Rapid Diagnostic Test-Based Management of Malaria: An Effectiveness Study in Papua New Guinean Infants With Plasmodium falciparum and Plasmodium vivax Malaria.

Background. In malaria-endemic areas it is recommended that febrile children be tested for malaria by rapid diagnostic test (RDT) or blood slide (BS) and receive effective malaria treatment only if results are positive. However, RDTs are known to perform less well for Plasmodium vivax. We evaluated the safety of withholding antimalarial drugs from young Papua New Guinean children with negative RDT results in areas with high levels of both Plasmodium falciparum and P. vivax infections. Methods. longitudinal prospective study of children aged 3-27 months visiting outpatient clinics for fever. RDT was administered at first visit. RDT and microscopy were performed if children returned because of persistent symptoms. Outcomes were rates of reattendance and occurrence of severe illnesses. Results. Of 5670 febrile episodes, 3942 (70%) involved a negative RDT result. In 133 cases (3.4%), the children reattended the clinic within 7 days for fever, of whom 29 (0.7%) were parasitemic by RDT or microscopy. Of children who reattended, 24 (0.7%) presented with a severe illness: 2 had lower respiratory tract infections (LRTIs) with low-density P. vivax on BS; 2 received a diagnosis of P. vivax malaria on the basis of RDT but BSs were negative; 16 had LRTIs; 3 had alternative diagnoses. Of these 24, 22 were cured at day 28. Two children died of illnesses other than malaria and were RDT and BS negative at the initial and subsequent visits. Conclusion. Treatment for malaria based on RDT results is safe and feasible even in infants living in areas with moderate to high endemicity for both P. falciparum and P. vivax infections.

Clinical consensus conference: survey on Gram-positive bloodstream infections with a focus on Staphylococcus aureus.

The increased incidence over the past decade of bloodstream infections (BSIs) caused by gram-positive bacteria, particularly methicillin-resistant Staphylococcus aureus, highlights the critical need for a consistent approach to therapy. However, there is currently no international consensus on the diagnosis and management of gram-positive BSIs. The Clinical Consensus Conference on Gram-Positive Bloodstream Infections was convened as a session at the 9th International Symposium on Modern Concepts in Endocarditis and Cardiovascular Infections held in 2007. Participants discussed various aspects of the practical treatment of patients who present with gram-positive BSI, including therapeutic options for patients with BSIs of undefined origin, the selection of appropriate empirical therapy, and treatment of complicated and uncomplicated BSIs. The opinions of participants about these key issues are reflected in this article.

Volemic status influences the response of plasma atrial natriuretic factor to positive airway pressure.

STUDY OBJECTIVE; To evaluate interactive effects of volemic status and positive end-expiratory pressure (PEEP) on the plasma levels of atrial natriuretic factor (ANF) in assist-controlled mechanical ventilation (MV). DESIGN: Three successive protocols applied in randomized order to each participant. SETTING: Clinical investigation laboratory. PARTICIPANTS: Twenty-one young, healthy adults. INTERVENTIONS: The three protocols were as follows: (1) MV+PEEP, normovolemia; (2) MV+PEEP, hypervolemia; and (3) spontaneous breathing (SB), hypervolemia. In protocols 1 and 2, a preliminary period of SB lasting 2 h was followed by MV alone (0.5 h), MV+20 cm H2O PEEP (1 h), and a recovery period of SB (1.5 h). Hypervolemia was induced by the continuous i.v. infusion of 3 L of 0.9% NaCl in 5 h (protocols 2 and 3). MEASUREMENTS AND RESULTS: Heart rate, BP, and the plasma levels of immunoreactive ANF and catecholamines were measured serially. During hypervolemia, ANF significantly decreased when PEEP was added to MV (protocol 2: from 31.1 +/- 2.7 to 20.7 +/- 1.5 fmol/mL; p < 0.01). This did not occur in normovolemia (protocol 1: from 20.0 +/- to 16.7 +/- 1.2 fmol/mL; p = NS). The different effects of MV+PEEP in normovolemia and hypervolemia were not related to differences in circulating catecholamine levels. CONCLUSIONS: These results demonstrate for the first time (to our knowledge) that volemic status modulates the response of plasma ANF to PEEP in humans. The role of ANF in the water and salt retention induced by MV with PEEP might be limited to hypervolemic conditions.

