Prospective evaluation of the management of urinary tract infections in 134 French nursing homes.

OBJECTIVE: Prospective assessment of the management of urinary tract infections (UTI) in the nursing homes of the Hauts-de-France region. PATIENTS AND METHODS: A 50-question form had to be filled in for up to five consecutive residents treated for UTI in each nursing home. If necessary, diagnoses were reclassified according to the 2014 French Infectious Diseases Society guidelines. Analyses were presented per supposed (reported) and reclassified diagnoses. RESULTS: Of 397 contacted facilities, 134 participated and informed 444 UTI episodes. Reported diagnostic criteria were burning urination (32%), malodorous urine (29%), confusion (28%), and turbid urine (19%). Twenty-one percent of diagnoses were based on erroneous criteria. Less than 50% of residents had a urine dipstick test performed and 94% a urine culture. The main pathogen was Escherichia coli. Reported indications were uncomplicated cystitis (32%), unspecified UTI (26%), complicated cystitis (9%), while no reason was given in 25% of cases. Only 10% of diagnoses were consistent with the guidelines: complicated cystitis (49%), asymptomatic bacteriuria (21%), acute pyelonephritis (21%), male UTI (9%). Almost 85% of prescriptions were active on the isolated bacteria. The empirical antibiotic therapy was consistent with the diagnosis in 16% of cases (30% for reclassified diagnoses). The two most prescribed antibiotic classes were fluoroquinolones (22.1%) and oral third-generation cephalosporins (19.1%). Only two of 157 possible de-escalations were performed. Duration of treatment was adequate for 19% of UTIs (9.6% of reclassified cases). CONCLUSION: Our study revealed multiple deficiencies in diagnosis, antibiotic choice, treatment duration, and reevaluation.

Providing Coverage for the Unique Lifelong Health Care Needs of Living Kidney Donors Within the Framework of Financial Neutrality.

Organ donation should neither enrich donors nor impose financial burdens on them. We described the scope of health care required for all living kidney donors, reflecting contemporary understanding of long-term donor health outcomes; proposed an approach to identify donor health conditions that should be covered within the framework of financial neutrality; and proposed strategies to pay for this care. Despite the Affordable Care Act in the United States, donors continue to have inadequate coverage for important health conditions that are donation related or that may compromise postdonation kidney function. Amendment of Medicare regulations is needed to clarify that surveillance and treatment of conditions that may compromise postdonation kidney function following donor nephrectomy will be covered without expense to the donor. In other countries lacking health insurance for all residents, sufficient data exist to allow the creation of a compensation fund or donor insurance policies to ensure appropriate care. Providing coverage for donation-related sequelae as well as care to preserve postdonation kidney function ensures protection against the financial burdens of health care encountered by donors throughout their lives. Providing coverage for this care should thus be cost-effective, even without considering the health care cost savings that occur for living donor transplant recipients.

Intra-cellular immunosuppressive drugs monitoring: A step forward towards better therapeutic efficacy after organ transplantation?

Immunosuppressive drugs (IS) used in solid organ transplantation are critical dose drugs with high intra- and inter-subject variability. Therefore, IS therapeutic drug monitoring (TDM), mainly as trough levels analysis, is a major support to patient management, mandatory to optimize clinical outcome. Even though transplant patients undoubtedly benefited by this pre-dose (C0) monitoring, the relationship between these C0 concentrations and the incidence of graft rejections remains hardly predictable. Identification and validation of additional biomarkers of efficacy are therefore very much needed. As the main IS effects are mediated through the inhibition of lymphocyte proliferation pathways, direct drug quantification within this target compartment would appear meaningful, providing hopefully more consistent information on drug efficacy. Due to the analytical performances improvement, these intracellular concentrations became accessible for comprehensive studies regarding clinical benefit of intracellular IS TDM after solid organ transplantation. Over the last ten years, number of studies investigated the potential relationship between IS blood and intracellular pharmacokinetics, genetic variability, and clinical efficacy after solid organ transplantation. A recent literature review suggests that calcineurin inhibitors (tacrolimus and cyclosporine) intracellular concentrations appear more closely related to drug efficacy than blood levels. This closer association has however not been described for the m-TOR inhibitors (sirolimus, everolimus) and the antimetabolite (mycophenolic acid). Additional larger and multicenter clinical trials are needed to confirm these observations.

