Valganciclovir Dosing According to Body Surface Area and Renal Function in Pediatric Solid Organ Transplant Recipients

Oral valganciclovir is effective prophylaxis for cytomegalovirus (CMV) disease in adults receiving solid organ transplantation (SOT). However, data in pediatrics are limited. This study evaluated the pharmacokinetics and safety of valganciclovir oral solution or tablets in 63 pediatric SOT recipients at risk of CMV disease, including 17 recipients ≤2 years old. Patients received up to 100 days' valganciclovir prophylaxis; dosage was calculated using the algorithm: dose (mg) = 7 × body surface area × creatinine clearance (Schwartz method; CrCLS). Ganciclovir pharmacokinetics were described using a population pharmacokinetic approach. Safety endpoints were measured up to week 26. Mean estimated ganciclovir exposures showed no clear relationship to either body size or renal function, indicating that the dosing algorithm adequately accounted for both these variables. Mean ganciclovir exposures, across age groups and organ recipient groups were: kidney 51.8 ± 11.9 μg * h/mL; liver 61.7 ± 29.5 μg * h/mL; heart 58.0 ± 21.8 μg * h/mL. Treatment was well tolerated, with a safety profile similar to that in adults. Seven serious treatment-related adverse events (AEs) occurred in five patients. Two patients had CMV viremia during treatment but none experienced CMV disease. In conclusion, a valganciclovir-dosing algorithm that adjusted for body surface area and renal function provides ganciclovir exposures similar to those established as safe and effective in adults     

Risk of thrombosis during coronary angioplasty with low osmolality contrast media

Studies in vitro have suggested that nonionic low osmolar contrast agents produce an increase in thrombogenicity. To determine the incidence of thrombi related to the use of nonionic low osmolar contrast media during coronary angioplasty, a double-blind randomized study was performed in 100 patients. Medication before angioplasty included oral aspirin (250 mg/day) in all cases. At the beginning of the procedure, aspirin (250 mg) and heparin (10,000 U) were intravenously administered. During the procedure patients were randomly assigned to receive either an ionic low osmolar contrast agent ioxaglate (n = 50), or a nonionic low osmolar contrast media iohexol (n = 50). The presence of thrombus was evaluated on the angiogram and on the guidewire immediately after its retrieval from the patients. Clinical, angiographic and procedural variables were similar in the 2 randomized groups. Angiographic evidence of thrombus was observed in 1 patient (2%) assigned to ioxaglate and in 11 patients (22%) assigned to iohexol (p less than 0.005). One patient (2%) from the ioxaglate group and 6 patients (12%) from the iohexol group showed thrombotic residues on the guidewire (p = not significant). Three patients had acute myocardial infarction, 1 patient (2%) receiving ioxaglate and 2 patients (4%) iohexol (p = not significant). There were no deaths. Thus, compared with an ionic low osmolar contrast media ioxaglate, the nonionic low osmolar contrast agent iohexol increases the incidence of thrombus during coronary angioplasty.     

Decreased infectivity despite unaltered C3 binding by a DeltahbhA mutant of Mycobacterium tuberculosis

HbhA of Mycobacterium tuberculosis is a multifunctional binding protein, binding to both sulfated sugars such as heparin and to human complement component C3. HbhA may therefore interact with host molecules and/or host cells during M. tuberculosis infection and play a role in the pathogenesis of this bacterium. The purpose of this study was to use allelic exchange to create an M. tuberculosis strain deficient in expression of HbhA to determine whether this protein's C3-binding activity plays a role in the pathogenesis of M. tuberculosis. An in-frame, 576-bp unmarked deletion in the hbhA gene was created using sacB as a counterselectable marker. Southern blotting and PCR analyses confirmed deletion of hbhA in the DeltahbhA mutant. The DeltahbhA mutant strain grew at a rate similar to that of the parent in broth culture and in J774.A1 murine macrophage-like cells but was deficient in growth compared to the parent strain in the lungs, liver, and spleen of infected mice. In addition, the DeltahbhA mutation did not reduce binding of M. tuberculosis to human C3 or to J774.A1 cells in the presence or absence of serum, suggesting that in the absence of HbhA, other molecules serve as C3-binding molecules on the M. tuberculosis surface. Taken together, these data indicate that HbhA is important in the infectivity of M. tuberculosis, but its ability to bind C3 is not required for mycobacterial adherence to macrophage-like cells. Using the DeltahbhA mutant strain, a second M. tuberculosis C3-binding protein similar in size to HbhA was identified as HupB, but the role of HupB as a C3-binding protein in intact organisms remains to be determined.     