A randomized controlled trial of the effectiveness of a Computer-Assisted Cognitive Remediation (CACR) program in adolescents with psychosis or at high risk of psychosis: Short term and long term outcomes

The present study investigates the short- and long-term outcomes of a computer-assisted cognitive remediation (CACR) program in adolescents with psychosis or at high risk. 32 adolescents participated in a blinded 8-week randomized controlled trial of CACR treatment compared to computer games (CG). Clinical and neuropsychological evaluations were undertaken at baseline, at the end of the program and at 6-month. At the end of the program (n = 28), results indicated that visuospatial abilities (Repeatable Battery for the Assessment of Neuropsychological Status, RBANS; P = .005) improved signifi cantly more in the CACR group compared to the CG group. Furthermore, other cognitive functions (RBANS), psychotic symptoms (Positive and Negative Symptom Scale) and psychosocial functioning (Social and Occupational Functioning Assessment Scale) improved signifi cantly, but at similar rates, in the two groups. At long term (n = 22), cognitive abilities did not demonstrated any amelioration in the control group while, in the CACR group, signifi cant long-term improvements in inhibition (Stroop; P = .040) and reasoning (Block Design Test; P = .005) were observed. In addition, symptom severity (Clinical Global Improvement) decreased signifi cantly in the control group (P = .046) and marginally in the CACR group (P = .088). To sum up, CACR can be successfully administered in this population. CACR proved to be effective over and above CG for the most intensively trained cognitive ability. Finally, on the long-term, enhanced reasoning and inhibition abilities, which are necessary to execute higher-order goals or to adapt behavior to the ever-changing environment, were observed in adolescents benefi ting from a CACR.

Targeted expression of human CD1d in transgenic mice reveals independent roles for thymocytes and thymic APCs in positive and negative selection of Valpha14i NKT cells.

CD1d-dependent invariant Valpha14 (Valpha14i) NKT cells are innate T lymphocytes expressing a conserved semi-invariant TCR, consisting, in mice, of the invariant Valpha14-Jalpha18 TCR alpha-chain paired mostly with Vbeta8.2 and Vbeta7. The cellular requirements for thymic positive and negative selection of Valpha14i NKT cells are only partially understood. Therefore, we generated transgenic mice expressing human CD1d (hCD1d) either on thymocytes, mainly CD4+ CD8+ double positive, or on APCs, the cells implicated in the selection of Valpha14i NKT cells. In the absence of the endogenous mouse CD1d (mCD1d), the expression of hCD1d on thymocytes, but not on APCs, was sufficient to select Valpha14i NKT cells that proved functional when activated ex vivo with the Ag alpha-galactosyl ceramide. Valpha14i NKT cells selected by hCD1d on thymocytes, however, attained lower numbers than in control mice and expressed essentially Vbeta8.2. The low number of Vbeta8.2+ Valpha14i NKT cells selected by hCD1d on thymocytes was not reversed by the concomitant expression of mCD1d, which, instead, restored the development of Vbeta7+ Valpha14i NKT cells. Vbeta8.2+, but not Vbeta7+, NKT cell development was impaired in mice expressing both hCD1d on APCs and mCD1d. Taken together, our data reveal that selective CD1d expression by thymocytes is sufficient for positive selection of functional Valpha14i NKT cells and that both thymocytes and APCs may independently mediate negative selection.

Reciprocal regulation of brain and muscle Arnt-like protein 1 and peroxisome proliferator-activated receptor alpha defines a novel positive feedback loop in the rodent liver circadian clock.

Recent evidence has emerged that peroxisome proliferator-activated receptor alpha (PPARalpha), which is largely involved in lipid metabolism, can play an important role in connecting circadian biology and metabolism. In the present study, we investigated the mechanisms by which PPARalpha influences the pacemakers acting in the central clock located in the suprachiasmatic nucleus and in the peripheral oscillator of the liver. We demonstrate that PPARalpha plays a specific role in the peripheral circadian control because it is required to maintain the circadian rhythm of the master clock gene brain and muscle Arnt-like protein 1 (bmal1) in vivo. This regulation occurs via a direct binding of PPARalpha on a potential PPARalpha response element located in the bmal1 promoter. Reversely, BMAL1 is an upstream regulator of PPARalpha gene expression. We further demonstrate that fenofibrate induces circadian rhythm of clock gene expression in cell culture and up-regulates hepatic bmal1 in vivo. Together, these results provide evidence for an additional regulatory feedback loop involving BMAL1 and PPARalpha in peripheral clocks.

Ulcerative fungal keratitis in a Brown Swiss cow.

An 11-year-old Brown Swiss cow was referred to the Farm Animal Department of the Veterinary Teaching Hospital in Zurich, Switzerland, because of lateral recumbency due to puerperal hemolytic anemia. The animal had developed enophthalmos due to dehydration at the time of presentation. Two days after hospitalization, the cow showed blepharospasm and epiphora of the right eye. Ophthalmic examination of the right eye revealed a fluorescein-positive, paraxial, superficial corneal ulcer with focal edema, and mild superficial neovascularization. White corneal stromal infiltrates were seen at the edges of the ulcer bed. After initial topical treatment with an antibiotic ointment (Neomycin 3.5 mg/g, Bacitracin 250 IU/g) three times a day, an increase in corneal infiltrates was noted on re-examination 2 days later. Several fluorescein-negative, punctate, stromal, white opacities were seen dorsal to the ulcer. Cytology demonstrated the presence of fungal hyphae. Topical treatment with 2% miconazole ointment and 0.36% K-EDTA eye drops six times daily and four times daily, respectively, from the second day and continued antibiotics three times daily resolved the clinical symptoms within 6 days. Fungal culture identified the fungal organism as Eurotium amstelodami.