Living and deceased organ donation should be financially neutral acts.

The supply of organs­particularly kidneys­donated by living and deceased donors falls short of the number of patients added annually to transplant waiting lists in the United States. To remedy this problem, a number of prominent physicians, ethicists, economists and others have mounted a campaign to suspend the prohibitions in the National Organ Transplant Act of 1984 (NOTA) on the buying and selling of organs. The argument that providing financial benefits would incentivize enough people to part with a kidney (or a portion of a liver) to clear the waiting lists is flawed. This commentary marshals arguments against the claim that the shortage of donor organs would best be overcome by providing financial incentives for donation. We can increase the number of organs available for transplantation by removing all financial disincentives that deter unpaid living or deceased kidney donation. These disincentives include a range of burdens, such as the costs of travel and lodging for medical evaluation and surgery, lost wages, and the expense of dependent care during the period of organ removal and recuperation. Organ donation should remain an act that is financially neutral for donors, neither imposing financial burdens nor enriching them monetarily.

Recent Y chromosome divergence despite ancient origin of dioecy in poplars (Populus).

All species of the genus Populus (poplar, aspen) are dioecious, suggesting an ancient origin of this trait. Despite some empirical counter examples, theory suggests that nonrecombining sex-linked regions should quickly spread, eventually becoming heteromorphic chromosomes. In contrast, we show using whole-genome scans that the sex-associated region in Populus trichocarpa is small and much younger than the age of the genus. This indicates that sex determination is highly labile in poplar, consistent with recent evidence of 'turnover' of sex-determination regions in animals. We performed whole-genome resequencing of 52 P. trichocarpa (black cottonwood) and 34 Populus balsamifera (balsam poplar) individuals of known sex. Genomewide association studies in these unstructured populations identified 650 SNPs significantly associated with sex. We estimate the size of the sex-linked region to be ~100 kbp. All SNPs significantly associated with sex were in strong linkage disequilibrium despite the fact that they were mapped to six different chromosomes (plus 3 unmapped scaffolds) in version 2.2 of the reference genome. We show that this is likely due to genome misassembly. The segregation pattern of sex-associated SNPs revealed this to be an XY sex-determining system. Estimated divergence times of X and Y haplotype sequences (6-7 Ma) are much more recent than the divergence of P. trichocarpa (poplar) and Populus tremuloides (aspen). Consistent with this, in P. tremuloides, we found no XY haplotype divergence within the P. trichocarpa sex-determining region. These two species therefore have a different genomic architecture of sex, suggestive of at least one turnover event in the recent past.

Oesophageal and gastric obstruction in a cocaine body packer.

While the management of asymptomatic body packers is mainly conservative, few individuals will require surgery for acute toxicity related to packets rupture, intestinal obstruction or very slow progression of the packages. Obstruction of the lower oesophagus or stomach is not frequently reported. We report the case of a 49-year-old woman who had ingested 92 cocaine-containing packages. She was admitted to the hospital after opioid syndrome related to the intake of morphine and codeine to decrease intestinal transit. The presence of more than 80 packages was suspected in the stomach on the initial abdomen computed tomography. Due to the absence of progression of the packages after four days of well-conducted laxative therapy and to major gastric distension at abdomen tomography, surgery was decided and gastrotomy allowed the evacuation of 80 packages that were still present in the stomach or in the lower oesophagus. In addition, 12 other packages had been retrieved either after laxative therapy (9) or by evacuation via the anal canal (3) after palpation of the intestine during the surgical procedure. No complication was observed.

Pink urine.

A 55-year-old man was admitted after a suspected hypnotic overdose of valerian extracts. In addition to altered consciousness, the first clinical symptoms included not only diffuse rash on the face, trunk, and limbs, but also an inspiratory dyspnea with a marked hypoxemia. A major laryngeal edema was noted during orotracheal intubation. After correction of hypoxemia, the patient became agitated and propofol was administered by continuous infusion. In addition, the patient passed pink urine staining the urine collection bag. The presence of an unidentified toxic substance was suspected.

The spectrum of acute heart failure after venlafaxine overdose.

