of 0.83. The sensitivity and specificity for NRM were 80% and 87%, respectively, with a cutoff of 0.6 mg/dL. With this cutoff value, multivariate analyses revealed that a higher baseline CRP level was an independent risk factor for NRM (HR 6.21, P<0.01), grade III-IV acute GVHD (HR 3.91, P=0.03) and poor overall survival (HR 3.27, P=0.0018). On the other hand, the baseline CRP level did not predict infectious events. These findings suggested that CRP levels before conditioning may be a useful predictive biomarker for poor survival.

Immune recovery after autologous PBSC transplantation without in vitro graft manipulation for refractory systemic lupus erythematosus.

Autologous hematopoietic SCT (ASCT) has been investigated as salvage therapy for refractory systemic lupus erythematosus (SLE). Although immune recovery after ASCT with in vitro purging of lymphocytes has been extensively studied, little information is available about immune recovery after ASCT without in vitro purging. Therefore, we analyzed the immune recovery of a patient who successfully underwent ASCT without in vitro purging for refractory SLE. In addition to the numbers of PBL subsets, T-cell receptor rearrangement excision circles (TRECs) and the T-cell receptor repertoire diversity of both CD4+ and CD8+ T cells were sequentially analyzed. All SLE-related symptoms disappeared within 3 months after ASCT and the serum anti-dsDNA Ab became undetectable. The number of CD4+CD45RO+ memory T cells remained lower than that in healthy adult controls, but the number of CD4+CD45RA+ naïve T cells showed a rapid increase after ASCT. TRECs of both CD4+ and CD8+ T cells were strongly suppressed before ASCT, but consistently increased after ASCT. The T-cell receptor repertoire of CD8+ T cells was skewed before ASCT, but the diversity recovered after ASCT. ASCT with the reinfusion of a large number of autologous T cells did not impair the recovery of naive T cells or resetting of the immune system.

Pharmacokinetics of CsA during the switch from continuous intravenous infusion to oral administration after allogeneic hematopoietic stem cell transplantation.

We investigated the serial changes in the blood CsA concentration during the switch from continuous intravenous infusion to twice-daily oral administration in allogeneic hematopoietic stem cell transplant recipients (n=12). The microemulsion form of CsA, Neoral, was started at twice the last dose in intravenous infusion in two equally divided doses. The area under the concentration-time curve during oral administration (AUC(PO)) was significantly higher than the AUC during intravenous infusion (AUC(IV)) (median 7508 vs 6705 ng/ml x h, P=0.050). The median bioavailability of Neoral, defined as (AUC(PO)/DOSE(PO)) divided by (AUC(IV)/DOSE(IV)), was 0.685 (range, 0.45-1.04). Concomitant administration of oral voriconazole (n=4) significantly increased the bioavailability of Neoral (median 0.87 vs 0.54, P=0.017), probably due to the inhibition of gut CYP3A4 by voriconazole. Although the conversion from intravenous to oral administration of CsA at a ratio of 1:2 seemed to be appropriate in most patients, a lower conversion ratio may be better in patients taking oral voriconazole. To obtain a similar AUC, the target trough concentrations during twice-daily oral administration should be halved compared with the target concentration during continuous infusion.

Perioperative plasma concentrations of atrial and brain natriuretic peptides in patients undergoing hip arthroplasty.

Acute hypotension, transient hypoxaemia and elevation of pulmonary artery pressure are well known to occur during cemented arthroplasty. The aim of this prospective clinical study was to characterize the relationship between plasma concentrations of atrial and brain natriuretic peptides (ANP, BNP), and changes in blood pressure in patients undergoing hip arthroplasty. Elevated ANP and BNP levels may be markers of inadequate myocardial reserve. We measured plasma ANP and BNP levels before the operation and 20 minutes after the cementing in 18 patients (54-90 yr). We defined a hypotensive response after cementing as a decrease in systolic blood pressure of more than 15 mm Hg below the pre-cementing value. In the hypotensive group, preoperative values of ANP were 123 +/- 48.5 pg/ml and BNP, 138 +/- 71.7 pg/ml. These values are significantly greater than those in the normotensive group (ANP 35.9 +/- 7.7, and BNP 17.2 +/- 3.2 pg/ml). High preoperative values of ANP and BNP are associated with more hypotension during cemented arthroplasty and could provide an indication of which patients are at risk of this complication.