Plus de femmes que d'hommes VIH positifs sont réferees à une consultation d'adhésion thérapeutique [More HIV-positive women are referred to a medication adherence clinic than men].

HIV-positive patients with antiretroviral medication adherence issues are referred to an outpatient adherence clinic. Surprisingly, two-third of referred patients are women although more than 60% of the patients at the Infectious Disease Outpatient service are men. Women seem to be referred because of specific social factors: children at home, black sub-Saharan ethnicity, difficulties in medication and disease management due to stigmatization. Literature is poor and controversial and it is not possible to conclude whether medication adherence varies with gender. However, recent data seem to show that reasons for nonadherence vary according to gender.

Positive contrast visualization of nitinol devices using susceptibility gradient mapping.

MRI visualization of devices is traditionally based on signal loss due to T(2)* effects originating from local susceptibility differences. To visualize nitinol devices with positive contrast, a recently introduced postprocessing method is adapted to map the induced susceptibility gradients. This method operates on regular gradient-echo MR images and maps the shift in k-space in a (small) neighborhood of every voxel by Fourier analysis followed by a center-of-mass calculation. The quantitative map of the local shifts generates the positive contrast image of the devices, while areas without susceptibility gradients render a background with noise only. The positive signal response of this method depends only on the choice of the voxel neighborhood size. The properties of the method are explained and the visualizations of a nitinol wire and two stents are shown for illustration.

Increased expression of urokinase-type plasminogen activator mRNA determines adverse prognosis in ErbB2-positive primary breast cancer.

PURPOSE: To evaluate and validate mRNA expression markers capable of identifying patients with ErbB2-positive breast cancer associated with distant metastasis and reduced survival. PATIENTS AND METHODS: Expression of 60 genes involved in breast cancer biology was assessed by quantitative real-time PCR (qrt-PCR) in 317 primary breast cancer patients and correlated with clinical outcome data. Results were validated subsequently using two previously published and publicly available microarray data sets with different patient populations comprising 295 and 286 breast cancer samples, respectively. RESULTS: Of the 60 genes measured by qrt-PCR, urokinase-type plasminogen activator (uPA or PLAU) mRNA expression was the most significant marker associated with distant metastasis-free survival (MFS) by univariate Cox analysis in patients with ErbB2-positive tumors and an independent factor in multivariate analysis. Subsequent validation in two microarray data sets confirmed the prognostic value of uPA in ErbB2-positive tumors by both univariate and multivariate analysis. uPA mRNA expression was not significantly associated with MFS in ErbB2-negative tumors. Kaplan-Meier analysis showed in all three study populations that patients with ErbB2-positive/uPA-positive tumors exhibited significantly reduced MFS (hazard ratios [HR], 4.3; 95% CI, 1.6 to 11.8; HR, 2.7; 95% CI, 1.2 to 6.2; and, HR, 2.8; 95% CI, 1.1 to 7.1; all P < .02) as compared with the group with ErbB2-positive/uPA-negative tumors who exhibited similar outcome to those with ErbB2-negative tumors, irrespective of uPA status. CONCLUSION: After evaluation of 898 breast cancer patients, uPA mRNA expression emerged as a powerful prognostic indicator in ErbB2-positive tumors. These results were consistent among three independent study populations assayed by different techniques, including qrt-PCR and two microarray platforms.

Gender differences in HIV-positive persons in use of cardiovascular disease-related interventions : D:A:D study