OBJECTIVE: Venlafaxine is a bicyclic antidepressant that may be associated with severe cardiotoxicity following large overdose. The purpose of this short case series is to present different patterns of venlafaxine-related cardiotoxicity and to discuss the potential mechanisms. CASE SERIES: Between January 2010 and July 2011, four patients were admitted to an ICU with acute left ventricular failure following large venlafaxine overdoses. The age of the four female patients ranged from 35 to 65 years. None of them had no history of cardiovascular disease. The amount of venlafaxine ingested by history ranged from 3150 to 13500 mg (extended-release preparation in two cases). The peak serum venlafaxine concentration was between 2153.3 and 9950 ng/ml. Three patients died and one recovered rapidly. The initial ECG revealed only mild abnormalities in two cases. In two patients, at least one ECG recording demonstrated a widening of QRS interval. In three patients, echocardiography disclosed a left ejection fraction of 15%-18%. Two patients presented a severe serotonin syndrome, with major rhabdomyolysis. Seizures were noted in two cases, including one patient with status epilepticus. Three patients were mechanically ventilated. The causes of death were refractory hypoxemia, malignant arrhythmias, and cardiogenic shock, respectively. DISCUSSION: Severe and diffuse left ventricular dysfunction may be observed after large venlafaxine overdoses and this is not always associated with severe cardiac conduction function abnormalities. The mechanisms underlying venlafaxine-related cardiac failure with preserved normal cardiac conduction are discussed. A possible explanation may be a catecholamine-induced myocardial damage in relationship with the inhibition of norepinephrine (and dopamine) reuptake.

Criteres echographiques predictifs d'hypertension portale due a Schistosoma mansoni dans une zone d'endemie recente

Les premiers cas de bilharziose a Schistosoma mansoni ont ete depistes dans la vallee du fleuve Senegal il y a dix ans. Aujourd'hui; le niveau d'endemie est tel que certains villages presentent des prevalences superieures a 90 p. 100. Le diagnostic de schistosomose n'est parfois porte qu'au stade d'hypertension portale (rupture de varices oesophagiennes). L'endoscopie est l'examen de reference pour detecter la presence de varices oesophagiennes; mais son application sur le terrain est delicate. C'est pourquoi leur recherche par echographie; acte non invasif; est d'un grand interet. Cette etude a recherche chez 101 sujets de la region de Richard-Toll l'existence de signes d'hypertension portale; simultanement par fibroscopie digestive et par echographie. Elle a montre que moins de 10 ans apres la description du premier cas de bilharziose; il existait deja des formes compliquees d'hypertension portale dans la region. Cette etude a egalement cherche a etablir un score echographique permettant de predire l'existence d'une hypertension portale. Les items retenus ont ete l'epaississement de la paroi des vaisseaux portes; le diametre de la veine porte et de la veine splenique et l'aspect collabe ou non de la veine splenique pendant l'inspiration. Au cours de l'etude; l'echelle de score ainsi etablie a semble etre un bon temoin predictif du developpement de varices oesophagiennes. L'echographie represente un examen utile pour le depistage des formes compliquees de schistosomoses susceptibles de representer un moyen simple de surveillance des populations residant en zone d'endemie recente et intense de schistosomose

Schistosomiasis co-infection in humans influences inflammatory markers in uncomplicated Plasmodium falciparum malaria.

Malaria and schistosomiasis are the two major parasite diseases present in developing countries. The epidemiological co-infection with schistosomiasis could influence the development of the physiological reaction associated with Plasmodium falciparum infection in human. Most studies have demonstrated the association of circulating levels of interferon-gamma (IFN-gamma), tumour necrosis factor-a (TNF-alpha), interleukin-10 (IL-10), transforming growth factor (TGF-beta) and soluble Tumour Necrosis Factor Receptors (sTNF-RI and sTNF-RII) with the morbidity of malaria. In the present study, we showed that Schistosoma haematobium co-infection influences, in an age-dependent manner, the unbalance between pro- and anti-inflammatory circulating cytokines that play a key role during malaria infection. Indeed, children co-infected by S. haematobium have higher levels of IFN-gamma and sTNF-RII than children infected only by P. falciparum. In contrast, co-infected adults presented a significant increase of IFN-gamma, IL-10, TGF-beta, sTNF-RI and sTNF-RII rates and IL-10/TNF-alpha ratio. Taken together, this study indicates that schistosomiasis co-infection can unbalance the regulation of inflammatory factors in uncomplicated P. falciparum malaria. The possible consequences of the schistosomiasis co-infection for age-dependent malaria morbidity are discussed.

