A Multicenter Case-control Study of the Effect of Acute Rejection and Cytomegalovirus Infection on Pneumocystis Pneumonia in Solid Organ Transplant Recipients.

BACKGROUND: Pneumocystis pneumonia (PCP) is associated with morbidity and mortality in solid organ transplant (SOT) recipients. In this case-control study, we determined the association between posttransplant PCP and 3 variables: cytomegalovirus (CMV) infection, allograft rejection, and prophylaxis. METHODS: Eight transplant centers participated. For each case (SOT recipient with PCP), 3-5 controls (SOT recipients without PCP) were included. Controls were matched to the cases based on transplant center, type of allograft, and date of transplantation (±6 months). RESULTS: We enrolled 53 cases and 209 controls. Transplant types included kidney (n = 198), heart (n = 30), liver (n = 15), kidney-pancreas (n = 14), and lung (n = 5). PCP occurred beyond 12 months after transplantation in 43 (81.1%) cases. Thirty-four cases (64.1%) required admission to the intensive care unit, and 28 (52.8%) had mechanical ventilation. Allograft failure occurred in 20 (37.7%) cases, and 14 (26.9%) died. No patient developed PCP prophylaxis breakthrough. The proportion of female sex (P = .009), kidney dysfunction (P = .001), cardiac diseases (P = .005), diabetes mellitus (P = .03), allograft rejection (P = .001), CMV infection (P = .001), and severe lymphopenia (P = .001) were significantly higher in cases. In the logistic regression model, CMV infection (adjusted odds ratio [aOR], 4.6 [95% confidence interval {CI}, 2.0-10.5]) and allograft rejection (aOR, 3.0 [95% CI, 1.5-6.1]) significantly increased the likelihood of PCP. CONCLUSIONS: PCP was mostly a late-onset disease occurring after complete course of prophylaxis, particularly among patients with CMV infection or allograft rejection. PCP is associated with significant allograft loss. Extended prophylaxis targeting recipients with allograft rejection or CMV infection may reduce the risk of PCP.

Serious fungal infections in Canada.

There are currently no nationwide epidemiological data on fungal infections in Canada. We estimated the burden of serious fungal diseases using literature review and modeling, as per a methodology previously described by the LIFE program ( http://www.LIFE-worldwide.org ). Among the population of Canada (35.5 million in 2014), it was estimated that approximately 1.8% are affected by a serious fungal infection. Recurrent vulvovaginal candidiasis, severe asthma with fungal sensitization, and allergic bronchopulmonary aspergillosis are the most frequent infections, with population prevalences of 498,688 (1403/100,000), 73,344 (206/100,000), and 61,854 (174/100,000) cases, respectively. Over 3000 invasive fungal infections are estimated to occur annually, with incidences of 2068 cases (5.8/100,000) of invasive candidiasis, 566 cases (1.6/100,000) of invasive aspergillosis, 252 cases (0.71/100,000) of Pneumocystis pneumonia, 99 cases (0.28/100,000) of endemic mycoses, and 63 cases (0.18/100,000) of cryptococcosis. These estimates warrant validation through more formal epidemiological studies in Canada.

Early Initiation Rather Than Prolonged Duration of Antiretroviral Therapy in HIV Infection Contributes to the Normalization of CD8 T-Cell Counts.

BACKGROUND: CD8 T-cell counts remain elevated in human immunodeficiency virus (HIV) infection even after long-term antiretroviral therapy (ART), which is associated with an increased risk of non-AIDS-related events. We assessed the impact of ART initiation in early versus chronic HIV infection on trajectories of CD8 cell counts over time. METHODS: Of 280 individuals enrolled during primary HIV infection (PHI), 251 were followed up for 24 months; 84 started ART before 6 months of infection (eART), 49 started between 6 and 24 months, and 118 remained untreated. Plasma HIV viral load (VL), CD4 and CD8 cell counts were assessed at each study visit. CD8 counts were also examined in 182 age-matched HIV-infected individuals who started ART during chronic infection and maintained undetectable plasma VL for ≥5 years. RESULTS: At PHI baseline, higher CD8 cell counts were associated with more recent infection (P = .02), higher CD4 cell counts (P < .001), and higher VL (P < .001). The CD8 count in the eART group decreased from 797 to 588 cells/µL over 24 months (P < .001), to a level lower than that in untreated PHI (834 cells/µL; P = .004) or in long-term-treated patients with chronic HIV infection (743 cells/µL; P = .047). More prominent CD4 T-cell recovery was observed in the eART group than in the delayed ART group. CONCLUSIONS: ART initiated in early HIV infection is associated with improved resolution of CD8 T-cell elevation compared with long-term ART initiated in chronic infection. Early ART may help reduce the risk of non-AIDS-related events by alleviating this elevation.