Latex agglutination for rapid identification of methicillin-resistantStaphylococcus aureus recovered from selective media

The accuracy of combining latex agglutination with selective media for the identification of methicillin-resistantStaphylococcus aureus (MRSA) was determined. Test strains were identified by latex agglutination on blood agar, the heat-stable thermonuclease test and broth microdilution MICs of oxacillin and included 97 MRSA, 56 methicillin-susceptibleStaphylococcus aureus, 52 methicillin resistant, and 49 methicillin-susceptibleStaphylococcus species. Isolates were grown on trypticase-soy agar with 5 % sheep red blood cells (TSAB), Mueller-Hinton agar (MHA), mannitol-salt agar (MSA), and four media designed for the selective growth of MRSA: TSAB with clindamycin and gentamicin, MHA with oxacillin, MSA with oxacillin, and lipovitellin-salt-mannitol agar (LVSM) with 1 µg oxacillin disks applied. The mean sensitivity, specificity, and positive predictive value for the combination of latex agglutination with selective media for the identification of MRSA was 96 %, 99 % and 98 % respectively.     

Human natural killer cell lysis of Salmonella typhi intracellularly-infected U937 cells

Peripheral blood mononuclear cell (PBMC) cytotoxicity against S. typhi (wild type or mutant strain TYT1231)-infected U937 cells was significantly higher than its lytic effect against noninfected cells (control) at the various effector-to-target cell ratio used (30:1, 50:1 and 70:1). Natural killer cell activity [expressed as % specific lysis (mean +/- SEM); 30:1 (25.4 +/- 3.6, 25.1 +/- 4.2 and 16.3 +/- 3.3); 50:1 (27.8 +/- 3.7, 26.7 +/- 4.5 and 20.9 +/- 2.9) and 70:1 ratio (33.2 +/- 5.9, 29.4 +/- 4.2 and 22.8 +/- 2.8), respectively] appeared to be dependent on such ratios and independent of the S strain studied. Most (80%) of individual samples tested showed at least a 20% specific lysis increase over their own control; essentially no changes or smaller increases in NKC activity were observed in all other samples. Similar results were obtained when using highly purified NKC (HPNKC) preparations as effector cells [NKC activity (mean +/- SEM); 5:1 (46.2 +/- 4.7, 43.2 +/- 5.0 and 25.2 +/- 2.3) and 10:1 effector-to-target cell ratio (49.3 +/- 4.9, 44.7 +/- 5.2 and 27.2 +/- 2.6, respectively)]. All individual samples tested showed at least a 20% specific lysis increase over their own control. These results show that S. typhi-infected U937 cells are a significantly better target for NKCs than control cells and indicate that intracellular bacteria survival capacity is not a critical factor for infected cells becoming a NKC target.     

Influence of Various Immunomodulators on the Induction of Experimental Autoimmune Encephalomyelitis in Lewis Rats

The effect of various immunomodulators on the induction of experimental autoimmune encephalomyelitis (EAE) is evaluated in the Lewis rat. Bordetella pertussis (BP) is the optimal inductor of EAE in this rat strain. Treatment of the animals with BP either before or after or simultaneously with guinea-pig spinal cord preparation (GpSC) resulted in an EAE about two weeks thereafter. Additional injection of living BCG, of CFA, IFA (incomplete Freund's adjuvant) or Vibrio cholerae neuraminidase (VCN) did not augment or mitigate the effect induced by BP or GpSC. Living BCG, IFA, VCN or Corynebacterium parvum (CP) did not induce EAE when given in combination with GpSC but without BP. CFA combined with GpSC only occasionally induced EAE. However, EAE could be induced by the combination of CFA and GpSC or IFA and GpSC in a part of the animals tested if they had been pretreated or simultaneously been injected with living BCG by intravenous route. EAE could not be enhanced by the additional injection of VCN. Surprisingly, most of the animals peracutely died after injection of CFA and BP in combination with GpSC when they had been pretreated with CP. This effect was most pronounced when pretreatment was done on day -4. No acute effect could be seen when CP was given simultaneously to CFA, BP and GpSC. Animals which did not peracutely succumb developed EAE similarly as those in the positive control groups. CP treatment simultaneously with BP but without CFA resulted in a reduction of the EAE specific mortality. This reduction could not be seen if treatment with CP was done after injection of GpSC and BP.     

