Genomic innovations, transcriptional plasticity and gene loss underlying the evolution and divergence of two highly polyphagous and invasive Helicoverpa pest species.

BACKGROUND: Helicoverpa armigera and Helicoverpa zea are major caterpillar pests of Old and New World agriculture, respectively. Both, particularly H. armigera, are extremely polyphagous, and H. armigera has developed resistance to many insecticides. Here we use comparative genomics, transcriptomics and resequencing to elucidate the genetic basis for their properties as pests. RESULTS: We find that, prior to their divergence about 1.5 Mya, the H. armigera/H. zea lineage had accumulated up to more than 100 more members of specific detoxification and digestion gene families and more than 100 extra gustatory receptor genes, compared to other lepidopterans with narrower host ranges. The two genomes remain very similar in gene content and order, but H. armigera is more polymorphic overall, and H. zea has lost several detoxification genes, as well as about 50 gustatory receptor genes. It also lacks certain genes and alleles conferring insecticide resistance found in H. armigera. Non-synonymous sites in the expanded gene families above are rapidly diverging, both between paralogues and between orthologues in the two species. Whole genome transcriptomic analyses of H. armigera larvae show widely divergent responses to different host plants, including responses among many of the duplicated detoxification and digestion genes. CONCLUSIONS: The extreme polyphagy of the two heliothines is associated with extensive amplification and neofunctionalisation of genes involved in host finding and use, coupled with versatile transcriptional responses on different hosts. H. armigera's invasion of the Americas in recent years means that hybridisation could generate populations that are both locally adapted and insecticide resistant.

Virologically suppressed patients with asymptomatic and symptomatic HIV-associated neurocognitive disorders do not display the same pattern of immune activation.

OBJECTIVES: Inversion of the CD4:CD8 ratio is a marker of immune activation and age-associated disease. We measured the CD4:CD8 ratio as a marker of cognitive impairment in HIV-infected patients and explored differences according to clinical severity. METHODS: Post hoc analysis of data from two prospective cohorts of HIV-infected patients randomly selected to undergo neuropsychological tests was performed. Test scores were adjusted for age, gender and education. Inclusion criteria were undetectable viral load and stable treatment for at least 6 months. Subjects with HIV-associated dementia were excluded. Patients were divided into an unimpaired group, a group with asymptomatic neurocognitive disorder (ANI) and a group with symptomatic HIV-associated neurocognitive disorder (sHAND), represented by mild neurocognitive disorder (MND). Demographic and background parameters, immune activation markers and the CD4:CD8 ratio were recorded. RESULTS: Two hundred patients were included in the study. The mean age was 52 years, 78% were male, the mean CD4 count was 624 cells/µL, the mean nadir CD4 count was 240 cells/µL, 27% were hepatitis C virus (HCV)-coinfected, the mean duration of HIV infection was 16 years, and the mean time on current combination antiretroviral therapy (cART) was 2.9 years. Twenty-nine per cent of subjects had HAND (21% had ANI and 8% had MND). In multivariate analysis, a CD4:CD8 ratio < 1 was associated with a nadir CD4 count < 200 cells/µL [odds ratio (OR) 3.68] and with the presence of CD4(+) CD38(+) HLA(+) cells (OR 1.23). Multinominal logistic regression showed that, in comparison with the unimpaired group, diagnosis of sHAND was associated with a CD4:CD8 ratio < 1 (OR 10.62), longer HIV infection (OR 1.15) and longer current cART (OR 1.34), while the ANI group differed from the unimpaired group only for education level. CONCLUSIONS: Aviraemic patients with sHAND did not display the same pattern of immune activation as subjects with ANI, suggesting that the underlying pathophysiological mechanisms could be different.

Total genomic alteration as measured by SNP-array-based molecular karyotyping is predictive of overall survival in a cohort of MDS or AML patients treated with azacitidine.

