We screened for malaria in 594 blood samples from febrile patients who tested negative by a Plasmodium falciparum-specific histidine-rich protein-2-based rapid diagnostic test at 12 health facilities in Zanzibar districts North A and Micheweni, from May to August 2010. Screening was with microscopy, polymerase chain reaction (PCR) targeting the cytochrome b gene (cytbPCR) of the four major human malaria species, and quantitative PCR (qPCR). The prevalence of cytbPCR-detectable malaria infection was 2% (12 of 594), including 8 P. falciparum, 3 Plasmodium malariae, and 1 Plasmodium vivax infections. Microscopy identified 4 of 8 P. falciparum infections. Parasite density as estimated by microscopy or qPCR was > 4,000 parasites/μL in 5 of 8 cytbPCR-detectable P. falciparum infections. The infections that were missed by the rapid diagnostic test represent a particular challenge in malaria elimination settings and highlight the need for more sensitive point-of-care diagnostic tools to improve case detection of all human malaria species in febrile patients.
Genetic polymorphisms in the malaria parasite Plasmodium falciparum mediate alterations in sensitivity to important antimalarial drugs. Surveillance for these polymorphisms is helpful in assessing the prevalence of drug resistance and designing strategies for malaria control. Multiple methods are available for the assessment of P. falciparum genetic polymorphisms, but they suffer from low throughput, technical limitations, and high cost. We have optimized and tested a multiplex ligase detection reaction-fluorescent microsphere (LDR-FM) assay for the identification of important P. falciparum genetic polymorphisms. For 84 clinical samples from Kampala, Uganda, a region where both transmission intensity and infection complexity are high, DNA was extracted from dried blood spots, genes of interest were amplified, amplicons were subjected to multiplex ligase detection reactions to add bead-specific oligonucleotides and biotin, fragments were hybridized to magnetic beads, and polymorphism prevalences were assessed fluorometrically in a multiplex format. A total of 19 alleles from the pfcrt, pfmdr1, pfmrp1, pfdhfr, and pfdhps genes were analyzed by LDR-FM and restriction fragment length polymorphism (RFLP) analyses. Considering samples with results from the two assays, concordance between the assays was good, with 78 to 100% of results identical at individual alleles, most nonconcordant results differing only between a mixed and pure genotype call, and full disagreement at individual alleles in only 0 to 3% of results. We estimate that the LDR-FM assay offers much higher throughput and lower cost than RFLP. Our results suggest that the LDR-FM system offers an accurate high-throughput means of classifying genetic polymorphisms in field samples of P. falciparum.
Malnutrition is a significant clinical problem in infants with biliary atresia. The natural history of poor growth and its potential association with early transplantation or death in children with biliary atresia was determined. Serial weight- and length-for-age z-scores were computed as part of a retrospective study of 100 infants who underwent hepatoportoenterostomy (HPE) for biliary atresia at 9 U.S. pediatric centers between 1997 and 2000. Poor outcome was defined as transplantation or death by 24 months of age (n = 46) and good outcome was defined as survival with native liver at 24 months of age with total serum bilirubin less than 6 mg/dL (n = 54). Growth velocity was significantly slower in the poor outcome group compared to the good outcome group (P < 0.001 for both weight and length). Mean weight z-scores were significantly lower by 6 months after HPE in the poor outcome group (−2.1 ± 1.4) compared to the good outcome group (−1.2 ± 1.4) (P < 0.001). In a subgroup with total bilirubin between 2 and 6 mg/dL at 3 months after HPE (n = 28), the weight z-scores at 3 months after HPE were significantly lower in the poor outcome group (−2.0 ± 1.2) compared to the good outcome group (−1.0 ± 1.2) (P = 0.04) despite similar bilirubin concentrations.
Growth failure after HPE was associated with transplantation or death by 24 months of age. The combination of intermediate bilirubin concentrations and poor mean weight z-scores 3 months after HPE was also associated with poor clinical outcome.