A novel cellular RNA helicase, RH116, differentially regulates cell growth, programmed cell death and human immunodeficiency virus type 1 replication.

In an effort to define novel cellular factors regulating human immunodeficiency virus type 1 (HIV-1) replication, a differential display analysis has been performed on endogenously infected cells stimulated with the HIV-suppressive immunomodulator Murabutide. In this study, the cloning and identification of a Murabutide-downregulated gene, named RH116, bearing classical motifs that are characteristic of the DExH family of RNA helicases, are reported. The 116 kDa encoded protein shares 99.9 % similarity with MDA-5, an inducible RNA helicase described recently. Ectopic expression of RH116 in HeLa-CD4 cells inhibited cell growth and cell proliferation but had no measurable effect on programmed cell death. RH116 presented steady state cytoplasmic localization and could translocate to the nucleus following HIV-1 infection. Moreover, the endogenous expression of RH116, at both the transcript and protein levels, was found to be considerably upregulated after infection. Overexpression of RH116 in HIV-1-infected HeLa-CD4 cells also resulted in a dramatic increase in the level of secreted viral p24 protein. This enhancement in virus replication did not stem from upregulated proviral DNA levels but correlated with increased unspliced and singly spliced viral mRNA transcripts. These findings implicate RH116 in the regulation of HIV-1 replication and point to an apoptosis-independent role for this novel helicase in inducing cell growth arrest.

Adjuvant activity of free Bordetella pertussis filamentous haemagglutinin delivered by mucosal routes.

The development of safe and potent mucosal adjuvants remains a major objective in vaccinology. The potential usefulness of filamentous haemagglutinin (FHA) of Bordetella pertussis as an adjuvant was assessed in a mouse model. The glutathione-S-transferase of Schistosoma mansoni (Sm28GST) was used for intranasal administration, while the gut-resistant keyhole limpet haemocyanin (KLH) was administrated by the oral route. For both antigens, coadministration with FHA increased antigen-specific immunoglobulin titres. This adjuvant effect did not require chemical cross-linking or direct interaction between FHA and the antigen tested. FHA also behaved as an adjuvant by the subcutaneous route, indicating that its adjuvanticity is not restricted to binding to mucosal surfaces. The FHA-induced adjuvanticity was also observed in mice with high anti-FHA antibody titres as a result of antipertussis vaccination, indicating that pre-existing anti-FHA antibodies do not impair FHA adjuvanticity. No mRNA coding for proinflammatory cytokines was induced in the lungs after intranasal FHA administration. However, an increase in the levels of mRNAs coding for B7-1, transforming growth factor (TGF)-beta and major histocompatibility complex (MHC)-II was detected in the lungs after FHA administration. Although the molecular mechanisms of the FHA-induced adjuvanticity remain to be elucidated, the data presented here indicate that this adhesin, already assessed for human use as a pertussis vaccine constituent, represents a promising adjuvant to improve the humoral immune response when given by mucosal routes.

Failure of a recombinant Schistosoma bovis-derived glutathione S-transferase to protect cattle against experimental Fasciola hepatica infection.

The potential of a recombinant Schistosoma bovis 28-kDa glutathione S-transferase (rSb28GST) to protect cattle against Fasciola hepatica was tested in a vaccination trial. Thirty two calves were randomly divided into four groups of eight animals. Calves of the three vaccine groups received two intramuscular injections at 3 weeks interval, of 0.250mg rSb28GST in either aluminium hydroxide (Al(OH)(3)), Quil A, or PBS emulsified in an equal volume of Freund's complete adjuvant (FCA).Animals of the control group received injections of Al(OH)(3)/PBS only. All animals were challenged orally with a total of 360 metacercariae of F. hepatica, spread over 6 weeks. All groups of vaccinated animals produced measurable IgG antibody titers to rSb28GST after vaccination. Animals immunised with FCA adjuvanted vaccine had the highest and more durable antibody titers and only sera from this group recognised an approximately 24kDa protein band from F. hepatica, that is thought to be a F. hepatica GST. Despite a good antibody response differences in cumulative faecal egg output between the groups were not statistically significant. In addition, no significant difference was found between groups in terms of total worm numbers or percentage of immature flukes recovered at necropsy. In conclusion, the recombinant S. bovis 28kDa GST was not found to adequately protect cattle against experimental F. hepatica challenge, using either aluminium hydroxide, Quil A or FCA as adjuvant.