Metaphase cytogenetics (MC) has a major role in the risk stratification of patients with myelodysplastic syndromes (MDSs) and can affect the choice of therapies. Azacitidine (AZA) has changed the outcome of patients with MDS or acute myeloid leukemia (AML) unfit for intensive chemotherapy. Identification of patients without the benefit of AZA would allow AZA combination or other drugs in first-line treatments. New whole-genome scanning technologies such as single nucleotide polymorphism microarray (SNP-A)-based molecular karyotyping (MK) improve the risk stratification in MDS and AML. Maintenance of genomic integrity is less than three megabases (Mbs) total disruption of the genome correlated with better overall survival (OS) in patients with lower-risk MDS. In this SNP-A study, we aimed at defining a cutoff value for total genomic copy number (CN) alterations (TGA) influencing the median OS in a cohort of 51 higher-risk MDS/AML patients treated with AZA. We observed that the relative risk of worse OS increased >100 Mb of TGA, as detected by SNP-A-based MK (8 and 15 months respectively, P=0.02). Our data suggest that precise measurement of TGA could provide predictive information in poor and very poor revised International Prognostic Scoring system (IPSS-R) patients treated with AZA.

A diversity of putative carboxylesterases are expressed in the antennae of the noctuid moth Spodoptera littoralis.

Recent studies have suggested that pheromone-degrading enzymes belonging to the carboxylesterase family could play a role in the dynamics of the olfactory response to acetate sex pheromones in insects. Bioinformatic analyses of a male antennal expressed sequence tag library allowed the identification of 19 putative esterase genes expressed in the antennae of the moth Spodoptera littoralis. Phylogenetic analysis revealed that these genes belong to different insect esterase clades, defined by their putative cellular localization and substrate preferences. Interestingly, two of the 19 genes appeared to be antennal specific, suggesting a specific role in olfactory processing. This high esterase diversity suggested that the antennae are the location for intense esterase-based metabolism, against potentially a large range of exogenous and endogenous molecules.

Variable virological outcomes according to the center providing antiretroviral therapy within the PharmAdapt clinical trial.

PURPOSE: Differences in virological response between HIV-infected patients at different study centers were analyzed as a substudy of PharmAdapt, a multicenter prospective randomized study to evaluate the utility of therapeutic drug monitoring after a genotypic-based treatment adaptation. RESULTS: After 12 weeks, the percentage of patients participating in PharmAdapt with HIV RNA < 200 copies/mL ranged from 17% to 69% between centers providing antiretroviral care. In a multivariate analysis, independent factors predictive of viral load <200 HIV RNA copies/mL at Week 12 included: lower baseline viral load, lower nonnucleoside reverse transcriptase inhibitor resistance, lower protease inhibitor resistance, and the center providing antiretroviral therapy. To evaluate the final factor, study sites were divided into two groups based on Week 12 HIV RNA values above or below the median. CONCLUSION: Using this definition, observed differences between centers included the use of stavudine, abacavir-, and/or efavirenz-based regimens and use of online expert advice.

[Delayed diagnosis of neurocysticercosis: two case reports]. / Neurocysticercose de diagnostic tardif: à propos de deux cas.

INTRODUCTION: Neurocysticercosis is the most frequently encountered cerebral parasitic infection worldwide. It is due to infection of the central nervous system by Taenia solium larval form. According to the location of the cysts, parenchymal and extra-parenchymal forms may be identified, with different clinical expressions. EXEGESIS: We report two cases of neurocysticercosis, one with typical parenchymal involvement and the second with extra-parenchymal involvement revealed by increased intra-cranial pressure. In both cases, the diagnosis was established over 10 years after the onset of symptoms. CONCLUSION: Neurocysticercosis is very frequent in non-Islamic developing countries, and its incidence is increasing in industrialized nations in relation to tourism and immigration from highly endemic areas. Symptoms usually appear several years after infection and this accounts for the frequent delays before the diagnosis is established.

[Endocarditis, meningitis, pneumopathy and pneumococcal cerebral abscess in an alcoholic smoker]. / Endocardite, méningite, pneumopathie et abcès cérébral à pneumocoque chez un alcoolo-tabagique.

We report a case of mitral endocarditis caused by Streptococcus pneumoniae in a 43 year old man with history of alcohol abuse and cigarette smoking. The pneumococcal endocarditis was associated with pneumonia, meningitis and brain abscess. Only transesophageal echocardiography could confirm the presence of vegetation. The patient was treated medically with good results.