A versatile laser-based apparatus for time-resolved ARPES with micro-scale spatial resolution.

We present the development of a versatile apparatus for 6.2 eV laser-based time and angle-resolved photoemission spectroscopy with micrometer spatial resolution (time-resolved µ-ARPES). With a combination of tunable spatial resolution down to ∼11 µm, high energy resolution (∼11 meV), near-transform-limited temporal resolution (∼280 fs), and tunable 1.55 eV pump fluence up to 3 mJ/cm2, this time-resolved µ-ARPES system enables the measurement of ultrafast electron dynamics in exfoliated and inhomogeneous materials. We demonstrate the performance of our system by correlating the spectral broadening of the topological surface state of Bi2Se3 with the spatial dimension of the probe pulse, as well as resolving the spatial inhomogeneity contribution to the observed spectral broadening. Finally, after in situ exfoliation, we performed time-resolved µ-ARPES on a ∼30 µm flake of transition metal dichalcogenide WTe2, thus demonstrating the ability to access ultrafast electron dynamics with momentum resolution on micro-exfoliated materials.

Histoplasmosis and subcutaneous nodules in a kidney transplant recipient: erythema nodosum versus fungal panniculitis.

Erythema nodosum (EN)-like lesions are a rare occurrence after solid organ transplantation. Differential diagnosis includes infective panniculitis, which can be a feature of progressive disseminated histoplasmosis (PDH), an uncommon but severe form affecting primarily immunocompromised hosts. We report on a fatal case of PDH, which presented as fungal panniculitis masquerading as EN in a renal allograft recipient 25 years after transplantation. We discuss the clinical, histopathological, and microbiological characteristics of this rare complication, with focus on its distinction from EN. This case emphasizes the central role of biopsy in transplant recipients presenting with cutaneous lesions, and the importance of clinicopathologic correlation and complementary microbiological investigations.

Sporadic Legionnaires' disease: the role of domestic electric hot-water tanks.

Sporadic community-acquired legionellosis (SCAL) can be acquired through contaminated aerosols from residential potable water. Electricity-dependent hot-water tanks are widely used in the province of Quebec (Canada) and have been shown to be frequently contaminated with Legionella spp. We prospectively investigated the homes of culture-proven SCAL patients from Quebec in order to establish the proportion of patients whose domestic potable hot-water system was contaminated with the same Legionella isolate that caused their pneumonia. Water samples were collected in each patient's home. Environmental and clinical isolates were compared using pulsed-field gel electrophoresis. Thirty-six patients were enrolled into the study. Legionella was recovered in 12/36 (33%) homes. The residential and clinical isolates were found to be microbiologically related in 5/36 (14%) patients. Contaminated electricity-heated domestic hot-water systems contribute to the acquisition of SCAL. The proportion is similar to previous reports, but may be underestimated.

Economic evaluation of isavuconazole for suspected invasive pulmonary aspergillosis in Canada.

BACKGROUND: Invasive mold infections (IMI) directly impact life expectancy, especially with delayed therapy. Among IMI, aspergillosis (IA) is more common than mucormycosis (IM), resulting in IA-targeted empirical treatment with voriconazole for suspected invasive pulmonary aspergillosis (IPA), despite IM ineffectiveness. Recently, isavuconazole was approved in Canada for IA and IM. The primary objective was to assess the cost-effectiveness of isavuconazole compared to voriconazole for suspected IPA in Canada. A secondary objective was to assess the impact of varying time horizons to address the wide spectrum of life expectancies, according to patients underlying diseases. RESEARCH DESIGN AND METHODS: A 5-year decision-tree was developed from the Canadian Ministry of Health (MoH) and societal perspectives. Efficacy parameters were extracted from SECURE/VITAL trials. Costs included treatment acquisition, hospitalization, adverse events and productivity loss. 3- and 10-year time horizon alternative scenarios and extensive sensitivity analyses were also conducted. RESULTS: From a MoH perspective, isavuconazole compared to voriconazole resulted in an incremental cost-utility ratio (ICUR) of $C30,160/QALY. 3- and10-year ICURs were also cost-effective, relative to a willingness-to-pay threshold of $C50,000/QALY. CONCLUSIONS: This study demonstrates that, in comparison to voriconazole, isavuconazole is a cost-effective strategy for the treatment of patients with suspected IPA, regardless of their life expectancy.

