Biochemical and molecular characteristics of patients with organic acidaemias and urea cycle disorders identified through newborn screening.

BACKGROUND: In recent years it has become clear that newborn screening (NBS) programmes using tandem mass spectrometry identify "patients" with "classical" inborn errors of metabolism who are asymptomatic. This observation raises issues regarding medicalization of "non-diseases," potentially unnecessary treatment and unnecessary anxiety to parents. AIMS: This study aims to identify possible markers that may assist in predicting the need for treatment of infants with "classical" organic acidaemias (OA) and urea cycle disorders (UCD) diagnosed through NBS. METHODS: Medical records of all patients with classical OA and UCD detected through the Victorian NBS programme from February 2002 to January 2014, or diagnosed clinically between 1990 and January 2002 were retrospectively reviewed. RESULTS: Neonatal presentation did not always predict the need for on-going strict treatment. Blood concentrations of amino acids and acyl-carnitines and the changes thereof in follow-up samples correlated with severity in citrullinaemia-I, possibly isovaleric acidaemia but not in argininosuccinic aciduria or propionic acidaemia. Some specific mutations correlate with "attenuated" citrullinaemia-I. Gender may affect clinical outcome in propionic acidaemia. CONCLUSIONS: Changes in blood concentration of certain metabolites (amino acids, acyl-carnitines) in the first weeks of life may be predictive of the need for treatment in some disorders but not in others. Mutation analysis may be predictive in some disorders but whether or not this should be considered as second-tier testing in NBS should be discussed separately.

Plasmodium vivax susceptibility to ferroquine.

The novel organometallic chloroquine analog ferroquine (SSR 97193) is effective against chloroquine-resistant Plasmodium falciparum. The ex vivo efficacy of ferroquine against Plasmodium vivax isolates was tested. Ferroquine has a potent ex vivo effect on P. vivax schizont maturation (median 50% inhibitory concentration, 15 nM; n = 42). No significant cross-sensitivity between ferroquine and other antimalarials was detected. This drug may be a suitable replacement for chloroquine in the treatment of drug-resistant P. vivax malaria.

Amplification of pvmdr1 associated with multidrug-resistant Plasmodium vivax.

BACKGROUND: Multidrug-resistant strains of Plasmodium vivax are emerging in Southeast Asia. METHODS: In vitro drug susceptibility and pvmdr1 genotype were determined in P. vivax field isolates from Indonesia and Thailand. RESULTS: Increased pvmdr1 copy number was present in 21% of isolates from Thailand (15/71) and none from Indonesia (0/114; P < .001). Compared with Indonesian isolates, the median IC(50) of Thai isolates was lower for chloroquine (36 vs. 114 nmol/L; P < .001) but higher for amodiaquine (34 vs. 13.7 nmol/L; P = .032), artesunate (8.33 vs. 1.58 nmol/L; P < .001), and mefloquine (111 vs. 9.87 nmol/L; P < .001). In 11 cryopreserved Thai isolates, those with increased pvmdr1 copy number had a higher IC(50) for mefloquine (78.6 vs. 38 nmol/L for single-copy isolates; P = .006). Compared with isolates with the wild-type allele, the Y976F mutation of pvmdr1 was associated with reduced susceptibility to chloroquine (154 nmol/L [range, 4.6-3505] vs. 34 nmol/L [range, 6.7-149]; P < .001) but greater susceptibility to artesunate (1.8 vs. 9.5 nmol/L; P = .009) and mefloquine (14 vs. 121 nmol/L; P < .001). CONCLUSIONS: Amplification of pvmdr1 and single-nucleotide polymorphisms are correlated with susceptibility of P. vivax to multiple antimalarial drugs. Chloroquine and mefloquine appear to exert competitive evolutionary pressure on pvmdr1, similar to that observed with pfmdr1 in Plasmodium falciparum.

An open, randomized comparison of artesunate plus mefloquine vs. dihydroartemisinin-piperaquine for the treatment of uncomplicated Plasmodium falciparum malaria in the Lao People's Democratic Republic (Laos).

OBJECTIVE: To determine the efficacy and safety of oral dihydroartemisinin-piperaquine (DP, Artekin) in the treatment of uncomplicated Plasmodium falciparum malaria in southern Laos. METHODS: An open, randomized clinical trial of oral artesunate-mefloquine (AM) vs. DP in 220 patients with acute uncomplicated falciparum malaria in Savannakhet Province, Laos. RESULTS: The 42-day cure rates (95% CI), as determined by survival analysis and adjusted for reinfection, were excellent and similar for the two groups [99 (94-100)% and 100 (100-100)% for AM and DP, respectively]. The median (range) fever and parasite clearance times for the AM and DP groups were also similar [20 (4-63) h and 2 (1-4) days vs. 20 (7-57) and 2 (1-4) days, logrank P = 0.4 and 0.17, respectively]. There were more patients with at least one potential side effect following treatment in the AM group when compared with the DP group [64/110 (58%) vs. 48/110 (44%), respectively, P = 0.031]. CONCLUSION: Dihydroartemisinin-piperaquine did not have superior efficacy to AM for the treatment of uncomplicated falciparum malaria in Laos but was associated with fewer adverse effects.

Efficacy of chloroquine + sulfadoxine--pyrimethamine, mefloquine + artesunate and artemether + lumefantrine combination therapies to treat Plasmodium falciparum malaria in the Chittagong Hill Tracts, Bangladesh.