Anchorage and lymphocyte function. Acquisition of spontaneous motile behaviour by human blood lymphocytes and its modulation by concanavalin A.

The majority of splenic lymphocytes were motile, showing lamellipodial activity almost immediately after purification. In contrast, fresh blood lymphocytes were non-motile and maintained their spherical suspension morphology. The number of motile blood lymphocytes increased markedly during a 2-day in vitro culture period. This increase was enhanced by high cell density and required a metabolically active cell with protein synthesis but not exogenous mitogens. The spontaneous development of motility in different subpopulations of blood lymphocytes was analysed by means of monoclonal antibodies. The results indicated that cells which were motile immediately after purification were almost exclusively non-T lymphocytes. Lymphocytes which became motile during in vitro culture included both T and non-T cells. Substrate adhesion mediated by concanavalin A (Con A) changed the morphology of motile T lymphocytes and instead of being polar, the cells flattened over the substratum and acquired a non-polar shape. Furthermore, the morphogenetic response induced by Con A-mediated substrate adhesion appeared to distinguish T and non-T lymphocytes. Thus, the length of the cell perimeter showing lamellar activity was greater in T than in non-T lymphocytes, and the degree of polarity was greater in non-T (with and without B-cell markers) than in T lymphocytes.     

Chile's health sector reform: lessons from four reform periods

This paper applies an interdisciplinary approach to analyze the process of health reform in four significant periods in Chilean history: (1) the consolidation of state responsibility for public health in the 1920s, (2) the creation of the state-run National Health Service in the 1950s, (3) the decentralization of primary care and privatization of health insurance in the 1980s, and (4) the strengthening of the mixed public-private market in the 1990s. Building on the authors' separate disciplines, the paper examines the epidemiological, political and economic contexts of these reforms to test simple hypotheses about how these factors shape reform adoption and implementation. The analysis underlines: (1) the importance of epidemiological data as an impetus to public policy; (2) the inhibiting role of economic recession in adoption and implementation of reforms: and (3) the importance of the congruence of reforms with underlying political ideology in civil society. The paper also tests several hypotheses about the reform processes themselves, exploring the role of antecedents, interest groups, and consensus-building in the policy process. It found that incremental processes building on antecedent trends characterize most reform efforts. However, interest group politics and consensus building were found to be complex processes that are not easily captured by the simple hypotheses that were tested. The interdisciplinary approach is found to be a promising form of analysis and suggests further theoretical and empirical issues to be explored.     

Clinical features of hepatic artery thrombosis after pediatric liver transplantation

Thrombosis of the hepatic artery (HAT) is a severe complication of liver transplantation, and most cases need regrafting. The aim of this study was to review our experience with this complication. From January 1986 through January 1992, 76 liver transplants were performed in 59 pediatric patients at the Children's Hospital La Paz, Madrid. The diagnosis of HAT was made in 12 cases (15.7%). The common patterns of clinical presentation were: fulminant liver necrosis (5), bile leak due to necrosis of the bile duct (4), and relapsing bacteremia (3). Clinical symptoms of fulminant liver necrosis started within the first 2 weeks after transplantation, with rapid deterioration and steep rises in SGOT and SGPT levels. All these patients were retransplanted on an urgent basis, but only 1 is alive 4 years later. Four patients developed bile leaks 13 to 60 days after transplantation; SGOT, SGPT, and total bilirubin were only slightly increased. Three children were retransplanted electively and are alive with a mean follow-up of 3 years. One exceptional patient had a Roux-en-Y jejunostomy and is doing well 30 months later with his original graft. The 3 remaining children had episodes of septicemia with hepatic abscess, liver infarction, and pleural effusion. Liver function tests were normal, with bilirubin levels below 2 mg/dl. All patients were retransplanted, but only 1 is alive and well 13 months later. In the present series, we found that early HAT produces fulminant clinical deterioration requiring an urgent regraft. Late HAT presenting with either infection or bile leak allows time for treatment by elective retransplantation. The best survival was obtained in the latter group. Correspondence to: J. Vázquez     

Use of three-dimensional MR angiography for tracking a contrast bolus in the carotid artery

Contrast-bolus tracking in the carotid bifurcation was accomplished using an MR angiographic technique with a 3D turbo field-echo readout (TR/TE = 6/3, flip angle = 50 degrees) modified by a keyhole scheme. Optimal visibility of the contrast bolus was achieved by digital subtraction from a reference volume. This technique reliably time-resolves the carotid arteries from the jugular veins.