Optical manipulation of Rashba-split 2-dimensional electron gas.

In spintronics, the two main approaches to actively control the electrons' spin involve static magnetic or electric fields. An alternative avenue relies on the use of optical fields to generate spin currents, which can bolster spin-device performance, allowing for faster and more efficient logic. To date, research has mainly focused on the optical injection of spin currents through the photogalvanic effect, and little is known about the direct optical control of the intrinsic spin-splitting. To explore the optical manipulation of a material's spin properties, we consider the Rashba effect. Using time- and angle-resolved photoemission spectroscopy (TR-ARPES), we demonstrate that an optical excitation can tune the Rashba-induced spin splitting of a two-dimensional electron gas at the surface of Bi2Se3. We establish that light-induced photovoltage and charge carrier redistribution - which in concert modulate the Rashba spin-orbit coupling strength on a sub-picosecond timescale - can offer an unprecedented platform for achieving optically-driven spin logic devices.

Immune profile at HIV infection diagnosis: Evolution in the French Alps area over the last 20 years.

OBJECTIVES: Health of HIV-infected people relies on early antiretroviral therapy, i.e. early diagnosis. We aimed to determine whether the characteristics at HIV diagnosis in two French medical centres changed over the last 20 years. PATIENTS AND METHODS: All individuals diagnosed with HIV infection in Grenoble University Hospital (N=814) and Annecy Hospital (N=246) between 1997 and 2015 were included. We collected age, country of birth, mode of transmission, CD4T cell count, CD4/CD8 ratio, and HIV viral load. RESULTS: Among the 1060 patients (mean age 37.4±11 years, 70.2% of men), 42.5% were men having sex with men (MSM); 65.2% were born in France, and 24.4% were born in Africa. Mean CD4T cell count at diagnosis was 396±288/mm3 and was stable over the study period when considering all patients; when considering the MSM group, a significant increase over time was observed, with a mean increase of 7.3 CD4/mm3 per year (P<0.001). A higher CD4 count at diagnosis was observed after 2005 (400±289 vs 468±271/mm3, P=0.005). The proportion of MSM patients with a CD4 count<200/mm3 at diagnosis was lower after 2005 (14.7% after 2005 and 25.6% before, P=0.028) This was not observed in heterosexual patients (born in Africa or not). CONCLUSION: In the MSM population, CD4 count at diagnosis is higher after 2005, suggesting that screening campaigns have become more efficient. This was not observed in other populations, who should be better targeted in future strategies.

Exercise stimulates the mitogen-activated protein kinase pathway in human skeletal muscle.

Physical exercise can cause marked alterations in the structure and function of human skeletal muscle. However, little is known about the specific signaling molecules and pathways that enable exercise to modulate cellular processes in skeletal muscle. The mitogen-activated protein kinase (MAPK) cascade is a major signaling system by which cells transduce extracellular signals into intracellular responses. We tested the hypothesis that a single bout of exercise activates the MAPK signaling pathway. Needle biopsies of vastus lateralis muscle were taken from nine subjects at rest and after 60 min of cycle ergometer exercise. In all subjects, exercise increased MAPK phosphorylation, and the activity of its downstream substrate, the p90 ribosomal S6 kinase 2. Furthermore, exercise increased the activities of the upstream regulators of MAPK, MAP kinase kinase, and Raf-1. When two additional subjects were studied using a one-legged exercise protocol, MAPK phosphorylation and p90 ribosomal S6 kinase 2, MAP kinase kinase 1, and Raf-1 activities were increased only in the exercising leg. These studies demonstrate that exercise activates the MAPK cascade in human skeletal muscle and that this stimulation is primarily a local, tissue-specific phenomenon, rather than a systemic response to exercise. These findings suggest that the MAPK pathway may modulate cellular processes that occur in skeletal muscle in response to exercise.