Disseminated intravascular coagulation in a patient undergoing removal of humeral head for pain relief.

Disseminated intravascular coagulation (DIC) was recently observed intraoperatively in a patient who required removal of her right humeral head for pain relief. Despite normal preoperative coagulation parameters, the patient developed wound oozing soon after suturing the skin. Coagulation profile revealed decreased platelets, plasma coagulation factors and fibrinogen in association with elevated fibrin degradation products. To manage the DIC, urinastatin and gabexate mesilate, along with blood component replacement, proved effective.

Platelet transfusion for surgery in the presence of polycythemia vera.

Surgery in the presence of uncontrolled polycythemia vera is associated with a high incidence of perioperative hemorrhage and postoperative venous thromboses. Control prior to surgery reduces the frequency of perioperative complications. A 73-year-old women suffering from polycythemia vera was scheduled for subtotal gastrectomy. Her platelet count before surgery was slightly elevated but bleeding time was prolonged. To manage the current case of polycythemia vera, hydroxyurea was effective for the control of hematocrit and transfusion of platelet concentrates was effective for hemostasis.

Postoperative seizure-like activity following sevoflurane anesthesia.

Generalized clonic and tonic seizure-like movements were observed during emergence from anesthesia with sevoflurane in a 32-year-old man. The movements lasted 40 sec and necessitated no therapy. There were no significant effects of the incident on the cardiovascular system, such as hypotension, arrhythmia or bradycardia. No neurological abnormalities were obvious after the anesthesia. The movements may have been the result of seizure activity in the central nervous system, or myoclonus of the whole body.

Comparison between pentazocine, pethidine and placebo in the treatment of post-anesthetic shivering.

BACKGROUND: We have compared the effects of pethidine, pentazocine and placebo in the treatment of post-anesthetic shivering. METHODS: Forty-five patients who shivered after routine surgery were allocated randomly to receive normal saline (n=15), pentazocine 7.5 mg (n=15) or pethidine 17.5 mg (n=15). RESULTS: After 10 min, 13 patients had stopped shivering in the pethidine group, which was significantly more than the incidence in the two other groups (placebo=2; pentazocine=4) (P<0.01). Pentazocine was not significantly different from normal saline in affecting shivering. CONCLUSION: We conclude that pentazocine 7.5 mg was not effective in the treatment of post-anesthetic shivering.

Halothane and enflurane constrict canine mesenteric arteries by releasing Ca2+ from intracellular Ca2+ stores.

BACKGROUND: Recent studies suggest that volatile anesthetics cause not only vasodilation but also vasoconstriction, depending on the experimental conditions. However, the mechanism of the constrictive effect of volatile anesthetics has not been clarified. The aim of this study was to evaluate the vasoconstrictor effects of halothane, enflurane, and isoflurane and to elucidate the underlying mechanism. METHODS: Vascular rings of canine mesenteric arteries were mounted in organ baths, and isometric tension changes were recorded. Changes in intracellular free Ca2+ concentration of vascular smooth muscle were examined by using the fluorescent Ca2+ indicator fura 2 and a dual-wavelength fluorometer. RESULTS: Halothane (0.75-2.3%) and enflurane (1.7-3.4%), but not isoflurane (1.2-3.5%), induced a concentration-dependent transient contraction, followed by a slight, sustained contraction. Halothane (1.5%)- and enflurane (3.4%)-induced contractions were reduced by endothelial denudation and enhanced by indomethacin (10(-5) M) treatment but were not affected by L-NG-nitroarginine (10(-5) M) or nifedipine (2 x 10(-7) M) treatment. Ryanodine (2 x 10(-5) M) treatment completely abolished the transient increases in tension and Ca2+ concentration. Even in ryanodine-treated arteries, however, both anesthetics induced a slowly developing sustained contraction, and the sustained contraction induced by enflurane (3.4%) was not accompanied by a significant increase in Ca2+ concentration. CONCLUSIONS: Halothane and enflurane, but not isoflurane, induce vasoconstriction by releasing Ca2+ from intracellular stores. Release of a vasodilating prostanoid and endothelium-derived constricting factor may also be involved in the vasoconstrictor effect. Furthermore, increased Ca2+ sensitivity of contractile machinery may be involved in the effect of enflurane.