Malaria co-infection in children influences antibody response to schistosome antigens and inflammatory markers associated with morbidity.

The epidemiological coexistence of schistosomiasis and malaria is frequently observed in developing countries. Co-infection with malaria in children could influence the development of acquired immunity associated with the resistance or the pathology of schistosomiasis. In the present study, performed during May to June 1996 in Senegal, the humoral immune response to Schistosoma haematobium 28 kDa glutathione S-transferase (Sh28GST) vaccinal antigen and to soluble egg antigens (SEA) has been evaluated in individuals infected by S. haematobium. Specific immunoglobulin G3 (IgG3) and IgE responses were significantly higher in co-infected children with Plasmodium falciparum compared with children infected with S. haematobium only. In addition, circulating levels of interferon-gamma (IFN-gamma), interleukin-10 (IL-10), and soluble tumor necrosis factor receptor II (sTNF-RII), 3 parameters associated with schistosomiasis morbidity, were significantly increased in co-infected children. Taken together, this study indicated that malaria co-infection can both influence the acquired specific immune response to schistosome antigens and unbalance the regulation of inflammatory factors closely involved in schistosomiasis pathology.

The transcriptional response of human macrophages to murabutide reflects a spectrum of biological effects for the synthetic immunomodulator.

The synthetic immunomodulator murabutide (MB) presents multiple biological activities with minimal toxicity in animals and in man. Although MB is known to target cells of the reticuloendothelial system and to regulate cytokine synthesis, the molecular mechanisms underlying several of its biological effects are still largely unknown. In an effort to define cellular factors implicated in the immunomodulatory and HIV-suppressive activities of MB, we have undertaken profiling the regulated expression of genes in human monocyte-derived macrophages (MDM) following a 6-h stimulation with this synthetic glycopeptide. Oligonucleotide microarray analysis was performed on RNA samples of differentiated MDM from four separate donors, using probe sets corresponding to 1081 genes. We have identified, in a reproducible fashion, the enhanced expression of 40 genes and the inhibition of 16 others in MB-treated MDM. These regulated genes belonged to different families of immune mediators or their receptors, transcription factors and kinases, matrix proteins and their inhibitors, ion channels and transporters, and proteins involved in cell metabolic pathways. Additional verification of the regulated expression of selected genes was carried out using Northern blots or the quantification of released proteins in MDM cultures. The profile of MB-regulated genes in MDM provides a molecular basis for some of its previously reported biological activities, and reveals new set of genes targeted by the immunomodulator suggesting potential application in novel therapeutic indications.

Cloning of the rat IL-5Ralpha gene: analysis of 5'-upstream region and expression by B cells.

Although rats are widely used for the analysis of allergic reactions and parasitic infections where IL-5 is involved, nothing is currently known of the expression of IL-5 receptor in this species. In this study, the cDNA sequence, genomic structure and the transcriptional regulation of the rat IL-5Ralpha were analyzed. The rat IL-5Ralpha gene, which we localized to chromosome 4q34-q41, spans more than 25 kb and consists of 12 exons. Promoter activity was seen in different cell lines and analysis by deletion experiments allowed to identify two negative regulatory regions which did not differ when tested either with IL-5Ralpha-negative or positive cells. Finally, the investigation of the expression of IL-5Ralpha showed that it is expressed in lung, spleen, liver, and purified rat B cells from normal rat. This can provide an explanation for the role of rat IL-5 as B-cell growth factor and a relevant model in order to better understand the activity of IL-5 on human B cells.

SS-56, a novel cellular target of autoantibody responses in Sjögren syndrome and systemic lupus erythematosus.