Exercise modulates postreceptor insulin signaling and glucose transport in muscle-specific insulin receptor knockout mice.

Physical exercise promotes glucose uptake into skeletal muscle and makes the working muscles more sensitive to insulin. To understand the role of insulin receptor (IR) signaling in these responses, we studied the effects of exercise and insulin on skeletal muscle glucose metabolism and insulin signaling in mice lacking insulin receptors specifically in muscle. Muscle-specific insulin receptor knockout (MIRKO) mice had normal resting 2-deoxy-glucose (2DG) uptake in soleus muscles but had no significant response to insulin. Despite this, MIRKO mice displayed normal exercise-stimulated 2DG uptake and a normal synergistic activation of muscle 2DG uptake with the combination of exercise plus insulin. Glycogen content and glycogen synthase activity in resting muscle were normal in MIRKO mice, and exercise, but not insulin, increased glycogen synthase activity. Insulin, exercise, and the combination of exercise plus insulin did not increase IR tyrosine phosphorylation or phosphatidylinositol 3-kinase activity in MIRKO muscle. In contrast, insulin alone produced a small activation of Akt and glycogen synthase kinase-3 in MIRKO mice, and prior exercise markedly enhanced this insulin effect. In conclusion, normal expression of muscle insulin receptors is not needed for the exercise-mediated increase in glucose uptake and glycogen synthase activity in vivo. The synergistic activation of glucose transport with exercise plus insulin is retained in MIRKO mice, suggesting a phenomenon mediated by nonmuscle cells or by downstream signaling events.

Altered extracellular signal-regulated kinase signaling and glycogen metabolism in skeletal muscle from p90 ribosomal S6 kinase 2 knockout mice.

The p90 ribosomal S6 kinase (RSK), a cytosolic substrate for the extracellular signal-regulated kinase (ERK), is involved in transcriptional regulation, and one isoform (RSK2) has been implicated in the activation of glycogen synthase by insulin. To determine RSK2 function in vivo, mice lacking a functional rsk2 gene were generated and studied in response to insulin and exercise, two potent stimulators of the ERK cascade in skeletal muscle. RSK2 knockout (KO) mice weigh 10% less and are 14% shorter than wild-type (WT) mice. They also have impaired learning and coordination. Hindlimb skeletal muscles were obtained from mice 10, 15, or 30 min after insulin injection or immediately after strenuous treadmill exercise for 60 min. While insulin and exercise significantly increased ERK phosphorylation in skeletal muscle from both WT and KO mice, the increases were twofold greater in the KO animals. This occurred despite 27% lower ERK2 protein expression in skeletal muscle of KO mice. KO mice had 18% less muscle glycogen in the fasted basal state, and insulin increased glycogen synthase activity more in KO than WT mice. The enhanced insulin-stimulated increases in ERK and glycogen synthase activities in KO mice were not associated with higher insulin receptor or with IRS1 tyrosine phosphorylation or with IRS1 binding to phosphatidylinositol 3-kinase. However, insulin-stimulated serine phosphorylation of Akt was significantly higher in the KO animals. c-fos mRNA was increased similarly in muscle from WT and KO mice in response to insulin (2. 5-fold) and exercise (15-fold). In conclusion, RSK2 likely plays a major role in feedback inhibition of the ERK pathway in skeletal muscle. Furthermore, RSK2 is not required for activation of muscle glycogen synthase by insulin but may indirectly modulate muscle glycogen synthase activity and/or glycogen content by other mechanisms, possibly through regulation of Akt. RSK2 knockout mice may be a good animal model for the study of Coffin-Lowry syndrome.

[Group therapy versus individual follow-up in the management of the obese child]. / Comparaison de l'education thérapeutique collective au suivi individuel pour la prise en charge de l'obésité de l'enfant.