With increasing resistance to existing antimalarials, there is an urgent need to discover new drugs at affordable prices for countries in which malaria is endemic. One approach to the development of new antimalarial drugs is to improve upon existing antimalarial agents, such as the tetracyclines. Tetracyclines exhibit potent, albeit relatively slow, action against malaria parasites, and doxycycline is used for both treatment (with other agents) and prevention of malaria. We synthesized 18 novel 7-position modified tetracycline derivatives and screened them for activity against cultured malaria parasites. Compounds with potent in vitro activity and other favorable drug properties were further tested in a rodent malaria model. Ten compounds inhibited the development of cultured Plasmodium falciparum with a 50% inhibitory concentration (IC50) after 96 h of incubation of <30 nM, demonstrating activity markedly superior to that of doxycycline (IC50 at 96 h of 320 nM). Most compounds showed little mammalian cell cytotoxicity and no evidence of in vitro phototoxicity. In a murine Plasmodium berghei model, 13 compounds demonstrated improved activity relative to that of doxycycline. In summary, 7-position modified tetracyclines offer improved activity against malaria parasites compared to doxycycline. Optimized compounds may allow lower doses for treatment and chemoprophylaxis. If safety margins are adequate, dosing in children, the group at greatest risk for malaria in countries in which it is endemic, may be feasible.
Biliary atresia (BA) frequently results in portal hypertension (PHT), complications of which lead to significant morbidity and mortality. The Childhood Liver Disease Research and Education Network (ChiLDREN) was utilized to perform a cross-sectional multi-centered analysis of PHT in children with BA.
BA subjects receiving medical management at a ChiLDREN site were enrolled. A priori, clinically evident PHT was defined as “definite” when there was either 1) history of a complication of PHT or 2) clinical findings consistent with PHT (both splenomegaly and thrombocytopenia). PHT was denoted as “possible” if one of the findings was present in the absence of a complication, while PHT was “absent” if none of the criteria were met.
163 subjects were enrolled between May 2006 and December 2009. At baseline, definite PHT was present in 49%, possible in 17% and absent in 34% of subjects. Demographics, growth and anthropometrics were similar amongst the 3 PHT categories. ALT, GGTP, and sodium levels were similar, while there were significant differences in AST, AST/ALT, albumin, total bilirubin, PT, WBC, platelet count and AST/platelet between definite and absent PHT. Thirty-four percent of those with definite PHT had either PT > 15s or albumin < 3 g/L.
Clinically definable PHT is present in two thirds of North American long-term BA survivors with their native livers. The presence of PHT is associated with measures of hepatic injury and dysfunction, although in this selected cohort the degree of hepatic dysfunction is relatively mild and growth is preserved.
varices; pediatric; ascites; hepatopulmonary syndrome; hypersplenism
The antiretroviral drug efavirenz (EFV) and the antimalarial artemisinin-based combination therapy (ACT) artemether-lumefantrine (AL) are commonly co-administered to treat HIV and malaria. EFV is a known inducer of cytochrome P450 3A4, which converts artemether to dihydroartemisinin (DHA) that is also active and metabolizes longer acting lumefantrine (LR). A study in healthy volunteers was completed to address the concern that EFV impacts AL pharmacokinetics (PK).
Adults received AL (80/480 mg BID) for 3-days prior to and during EFV co-administration (600 mg daily for 26-days) with intensive PK for artemether, DHA, and LR conducted after the last AL dose for each period. EFV PK was evaluated with and without AL. PK parameters were estimated using non-compartmental methods.
Twelve subjects completed the two-period study. PK exposure for artemether, DHA, and LR [as estimated by the area under the concentration time curve (AUClast)] decreased or trended toward decrease with EFV, compared to when administered alone [−51% (p=0.084), −46% (p=0.005), and −21% (p=0.102), respectively]. Day 7 LR levels, previously deemed predictive of treatment success, were 46% lower (p=0.002) with EFV, but the LR half-life was unchanged. EFV PK exposure was minimally altered following AL co-administration [AUC0–24h decreased by 17% (p=0.034)].