INTRODUCTION: There is a lack of data on potential gender differences in the use of interventions to prevent and treat cardiovascular disease (CVD) in HIV-positive individuals. We investigated whether such differences exist in the D:A:D study. MATERIALS AND METHODS: Follow-up was from 01/02/99 until the earliest of death, 6 months after last visit or 01/02/13. Rates of initiation of lipid-lowering drugs (LLDs), angiotensin-converting enzyme inhibitors (ACEIs), anti-hypertensives and receipt of invasive cardiovascular procedures (ICPs; bypass, angioplasty, endarterectomy) were calculated in those without a myocardial infarction (MI) or stroke at baseline, overall and in groups known to be at higher CVD risk: (i) age >50, (ii) total cholesterol >6.2 mmol/l, (iii) triglyceride >2.3 mmol/l, (iv) hypertension, (v) previous MI, (vi) diabetes, or (vii) predicted 10-year CVD risk >10%. Poisson regression was used to assess whether rates of initiation were higher in men than women, after adjustment for these factors. RESULTS: At enrolment, women (n=13,039; median (interquartile range) 34 (29-40) years) were younger than men (n=36,664, 39 (33-46) years, p=0.001), and were less likely to be current smokers (29% vs. 39%, p=0.0001), to have diabetes (2% vs. 3%, p=0.0001) or to have hypertension (7% vs. 11%, p=0.0001). Of 49,071 individuals without a MI/stroke at enrolment, 0.6% women vs. 2.1% men experienced a MI while 0.8% vs. 1.3% experienced a stroke. Overall, women received ICPs at a rate of 0.07/100 person-years (PYRS) compared to 0.29/100 PYRS in men. Similarly, the rates of initiation of LLDs (1.28 vs. 2.46), anti-hypertensives (1.11 vs. 1.38) and ACEIs (0.82 vs. 1.37) were all significantly lower in women than men (Table 1). As expected, initiation rates of each intervention were higher in the groups determined to be at moderate/high CVD risk; however, within each high-risk group, initiation rates of most interventions (with the exception of anti-hypertensives) were generally lower in women than men. These gender differences persisted after adjustment for potential confounders (Table 1). CONCLUSION: Use of most CVD interventions was lower among women than men in the D:A:D study. Our findings suggest that actions should be taken to ensure that both men and women are monitored for CVD and, if eligible, receive appropriate CVD interventions.

Granular layer in the periplasmic space of gram-positive bacteria and fine structures of Enterococcus gallinarum and Streptococcus gordonii septa revealed by cryo-electron microscopy of vitreous sections.

High-resolution structural information on optimally preserved bacterial cells can be obtained with cryo-electron microscopy of vitreous sections. With the help of this technique, the existence of a periplasmic space between the plasma membrane and the thick peptidoglycan layer of the gram-positive bacteria Bacillus subtilis and Staphylococcus aureus was recently shown. This raises questions about the mode of polymerization of peptidoglycan. In the present study, we report the structure of the cell envelope of three gram-positive bacteria (B. subtilis, Streptococcus gordonii, and Enterococcus gallinarum). In the three cases, a previously undescribed granular layer adjacent to the plasma membrane is found in the periplasmic space. In order to better understand how nascent peptidoglycan is incorporated into the mature peptidoglycan, we investigated cellular regions known to represent the sites of cell wall production. Each of these sites possesses a specific structure. We propose a hypothetic model of peptidoglycan polymerization that accommodates these differences: peptidoglycan precursors could be exported from the cytoplasm to the periplasmic space, where they could diffuse until they would interact with the interface between the granular layer and the thick peptidoglycan layer. They could then polymerize with mature peptidoglycan. We report cytoplasmic structures at the E. gallinarum septum that could be interpreted as cytoskeletal elements driving cell division (FtsZ ring). Although immunoelectron microscopy and fluorescence microscopy studies have demonstrated the septal and cytoplasmic localization of FtsZ, direct visualization of in situ FtsZ filaments has not been obtained in any electron microscopy study of fixed and dehydrated bacteria.

MicroRNA Profile of Circulating CD4-positive Regulatory T Cells in Human Adults and Impact of Differentially Expressed MicroRNAs on Expression of Two Genes Essential to Their Function.

Regulatory T cells (Tregs) are characterized by a high expression of IL-2 receptor α chain (CD25) and of forkhead box P3 (FOXP3), the latter being essential for their development and function. Another major player in the regulatory function is the cytotoxic T-lymphocyte associated molecule-4 (CTLA-4) that inhibits cytotoxic responses. However, the regulation of CTLA-4 expression remains less well explored. We therefore studied the microRNA signature of circulating CD4(+) Tregs isolated from adult healthy donors and identified a signature composed of 15 differentially expressed microRNAs. Among those, miR-24, miR-145, and miR-210 were down-regulated in Tregs compared with controls and were found to have potential target sites in the 3'-UTR of FOXP3 and CTLA-4; miR-24 and miR-210 negatively regulated FOXP3 expression by directly binding to their two target sites in its 3'-UTR. On the other hand, miR-95, which is highly expressed in adult peripheral blood Tregs, positively regulated FOXP3 expression via an indirect mechanism yet to be identified. Finally, we showed that miR-145 negatively regulated CTLA-4 expression in human CD4(+) adult peripheral blood Tregs by binding to its target site in CTLA-4 transcript 3'-UTR. To our knowledge, this is the first identification of a human adult peripheral blood CD4(+) Treg microRNA signature. Moreover, unveiling one mechanism regulating CTLA-4 expression is novel and may lead to a better understanding of the regulation of this crucial gene.