Certain autoimmune disorders, including Sjögren syndrome (SS) and systemic lupus erythematosus (SLE), are characterized by autoantibodies against the Ro/SSA and La/SSB cellular antigens. Although the implication of these autoantibodies in disease pathogenesis is still unclear, it is believed that the aberrant responses against autoantigens may extend to other proteins that are not yet well defined. In an attempt to analyze the regulated gene expression in lymphocytes by an HIV-suppressive immunomodulator, we have identified and cloned a novel gene encoding a 56-kDa protein, named SS-56, which is structurally related to the 52-kDa Ro/SSA antigen. The new protein showed primarily perinuclear cytoplasmic localization, and recombinant SS-56 was found to react in ELISA with sera from most patients with SS or SLE. Western blot analysis confirmed the autoantigenic nature of native SS-56 in extracts from HeLa cells. Interestingly, the incidence of antibodies to SS-56 was associated with visceral complications in SLE, and roughly half of the 17 SS or SLE patients with no detectable antibodies to SSA and SSB antigens presented measurable antibodies against recombinant SS-56. Thus, SS-56 represents a new member of the SS family of autoantigens and could become an additional and important diagnostic marker for SS and SLE.

Features of the antibody response attributable to plasmid backbone adjuvanticity after DNA immunization.

DNA vaccination induces antigen-specific immune responses with characteristics distinct from other vaccination modes. In the present study, the contribution of the plasmid backbone adjuvant effect to the quality of the DNA-raised antibody response was investigated. For this purpose, three intradermal primings were compared in mice using: (1) the recombinant Schistosoma haematobium glutathione S-transferase antigen (rSh28GST): (2) rSh28GST supplemented with a non-coding plasmid; and (3) a Sh28GST-encoding plasmid. In contrast to immunization with the protein, DNA immunization elicited a very stable antibody (Ab) response over a prolonged period of time. This feature was attributed to the plasmid backbone, because co-administration of the non-coding plasmid with rSh28GST allowed the maintenance of the specific Ab response. A strong anamnestic Ab response was induced after intradermal boost with rSh28GST only in the mice primed with pMSh. This indicated that the selective ability of DNA vaccination to induce memory humoral response was independent of the plasmid backbone. In contrast the plasmid backbone was found to strongly participate in the preferential IgG2a Ab production observed. These results suggest that, following DNA immunization, the Th1-biased profile and the maintenance of the long-lived Ab response could be attributed to an adjuvant effect of the plasmid backbone during priming, whereas the strength of B-cell memory was independent of this effect.

Selective regulation of human immunodeficiency virus-infected CD4(+) lymphocytes by a synthetic immunomodulator leads to potent virus suppression in vitro and in hu-PBL-SCID mice.

We have previously observed that the synthetic immunomodulator Murabutide inhibits human immunodeficiency virus type 1 (HIV-1) replication at multiple levels in macrophages and dendritic cells. The present study was designed to profile the activity of Murabutide on CD8-depleted phytohemagglutinin-activated lymphocytes from HIV-1-infected subjects and on the outcome of HIV-1 infection in severe combined immunodeficiency mice reconstituted with human peripheral blood leukocytes (hu-PBL-SCID mice). Maintaining cultures of CD8-depleted blasts from 36 patients in the presence of Murabutide produced dramatically reduced levels of viral p24 protein in the supernatants. This activity correlated with reduced viral transcripts and proviral DNA, was evident in cultures harboring R5, X4-R5, or X4 HIV-1 isolates, was not linked to inhibition of cellular DNA synthesis, and did not correlate with beta-chemokine release. Moreover, c-myc mRNA expression was down-regulated in Murabutide-treated cells, suggesting potential interference of the immunomodulator with the nuclear transport of viral preintegration complexes. On the other hand, daily treatment of HIV-1-infected hu-PBL-SCID mice with Murabutide significantly reduced the viral loads in plasma and the proviral DNA content in human peritoneal cells. These results are the first to demonstrate that a clinically acceptable synthetic immunomodulator with an ability to enhance the host's nonspecific immune defense mechanisms against infections can directly regulate cellular factors in infected lymphocytes, leading to controlled HIV-1 replication.