Exposure to DHA, but not LR, was significantly lower during EFV-AL co-administration compared to that during administration of AL alone. These findings may have implications for the treatment efficacy of AL, particularly in children. However, the observed modest changes probably do not warrant dosage adjustment during co-administration of AL with EFV.
efavirenz; artemether; dihydroartemisinin; lumefantrine; pharmacokinetic; drug-drug interaction
The malaria parasites Plasmodium falciparum and Plasmodium vivax generate significant concentrations of free unbound ferrous iron heme as a side product of hemoglobin degradation. The presence of these chemically reactive forms of iron, rare in healthy cells, presents an opportunity for parasite-selective drug delivery. Accordingly, our group is developing technologies for the targeted delivery of therapeutics to the intra-erythrocytic malaria parasite. These so-called ‘fragmenting hybrids’ employ a 1,2,4-trioxolane ring system as an iron(II)-sensing ‘trigger’ moiety and a ‘traceless’ retro-Michael linker to which a variety of partner drug species may be attached. After ferrous iron-promoted activation in the parasite, the partner drug is released via a β-elimination reaction.
In this report, we describe three orthogonal experimental approaches that were explored in order to generate in vitro proof-of-concept for ferrous iron-dependent drug delivery from a prototypical fragmenting hybrid.
Studies of two fragmenting hybrids by orthogonal approaches confirm that a partner drug species can be delivered to live P. falciparum parasites. A key advantage of this approach is the potential to mask a partner drug’s intrinsic bioactivity prior to release in the parasite.
Sickle cell trait (HbAS) is the best-characterized genetic polymorphism known to protect against falciparum malaria. Although the protective effect of HbAS against malaria is well known, the mechanism(s) of protection remain unclear. A number of biochemical and immune-mediated mechanisms have been proposed, and it is likely that multiple complex mechanisms are responsible for the observed protection. Increased evidence for an immune component of protection as well as novel mechanisms, such as enhanced tolerance to disease mediated by HO-1 and reduced parasitic growth due to translocation of host micro-RNA into the parasite, have recently been described. A better understanding of relevant mechanisms will provide valuable insight into the host-parasite relationship, including the role of the host immune system in protection against malaria.
Malaria; Plasmodium falciparum; Sickle cell trait; Genetics; Red blood cell polymorphisms; Sickle haemoglobin; Immunology; Immunopathogenesis; Protection
Among key potential drug target proteolytic systems in the malaria parasite Plasmodium falciparum are falcipains, a family of hemoglobin-degrading cysteine proteases, and the ubiquitin proteasomal system (UPS), which has fundamental importance in cellular protein turnover. Inhibition of falcipains blocks parasite development, primarily due to inhibition of hemoglobin degradation that serves as a source of amino acids for parasite growth. Falcipains prefer P2 leucine in substrates and peptides, and their peptidyl inhibitors with leucine at the P2 position show potent antimalarial activity. The peptidyl inhibitor MG132 (Z-Leu-Leu-Leu-CHO) is a widely used proteasome inhibitor, which also has P2 leucine, and has also been shown to inhibit parasite development. However, the antimalarial targets of MG132 are unclear. We investigated whether MG132 blocks malaria parasite development by inhibiting hemoglobin degradation and/or by targeting the UPS. P. falciparum was cultured with inhibitors of the UPS (MG132, epoxomicin, and lactacystin) or falcipains (E64), and parasites were assessed for morphologies, extent of hemoglobin degradation, and accumulation of ubiquitinated proteins. MG132, like E64 and unlike epoxomicin or lactacystin, blocked parasite development, with enlargement of the food vacuole and accumulation of undegraded hemoglobin, indicating inhibition of hemoglobin degradation by MG132, most likely due to inhibition of hemoglobin-degrading falcipain cysteine proteases. Parasites cultured with epoxomicin or MG132 accumulated ubiquitinated proteins to a significantly greater extent than untreated or E64-treated parasites, indicating that MG132 inhibits the parasite UPS as well. Consistent with these findings, MG132 inhibited both cysteine protease and UPS activities present in soluble parasite extracts, and it strongly inhibited recombinant falcipains. MG132 was highly selective for inhibition of P. falciparum (IC50 0.0476 µM) compared to human peripheral blood mononuclear cells (IC50 10.8 µM). Thus, MG132 inhibits two distinct proteolytic systems in P. falciparum, and it may serve as a lead molecule for development of dual-target inhibitors of malaria parasites.