Importance of protease inhibitor plasma levels in HIV-infected patients treated with genotypic-guided therapy: pharmacological data from the Viradapt Study.

OBJECTIVE: In a prospective randomized study, the impact of plasma protease inhibitor (PI) trough levels on changes in HIV RNA were assessed in patients treated with genotypic-guided therapy. METHODS: Patients failing combination therapy (HIV-1 RNA > 10,000 copies/ml, and at least 6 months of therapy with nucleoside analogues and 3 months with PI) were randomly assigned into two arms: control group (C) in which the treatment was modified according to the standard of care; genotypic group (G) in which the treatment was modified according to resistance mutation profiles. Serial PI plasma levels were performed in patients throughout the 12 month study. PI levels were determined by high performance liquid chromatography. 'Suboptimal' concentration (SOC) was defined as at least two PI plasma levels below 2 x IC95. Others were defined as 'optimal' concentration (OC). Patients were categorized into four groups: G1 (SOC/control); G2 (OC/control); G3 (SOC/genotype); G4 (OC/genotype). An intent-to-treat analysis was performed with viral load as the primary endpoint. RESULTS: A total of 81 patients [mean age 39.7 +/- 8 years, 59 men, 52.7% Centers for Disease Control and Prevention (CDC) stage C] were included in the pharmacological substudy. The two groups according to randomization arms were comparable in terms of risk factor, age, sex, previous treatments, baseline CD4 cell count, HIV-1 RNA and mean PI plasma concentrations. Linear regression analysis showed a significant relationship between PI concentration and HIV RNA in the plasma. OC and SOC were found in 67.9% (55/81) and 32.1% (26/81) of patients, respectively. Mean changes in HIV RNA from baseline at month 6 were: -0.23 +/- 0.29 log10 copies/ml (G1); -0.97 +/- 0.28 (G2); -0.68 +/- 0.37 (G3); -1.38 +/- 0.20 (G4). Multivariate analysis showed PI plasma concentrations to be an independent predictor of HIV-RNA evolution (P = 0.017). CONCLUSION: Multiple parameters determine the response to antiretroviral therapy and causes other than the development of drug resistance should be considered in the setting of therapeutic failure. Suboptimal concentrations of PI limit the response to antiretroviral therapy. Therapeutic drug monitoring of the PI plasma concentration may therefore prove useful in optimizing antiretroviral therapy.

Persisting long-term benefit of genotype-guided treatment for HIV-infected patients failing HAART. The Viradapt Study: week 48 follow-up.

OBJECTIVE: We report the 12 months follow-up of the patients who participated in the Viradapt study. METHODS: A total of 108 HIV-infected patients failing antiretroviral (ARV) therapy (HIV RNA > 10,000 copies/ml, therapy > 6 months with nucleoside reverse transcriptase inhibitors, > 3 months with protease inhibitors (PIs) were randomized into two arms: standard of care in the control arm, and treatment according to the resistance mutations in the protease and reverse transcriptase genes in the study arm. After the first 6 months of the randomized study, open-label, genotype-guided treatment was offered in both arms. A multivariate analysis was performed to assess the predictive factors of treatment success (HIV RNA < 200 copies/ml). RESULTS: The two arms were comparable in terms of risk factors, age, sex, previous treatments, CD4 cell count and log10 HIV-1 RNA at baseline. At week 24, an interim combined analysis showed a statistically significant difference in the drop in viral load at months 3 and 6 (P = 0.015, repeated measures analysis of variance) in favour of the genotype group. Patients in both arms were then offered open-label genotyping. Genotype analysis was performed every 3 months, and treatment changes could accordingly be made. As some of the patients in the control arm had already progressed to months 9 or 12, only 69% (30/43) of these patients received genotype-guided treatment changes. In the genotype arm, the mean drop in HIV RNA of 1.15 log10 copies/ml, obtained at month 6, persisted at months 9 and 12 (1.15 log10 copies/ml +/- 0.17). In the control arm, an additional drop in HIV RNA to 0.98 log10 +/- 0.22 copies/ml was observed by month 12. In control patients receiving open-label genotype, the percentage of patients with HIV-1 RNA levels below detection limit (200 copies/ml) rose from 14% at month 6 to 30.5% at month 12. This percentage in the study arm remained stable at 31.3% and 30% at months 9 and 12, respectively. Genotype-guided therapy, primary protease mutations and PI plasma concentrations were significantly correlated with virological success. CONCLUSION: In this heavily pretreated patient population, genotype-guided therapy resulted in a sustained reduction in HIV RNA of greater than one log10 throughout a 1 year follow-up period. Performance of genotype-guided therapy may have contributed to the additional viral load reduction seen in patients in the control group who received open-label genotyping after the 6 months point. Multivariate analysis showed that the presence of primary protease mutations, performance of genotype-guided treatment changes and PI plasma concentrations independently affected virological response.