Bangladesh faces growing levels of Plasmodium falciparum resistance to chloroquine (CQ) and sulfadoxine-pyrimethamine (SP). Alternative antimalarial therapies, particularly combination regimens, need to be considered. Therefore, the efficacy of three antimalarial combination therapies was assessed in Chittagong Hill Tracts. A total of 364 P. falciparum patients were recruited and randomly assigned to either CQ + SP, mefloquine + artesunate (MQ + AS) or lumefantrine + artemether (Coartem). Results showed that CQ + SP therapy was less effective than the two artemisinin-based combination therapies. The day 42 PCR-corrected efficacy rate was 62.4% for CQ + SP, 100% for MQ + AS and 97.1% for Coartem. Failures occurred at a shorter interval after CQ + SP treatment than after Coartem. The artemisinin-based therapies effectively prevented development of gametocytes, whereas CQ + SP did not. All three therapies were well tolerated, although reports of mild complaints during treatment appeared higher with MQ + AS. We conclude that CQ + SP is not a viable option for replacing CQ monotherapy as first-line P. falciparum treatment in this area of Bangladesh. A change to artemisinin-based combination therapy is recommended. Both Coartem and MQ + AS appear to be good options, effective in curing P. falciparum malaria and in preventing recrudescences following treatment.

Timing of infection and prior immunization with respiratory syncytial virus (RSV) in RSV-enhanced allergic inflammation.

Respiratory syncytial virus (RSV) infection has been shown to be a risk factor for the development of allergy in humans and mice. The allergy-enhancing properties of RSV may be dependent on atopic background and an individual's history of RSV infection. We examined the influence of the timing of infection and prior inoculation with RSV in a mouse model of allergic asthma. Mice were sensitized to and challenged with ovalbumin (OVA) and were inoculated with RSV either before or during the sensitization or challenge period. One group of mice was inoculated with RSV both before sensitization to OVA and during challenge with OVA. Increased pulmonary expression of interleukin (IL)-4, IL-5, and IL-13 mRNA and aggravated alveolitis and hypertrophy of mucus-producing cells were observed only when OVA-sensitized mice were inoculated with RSV shortly before or during challenge with OVA. Despite protection against viral replication, prior inoculation with RSV did not abrogate RSV-enhanced, OVA-induced expression of T helper 2 (Th2) cytokines in the lung. In conclusion, inoculation with RSV enhances allergic disease only when the immune system has already been Th2-primed by the allergen (i.e., OVA). This RSV-enhanced allergy is not completely abrogated by prior inoculation with RSV.

Respiratory syncytial virus, pneumonia virus of mice, and influenza A virus differently affect respiratory allergy in mice.

BACKGROUND: Respiratory viral infections in early childhood may interact with the immune system and modify allergen sensitization and/or allergic manifestations. In mice, respiratory syncytial virus (RSV) infection during allergic provocation aggravates the allergic T helper (Th) 2 immune response, characterized by the production of IL-4, IL-5, and IL-13, and inflammatory infiltrates. However, it is unclear whether the RSV-enhanced respiratory allergic response is a result of non-specific virus-induced damage of the lung, or virus-specific immune responses. OBJECTIVE: In the present study we investigated whether RSV, pneumonia virus of mice (PVM) and influenza A virus similarly affect the allergic response. METHODS: BALB/c mice were sensitized and challenged with ovalbumin (OVA), and inoculated with virus during the challenge period. Pulmonary inflammation, lung cytokine mRNA responses, and IgE production in serum were assessed after the last OVA-challenge. RESULTS: Like RSV, PVM enhanced the OVA-induced pulmonary IL-4, IL-5, and IL-13 mRNA expression, which was associated with enhanced perivascular inflammation. In addition, PVM increased the influx of eosinophils in lung tissue. In contrast, influenza virus decreased the Th2 cytokine mRNA expression in the lungs. However, like PVM, influenza virus enhanced the pulmonary eosinophilic infiltration in OVA-allergic mice. CONCLUSION: The Paramyxoviruses RSV and PVM both are able to enhance the allergic Th2 cytokine response and perivascular inflammation in BALB/c mice, while the Orthomyxovirus influenza A is not.

Influence of respiratory syncytial virus infection on cytokine and inflammatory responses in allergic mice.

BACKGROUND: Th2 lymphocyte responses are associated with inflammation and disease during allergic responses. Exposure to particular environmental factors during the expression of allergy could result in more pronounced Th2-like immune responses and more severe disease. One factor might be a respiratory virus infection. OBJECTIVE: The aim of our study was to investigate the influence of respiratory syncytial virus (RSV) infection on the expression of ovalbumin (OVA)-induced allergy in BALB/c mice. METHODS: We determined OVA-specific IgE in serum, cytokine profiles and histopathological lesions in lungs of OVA-allergic mice after RSV infection. RESULTS: OVA sensitization and challenge induced OVA-specific IgE in serum, Th2 cytokine mRNA expression, and mononuclear and eosinophilic inflammation in the lungs. RSV inoculation during the challenge period enhanced OVA-induced IL-4 and IL-5 mRNA expression in lung tissue. RSV further enhanced the OVA-induced hypertrophy of mucous cells and eosinophilic infiltration in lung tissue. Surprisingly, RSV infection decreased Th2 cytokine secretion and eosinophilic influx in bronchoalveolar lavage of OVA-allergic mice. Because inactivated RSV did not influence these responses, replication of RSV appeared essential for the modification of OVA-induced Th2 cytokine expression. RSV did not change OVA-specific IgE levels in serum. Furthermore, the RSV-induced IL-12 mRNA expression in lung tissue of OVA-allergic mice was diminished, but IFN-gamma mRNA expression was not affected. CONCLUSION: RSV infection enhanced particular OVA-induced Th2 cytokine mRNA responses and pulmonary lesions in allergic mice and thus aggravated allergic respiratory disease.