Cholestasis predisposes to fat-soluble vitamin (FSV) deficiencies. A liquid multiple FSV preparation made with tocopheryl polyethylene glycol-1000 succinate (TPGS) is frequently used in infants with biliary atresia (BA) because of ease of administration and presumed efficacy. In this prospective multicenter study, we assessed the prevalence of FSV deficiency in infants with BA who received this FSV/TPGS preparation.
Infants received FSV/TPGS coadministered with additional vitamin K as routine clinical care in a randomized double-blinded, placebo-controlled trial of corticosteroid therapy after hepatoportoenterostomy (HPE) for BA (identifier NCT 00294684). Levels of FSV, retinol binding protein, total serum lipids, and total bilirubin (TB) were measured 1, 3, and 6 months after HPE.
Ninety-two infants with BA were enrolled in this study. Biochemical evidence of FSV insufficiency was common at all time points for vitamin A (29%–36% of patients), vitamin D (21%–37%), vitamin K (10%–22%), and vitamin E (16%–18%). Vitamin levels were inversely correlated with serum TB levels. Biochemical FSV insufficiency was much more common (15%–100% for the different vitamins) in infants whose TB was ≥2 mg/dL. At 3 and 6 months post HPE, only 3 of 24 and 0 of 23 infants, respectively, with TB >2 mg/dL were sufficient in all FSV.
Biochemical FSV insufficiency is commonly observed in infants with BA and persistent cholestasis despite administration of a TPGS containing liquid multiple FSV preparation. Individual vitamin supplementation and careful monitoring are warranted in infants with BA, especially those with TB >2 mg/dL.
cholestasis; nutrition; liver; vitamin deficiency
In long-term follow-up, 18-67% of pediatric liver transplant recipients are overweight or obese— with rates varying by age and pre-transplant weight status. Similar prevalence of post-transplant obesity is seen in adults. Adults also develop post-transplant metabolic syndrome, with consequent cardiovascular disease, at rates that exceed age and gender-matched populations. Post-transplant metabolic syndrome has never been studied in pediatric liver transplant recipients—a growing population as transplant outcomes continue to improve. This paper systematically reviews the literature on each component of metabolic syndrome—obesity, hypertension, dyslipidemia, and glucose intolerance—in pediatric liver transplant recipients. Rates of obesity are similar to that of the general U.S. population of children. But hypertension, dyslipidemia, and diabetes are more common than expected for age, gender, and obesity severity in transplant recipients. Immunosuppressive medications are major contributors. Limitations of prior studies—including heterogeneous methods of diagnosis, follow-up times, and immunosuppressive regimen—hinder the analysis of risk factors. Importantly, no studies report on graft or patient outcomes associated with metabolic syndrome components after pediatric liver transplant. However, if trends in children are similar to those seen in adults, these conditions may lead to significant long-term morbidity. Further research on the prevalence, causes, and consequences of post-transplant metabolic syndrome in pediatric liver transplant is needed and ultimately will help improve long-term outcomes.