Drug-resistance genotyping in HIV-1 therapy: the VIRADAPT randomised controlled trial.

BACKGROUND: Growing evidence has linked HIV-1 resistance mutations and drug failure. The use of genotypic-resistance analysis to assist therapeutic decision-making in patients failing therapy has not been investigated. We assessed the virological and immunological impact of genotypic-resistance testing. METHODS: We did a prospective, open, randomised, controlled study of HIV-1-infected patients in whom combination therapy was not successful. We randomly assigned patients standard care (control, n=43) or treatment according to the resistance mutations in protease and reverse-transcriptase genes (genotypic group, n=65). The major endpoint was the change in HIV-1 RNA viral load. Analysis was by intention to treat. FINDINGS: 108 patients were enrolled. All patients were similar for risk factors, age, sex, previous treatment, CD4-cell count (214/microL [SD14]) and log HIV-1 RNA viral load at baseline (4.7 copies/mL [0.1]). At month 3, the mean change in HIV-1 RNA was -1.04 log (0.14) in the study group compared with -0.46 log (0.17) in the control group (mean difference 0.58 log [95% CI 0.14-1.02], p=0.01). At month 6, changes were -1.15 (0.15) log copies/mL, and -0.67 (0.19) log copies/mL in the genotypic group and the control group, respectively (mean difference 0.48 log [0.01-0.97], p=0.05). Difference in the drop in viral load combined at 3 months and 6 months was significant (p=0.015). At month 3, HIV-1 RNA was lower than detection level (200 copies/mL) in 29% (19/65) of patients in the genotypic group versus 14% (6/43) in the control group (p=0.017). At month 6, the values were 32% (21/65) and 14% (6/43) (p=0.067) for the genotypic group and the control group, respectively. Therapy was generally well tolerated, with ten patients (six in the genotypic group, four in the control group) requiring toxic-effect-related drug modification. INTERPRETATION: We found genotypic-resistance testing to have a significant benefit on the virological response when choosing a therapeutic alternative. Further study of the use of genotypic-resistance testing in assisting clinical decision-making is warranted.

[Useful investigations for the prevention of recurring lithiasis (in the absence of anomalies of the urinary tract)]. / Les investigations utiles pour la prévention des récidives des lithiases (en l'absence d'anomalies des voies urinaires).

The prevalence of renal lithiasis and the rate of recurrences in affected patients raises the problem of the minimum number of investigations really needed to arrive at an accurate diagnosis and establish a potentially effective treatment. Stone recuperation is very important as it allows to carry out an accurate analysis of its constituent(s) (frequently heterogenous). Such analysis already brings forth accurate indications as to the etiology. Other biological investigations should be limited after a first episode of kidney stone disease, but recurring lithiasis will necessitate a much more thorough work-up. Recurrences in certain lithiases, such as those caused by urate calculi, are readily prevented by conventional therapy (uricosuric agents, alkalinization of urine). Withdrawal of certain medicines is paramount in iatrogenic lithiasis. Regarding calcium stones associated with hypercalciuria, results from dynamic tests and their pertinence for differentiating between hypercalciuria due to abnormally high digestive absorption and that due to excessive elimination are currently strongly contested. The role of alimentary factors seems extremely important and prescription of adapted diets appears to be quite effective in view of the present lack of crystal formation inhibitors.