OBJECTIVE: To compare the 1-year outcome of obese children managed medically and dietetically in a group setting with those managed individually. PATIENTS AND METHODS: Two hundred and seventy-eight obese children [168 girls and 110 boys; body mass index (BMI) > + 2 SD] were followed by the Department of Pediatrics of the University Hospital of Angers between January 1996 and December 2002 (175 children in a group setting and 103 individually). The group program consisted of 3 monthly sessions of slide shows for groups of 10 children, followed by individual consultations once every 3 months alternating medical and dietetic concerns. The individual program consisted of successive medical and dietetic consultations on the same day once every 3 months. RESULTS: The children were 10.3 +/- 2.9 years old, and their BMI was 5.5 +/- 2.1 SD, with no difference between groups. The drop-out rate (children not returning after the 1st consultation) was 17%, with no difference between groups. The drop-out rate after 1 year was 65% in the group program and 41% in the individual program (p < 0.05). Of the children who were followed for 1 year, 88% of those treated in a group setting had stabilized or reduced their BMI, whereas 74% of the individually-treated children had done so (p < 0.05). CONCLUSION: Among obese children followed for 1 year, group treatment resulted in a greater percentage of stabilization or reduction in BMI than did individual treatment, although the drop-out rate was higher in the group setting. Psychological support and physical activity sessions adapted for obese children would help to maintain motivation in these children.

Epinephrine and insulin stimulate different mitogen-activated protein kinase signaling pathways in rat skeletal muscle.

Little is known about the regulation of the mitogen-activated protein (MAP) kinase signaling cascades by hormonal stimulation in vivo. The extracellular signal-regulated kinase (ERK) and the c-jun kinase (JNK) are two MAP kinase signaling pathways that could play a role in the cellular response to hormones such as insulin and epinephrine. We studied the effects of insulin (20 U/rat) and epinephrine (25 microg/100 g body wt) injected in vivo on ERK and JNK signaling in skeletal muscle from Sprague-Dawley rats. Insulin significantly increased ERK phosphorylation and the activity of its downstream substrate, the p90 ribosomal S6 kinase 2 (RSK2), by 1.4-fold, but it had no effect on JNK activity. In contrast, epinephrine had no effect on ERK phosphorylation or RSK2 activity, but it increased JNK activity by twofold, an effect that was inhibited by the presence of combined alpha and beta blockade. Furthermore, the phosphorylation of both p46 and p55 isoforms of JNK, measured by phosphospecific antibody, was increased severalfold. The activity and phosphorylation of MAP kinase kinase (MKK)-4, an upstream regulator of JNK, was unchanged by epinephrine. Incubation of isolated soleus muscles in vitro with epinephrine (10(-5) mol/l) also increased JNK activity by twofold. These data are the first to demonstrate that epinephrine can increase JNK activity. Insulin and epinephrine have different effects on MAP kinase signaling pathways in skeletal muscle, which may be one of the underlying molecular mechanisms through which these hormones regulate opposing metabolic functions.

Biochemical and radiologic improvement in Paget's disease of bone treated with alendronate: a randomized, placebo-controlled trial.

PURPOSE: The potent bisphosphonates offer great promise in the management of Paget's disease of bone, but are currently available only as parenteral preparations in most countries. There is a need for a well-tolerated, oral therapy. Furthermore, none of the currently available therapies have been rigorously demonstrated to heal the lytic bone lesions characteristic of this condition. Alendronate is a potent new oral aminobisphosphonate that has shown promising effects on Paget's disease in preliminary studies. METHODS: We report a double-blind, randomized comparison of oral alendronate 40 mg/day and placebo over 6 months in 55 patients with Paget's disease. Efficacy was determined from measurements of biochemical indices of bone turnover (serum alkaline phosphatase and urine N-telopeptide) and blinded radiologic assessment of lytic bone lesions. RESULTS: N-telopeptide excretion declined by 86% and serum alkaline phosphatase by 73% in patients receiving alendronate, but remained stable in patients receiving placebo (P < 0.001 between groups for both indices). Responses were similar whether or not patients had previously received bisphosphonate treatment. Alendronate treatment normalized alkaline phosphatase in 48% of patients. Forty-eight percent of alendronate-treated patients showed radiologic improvement in osteolysis whereas in the placebo group only 4% improved (P = 0.02 for between-groups comparison). No patient in either group showed worsening of osteolysis. Bone histomorphometry indicated that alendronate tended to normalize turnover indices. There was no evidence of abnormal mineralization in bone biopsies taken from 12 alendronate-treated subjects. The treatment was well tolerated. CONCLUSION: Oral alendronate appears to be a safe and effective therapy for Paget's disease and results in healing of lytic bone lesions.