pediatric; liver transplant; metabolic syndrome; obesity; hypertension; dyslipidemia; diabetes mellitus; insulin resistance
There is relatively little information in the literature on the histopathology of chronic hepatitis C in children. The Peds-C Trial, designed to test the efficacy and safety of peginterferon alfa-2a and ribavirin in children, provided an opportunity to examine liver biopsies from 121 treatment-naïve children, ages 2 to 16 (mean, 9.8 years) infected with the hepatitis C virus (HCV) and with no other identifiable cause for liver disease, signs of hepatic decompensation, or another significant nonhepatic disease. Liver biopsies were scored for inflammation, fibrosis, steatosis, and other histological features. Inflammation in the biopsy was minimal in 42%, mild in 17%, moderate in 38%, and severe in only 3%. Five had bridging fibrosis, and 2 had cirrhosis. Steatosis was absent in 56%, minimal in 34%, and mild in 10%. Inflammation scores correlated with fibrosis scores, serum alanine aminotransferase levels, and duration of infection, but not with age, body mass index z score, or HCV genotype. Fibrosis scores correlated with inflammation but not with age, HCV genotype, body mass index z score, or steatosis parameters. Steatosis correlated with serum alanine aminotransferase levels and body mass index z scores; overweight children had more fibrosis than the non-overweight. In conclusion, in this cohort of HCV-infected children, inflammation, fibrosis, and steatosis were milder than reported for treatment-naïve adults with chronic hepatitis C, but there were several with bridging fibrosis or cirrhosis. The positive correlation of inflammation with duration of infection and fibrosis and of obesity with fibrosis suggest that children with chronic hepatitis C will be at risk for progressive liver disease as they age and possibly acquire other comorbid risk factors.
Hepatitis B virus (HBV) is a major human pathogen that causes immune-mediated hepatitis. Successful immunity to HBV is age dependent: viral clearance occurs in most adults, whereas neonates and young children usually develop chronic infection. Using a mouse model of HBV infection, we sought mechanisms underpinning the age-dependent outcome of HBV and demonstrated that hepatic macrophages facilitate lymphoid organization and immune priming within the adult liver and promote successful immunity. In contrast, lymphoid organization and immune priming was greatly diminished in the livers of young mice, and of macrophage-depleted adult mice, leading to abrogated HBV immunity. Furthermore, we found that CXCL13, which is involved in B lymphocyte trafficking and lymphoid architecture and development, is expressed in an age-dependent manner in both adult mouse and human hepatic macrophages and plays an integral role in facilitating an effective immune response against HBV. Taken together, these results identify some of the immunological mechanisms necessary for effective control of HBV.
Weight loss and changes in growth are noted in children treated with interferonα
To prospectively determine changes in weight, height, body mass index and body composition during and after treatment of children with hepatitis C.
Children treated with PEG-IFNα2a +/− ribavirin in the PEDS-C trial underwent anthropometric measurements, DXA scan, dietary and activity assessments during and after treatment.
114 (55% male) children mean age 11±3 years were randomized, and 107 received treatment for at least 24 weeks. Subjects were divided into 3 groups according to duration of treatment: 24 (N=14), 48 (N=82), or 72 (N=11) weeks. Decrements of up to 0.50 z score were observed for weight, height and BMI while on therapy among all groups (P≤0.01 compared to baseline). In the group treated for 48 weeks, 29 (33%) subjects had greater than 0.5 unit decrement in height-for-age Z score. While weight-for-age and BMI z scores returned to baseline after cessation of therapy, mean HAZ score was slower to rebound, still lower than baseline at 96 weeks post-therapy for the long treatment duration group (P=0.03) and lower than baseline in most children treated for 48 weeks. Percent body fat, fat-free mass z scores and triceps skinfold z scores decreased with therapy. Dietary energy intake and levels of physical activity did not change during treatment.
PEG-IFNα2a was associated with significant changes in body weight, linear growth, body mass index and body composition in children. These effects were generally reversible with cessation of therapy, although height-for-age z scores had not returned to baseline after 2 years of observation in many. Longer term growth data are needed among children treated for chronic HCV.
Adjacent segment pathology affects 25% of patients within ten years of anterior cervical diskectomy and fusion (ACDF). Laboratory studies demonstrate fused segments increase adjacent level stress including elevated intradiscal pressure and increased range of motion. Radiographic adjacent segment pathology (RASP) has been associated to ACDF in multiple statistically significant studies. Randomized controlled trials (RCTs) comparing anterior cervical discectomy and arthroplasty (ACDA) and ACDF have confirmed ACDF accelerates RASP. The question of greatest clinical interest is whether ACDA, artificial disc surgery, results in fewer adjacent level surgeries than ACDF. Current RCT follow up results reveal only non statistically significant trends favoring ACDA yet the post operative periods are only two to four years. Statistically significant increased RASP in ACDF patients however is already documented. The RCT patients’ average ages are in the mid forties with an expected longevity of up to forty more years. Early statistically significant increased RASP in the ACDF patients supports our prediction that given sufficient follow up of ten or more years, fusion will lead to statistically significant higher rate of adjacent level surgery compared to artificial disc surgery.
Cervical; Diskectomy; Fusion; Arthroplasty; Adjacent; Degeneration
The hydroxynaphthoquinones have been extensively investigated over the past 50 years for their anti-malarial activity. One member of this class, atovaquone, is combined with proguanil in Malarone®, an important drug for the treatment and prevention of malaria.
Anti-malarial activity was assessed in vitro for a series of 3-alkyl-2-hydroxy-1,4-naphthoquinones (N1-N5) evaluating the parasitaemia after 48 hours of incubation. Potential cytotoxicity in HEK293T cells was assessed using the MTT assay. Changes in mitochondrial membrane potential of Plasmodium were measured using the fluorescent dye Mitrotracker Red CMXROS.
Four compounds demonstrated IC50s in the mid-micromolar range, and the most active compound, N3, had an IC50 of 443 nM. N3 disrupted mitochondrial membrane potential, and after 1 hour presented an IC50ΔΨmit of 16 μM. In an in vitro cytotoxicity assay using HEK 293T cells N3 demonstrated no cytotoxicity at concentrations up to 16 μM.
N3 was a potent inhibitor of mitochondrial electron transport, had nanomolar activity against cultured Plasmodium falciparum and showed minimal cytotoxicity. N3 may serve as a starting point for the design of new hydroxynaphthoquinone anti-malarials.
Plasmodium falciparum; Hydroxynaphthoquinone; 2-hydroxy-1,4-naphthoquinone; Mitochondria; Malaria; Plasmodium berghei
Human immunodeficiency virus (HIV) protease inhibitors show activity against Plasmodium falciparum in vitro. We hypothesized that the incidence of malaria in HIV-infected children would be lower among children receiving lopinavir–ritonavir–based antiretroviral therapy (ART) than among those receiving nonnucleoside reverse-transcriptase inhibitor (NNRTI)–based ART.
We conducted an open-label trial in which HIV-infected children 2 months to 5 years of age who were eligible for ART or were currently receiving NNRTI-based ART were randomly assigned to either lopinavir–ritonavir–based ART or NNRTI-based ART and were followed for 6 months to 2 years. Cases of uncomplicated malaria were treated with artemether–lumefantrine. The primary end point was the incidence of malaria.
We enrolled 176 children, of whom 170 received the study regimen: 86 received NNRTI-based ART, and 84 lopinavir–ritonavir–based ART. The incidence of malaria was lower among children receiving the lopinavir–ritonavir–based regimen than among those receiving the NNRTI-based regimen (1.32 vs. 2.25 episodes per person-year; incidence-rate ratio, 0.59; 95% confidence interval [CI], 0.36 to 0.97; P = 0.04), as was the risk of a recurrence of malaria after treatment with artemether–lumefantrine (28.1% vs. 54.2%; hazard ratio, 0.41; 95% CI, 0.22 to 0.76; P = 0.004). The median lumefantrine level on day 7 after treatment for malaria was significantly higher in the lopinavir–ritonavir group than in the NNRTI group. In the lopinavir–ritonavir group, lumefantrine levels exceeding 300 ng per milliliter on day 7 were associated with a reduction of more than 85% in the 63-day risk of recurrent malaria. A greater number of serious adverse events occurred in the lopinavir–ritonavir group than in the NNRTI group (5.6% vs. 2.3%, P = 0.16). Pruritus occurred significantly more frequently in the lopinavir–ritonavir group, and elevated alanine aminotransferase levels significantly more frequently in the NNRTI group.
Lopinavir–ritonavir–based ART as compared with NNRTI-based ART reduced the incidence of malaria by 41%, with the lower incidence attributable largely to a significant reduction in the recurrence of malaria after treatment with artemether–lumefantrine. Lopinavir–ritonavir–based ART was accompanied by an increase in serious adverse events. (Funded by the Eunice Kennedy Shriver National Institute of Child Health and Human Development; ClinicalTrials.gov number, NCT00978068.)