The interactions of amphotericin B with various sterols in relation to its possible use in anticancer therapy.

Amphotericin B (AmB) is still the most common anti-fungal agent used to treat systemic fungal infections. It is known that this antibiotic acts by forming pores with the ergosterol contained in the membranes of fungi, but it also interacts with the cholesterol contained in the membranes of eukaryotic cells, hence its toxicity. AmB may also interact with the most common oxidation products of cholesterol found in vivo, together with interacting with biosynthetic precursors of cholesterol, namely, lanosterol and 7-dehydrocholesterol (7-DHC). The purpose of the present work was to study the interactions in solution between AmB and these various sterols, the techniques used being UV-Vis spectroscopy and differential scanning calorimetry. The results are globally interpreted in terms of the structural differences between the sterols. We show that AmB selectively interacts with 7-DHC which, according to a recent hypothesis proposed in the literature, has been identified in connexion with a therapeutic strategy against hepatocellular carcinomas. We find that the affinity of AmB towards 7-DHC is even greater than the affinity of the antibiotic towards ergosterol. We also find that AmB selectively interacts with the principal oxidation product of cholesterol, 7-ketocholesterol, a situation that has to be taken into account when AmB is administered.

A large prospective study assessing injection site reactions, quality of life and preference in patients using the Biojector vs standard needles for enfuvirtide administration.

OBJECTIVES: To determine the severity of injection site reactions (ISRs), patient quality of life (QoL) and preference when enfuvirtide is administered by the Biojector (Bioject, Medical Technologies, Inc., Tualatin, OR, USA) relative to standard needles. METHODS: A total of 201 HIV-positive patients on stable enfuvirtide-based therapy (n=184) or initiating such therapy (n=17) were evaluated prospectively after switching from standard needles to the Biojector system. Patients used needles for a minimum of 2 weeks prior to switching to the Biojector. Questionnaires to assess the incidence and severity of ISRs (31-item score) and QoL [Medical Outcomes Study HIV Health Survey (MOS-HIV)] were administered at baseline and following a minimum of 14 days of Biojector use. RESULTS: The median changes in ISR score and number of ISRs following a median of 1.0 month [interquartile range (IQR) 0.9, 1.3] of Biojector use were -3 (IQR -7, 1) and -1 (IQR -3, 1), respectively. The severity of pain (P<0.0001), induration (P<0.0001), pruritus (P<0.0001), nodules (P<0.0001) and erythema (P<0.0001) all decreased with the Biojector. Administration of enfuvirtide with the Biojector was associated with an improved patient QoL (P<0.0001), and was preferred by 72% of patients. CONCLUSIONS: Compared with needles, the Biojector was associated with a decreased severity of ISRs and improved QoL in patients taking enfuvirtide.

Sulfobacillus disulfidooxidans sp. nov., a new acidophilic, disulfide-oxidizing, gram-positive, spore-forming bacterium.

An acidophilic, disulfide-oxidizing, mesophilic, aerobic bacterium was isolated from wastewater sludge. The new organism is a gram-positive sporulated rod. It can use elemental sulfur and pyrite as sole energy sources and grows on organic substrates such as glutamate and glucose. It also grows on the following organic sulfur substrates: oxidized and reduced glutathione, cysteine, cystine, and dithio(bis)benzothiazole and clearly shows a preference for disulfide bond-containing substrates. The optimal pH of growth is between 1.5 and 2.5, depending on the substrate used, and the growth temperature range varies from 4 to 40 degrees C, with an optimal value at 35 degrees C. The G + C chromosomal DNA content was measured at 53 +/- 1 mol%. Phylogenetic analysis of 16S genes coding for rRNA sequences places the new isolate in the genus Sulfobacillus. In addition, unique phenotypic and physiologic characteristics and DNA homology values assign the isolate to a new species in the genus. Therefore, this new isolate has been named Sulfobacillus disulfidooxidans and has been assigned ATCC number 51911.