Phosphonium lipocations were synthesized and evaluated for inhibition of the development of Plasmodium falciparum and Trypanosoma cruzi, etiological agents of malaria and Chagas disease, respectively. Optimal phthalimides and 1,4-naphthoquinone-based lipocations were active in vitro at mid-high nM concentrations against P. falciparum and low μM concentrations against T. cruzi.
Malaria; Chagas; Antiparasitic drugs; Plasmodium; Trypanosoma
Human immunodeficiency virus (HIV)-infected antiretroviral therapy-naive Ugandan children with CD4 cell counts of ∼350 cells/μL and percentages of >15% have significant motor and cognitive deficits compared with HIV-uninfected children. Study of whether early initiation of treatment could prevent or reverse such deficits is needed.
(See the Editorial Commentary by Wagner and Frenkel, on pages 1010–2.)
Background. Human immunodeficiency virus (HIV) infection causes neurocognitive or motor function deficits in children with advanced disease, but it is unclear whether children with CD4 cell measures above the World Health Organization (WHO) thresholds for antiretroviral therapy (ART) initiation suffer significant impairment.
Methods. The neurocognitive and motor functions of HIV-infected ART-naive Ugandan children aged 6–12 years with CD4 cell counts of >350 cells/μL and CD4 cell percentage of >15% were compared with those of HIV-uninfected children, using the Test of Variables of Attention (TOVA), the Kaufman Assessment Battery for Children, second edition (KABC-2), and the Bruininks-Oseretsky Test of Motor Proficiency, second edition (BOT-2).
Results. Ninety-three HIV-infected children (median CD4 cell count, 655 cells/μL; plasma HIV RNA level, 4.7 log10 copies/mL) were compared to 106 HIV-uninfected children. HIV-infected children performed worse on TOVA visual reaction times (multivariate analysis of covariance; P = .006); KABC-2 sequential processing (P = .005), simultaneous processing (P = .039), planning/reasoning (P = .023), and global performance (P = .024); and BOT-2 total motor proficiency (P = .003). High plasma HIV RNA level was associated with worse performance in 10 cognitive measures and 3 motor measures. In analysis of only WHO clinical stage 1 or 2 HIV-infected children (n = 68), significant differences between the HIV-infected and HIV-uninfected groups (P < .05) remained for KABC-2 sequential processing, KABC-2 planning/reasoning, and BOT-2 motor proficiency.
Conclusions. Significant motor and cognitive deficits were found in HIV-infected ART-naive Ugandan children with CD4 cell counts of ∼350 cells/μL and percentages of >15%. Study of whether early initiation of ART could prevent or reverse such deficits is needed.
Background & Aims
Criteria for the diagnosis of autoimmune hepatitis (AIH) were formalized in 1993 and revised in 1999. Simplified criteria were developed in 2008, for adults only. We aimed to establish clinically useful diagnostic criteria for AIH in children by validating the 2008 criteria in a pediatric cohort.
Baseline data were available from 37 and 31 subjects with AIH (70% female) and 40 and 26 subjects without AIH (30% female), which were used to calculate the 1999 and 2008 criteria, respectively. Sensitivity and specificity of the simplified criteria were calculated using 1999 criteria as the standard for subjects with available data for both criteria.
The 1999 standard designated 29/31 subjects (94%) as definite AIH and 2/31 subjects (6%) as probable AIH. The simplified criteria identified 25/31 subjects (81%) as definite AIH, 2/31 subjects (6%) as probable AIH. Only 1/5 patients with AIH who presented with fulminant hepatic failure (FHF) was identified by the simplified criteria as having AIH. The 2008 diagnostic criteria had a sensitivity of 87% and specificity of 89% (area under the receiver operating characteristic [AUROC] curve=0.98). After removing data from patients with FHF from the analysis, the sensitivity increased to 100%. Modifying the 2008 diagnostic criteria to include either level of globulin or immunoglobulin (Ig)G resulted in similar sensitivity (92%) and specificity (95%; AUROC curve=0.99) values.
The 2008 criteria diagnose AIH in children with high levels of sensitivity and specificity, and are easier to use in the clinic. Diagnosis of AIH in patients who present in FHF requires the 1999 criteria. Levels of globulin and IgG can be used interchangeably in the simplified diagnostic criteria.
pediatric liver disease; scoring system; diagnostic; autoimmunity
Malaria remains one of the leading health problems of the developing world, and Uganda bears a particularly large burden from the disease. Our understanding is limited by a lack of reliable data, but it is clear that the prevalence of malaria infection, incidence of disease, and mortality from severe malaria all remain very high. Uganda has made progress in implementing key malaria control measures, in particular distribution of insecticide impregnated bednets, indoor residual spraying of insecticides, utilization of artemisinin-based combination therapy to treat uncomplicated malaria, and provision of intermittent preventive therapy for pregnant women. However, despite enthusiasm regarding the potential for the elimination of malaria in other areas, there is no convincing evidence that the burden of malaria has decreased in Uganda in recent years. Major challenges to malaria control in Uganda include very high malaria transmission intensity, inadequate health care resources, a weak health system, inadequate understanding of malaria epidemiology and the impact of control interventions, increasing resistance of parasites to drugs and of mosquitoes to insecticides, inappropriate case management, inadequate utilization of drugs to prevent malaria, and inadequate epidemic preparedness and response. Despite these challenges, prospects for the control of malaria have improved, and with attention to underlying challenges, progress toward the control of malaria in Uganda can be expected.
Malaria; Plasmodium; Uganda; Insecticide-treated nets; Indoor residual spraying; Artemisinin-based combination therapy; Intermittent preventive therapy
In the recent past there have been several reports of successes in malaria control, leading some public health experts to conclude that Africa is witnessing an epidemiological transition, from an era of failed malaria control to progression from successful control to elimination. Successes in control have been attributed to increased international donor support leading to increased intervention coverage. However, these changes are not uniform across Africa. In Uganda, where baseline transmission is very high and intervention coverage not yet to scale, the malaria burden is not declining and has even likely increased in the last decade. In this article we present perspectives for the future for Uganda and other malaria endemic countries with high baseline transmission intensity and significant health system challenges. For these high burden areas,malaria elimination is currently not feasible, and early elimination programs are inappropriate, as they would further fragment already fragmented and inefficient malaria control systems. Rather, health impacts will be maximized by aiming to achieve universal coverage of proven interventions in the context of a strengthened health system.
Malaria; Plasmodium; Uganda; Insecticide-treated nets; Indoor residual spraying; Artemisinin-based combination therapy; Intermittent preventive therapy; health systems
Biliary atresia (BA) is characterized by progressive inflammation and fibrosis of bile ducts. A theory of pathogenesis entails autoimmune-mediated injury targeting bile duct epithelia. One of the strongest genetic associations with autoimmunity is with HLA genes. In addition, apparently dissimilar HLA alleles may have similar antigen-binding sites, called shared epitopes, that overlap in their capacity to present antigens. In autoimmune disease, the incidence of the disease may be related to the presence of shared epitopes, not simply the HLA allelic association. Aim: To determine HLA allele frequency (high-resolution genotyping) and shared epitope associations in BA. Results: Analysis of every allele for HLA-A, -B, -C, -DRB1, -DPB1 and -DQB1 in 180 BA and 360 racially-matched controls did not identify any significant HLA association with BA. Furthermore, shared epitope analysis of greater than 10 million possible combinations of peptide sequences was not different between BA and controls. Conclusions: This study encompasses the largest HLA allele frequency analysis for BA in the United States and is the first study to perform shared epitope analysis. When controlling for multiple comparisons, no HLA allele or shared epitope association was identified in BA. Future studies of genetic links to BA that involve alterations of the immune response should include investigations into defects in regulatory T cells and non-HLA linked autoinflammatory diseases.
Electronic supplementary material
The online version of this article (doi:10.1186/2193-1801-2-42) contains supplementary material, which is available to authorized users.