Estimation de la fonction rénale par l'equation MDRD: intérêt et limites pour l'adaptation des doses de médicaments [Renal function estimation by MDRD equation: interest and limitations for drug dosing].

The MDRD (Modification of diet in renal disease) equation enables glomerular filtration rate (GFR) estimation from serum creatinine only. Thus, the laboratory can report an estimated GFR (eGFR) with each serum creatinine assessment, increasing therefore the recognition of renal failure. Predictive performance of MDRD equation is better for GFR < 60 ml/min/1,73 m2. A normal or near-normal renal function is often underestimated by this equation. Overall, MDRD provides more reliable estimations of renal function than the Cockcroft-Gault (C-G) formula, but both lack precision. MDRD is not superior to C-G for drug dosing. Being adjusted to 1,73 m2, MDRD eGFR has to be back adjusted to the patient's body surface area for drug dosing. Besides, C-G has the advantage of a greater simplicity and a longer use.

Exhaustion of bacteria-specific CD4 T cells and microbial translocation in common variable immunodeficiency disorders.

In the present study, we have investigated the functional profile of CD4 T cells from patients with common variable immunodeficiency (CVID), including production of cytokines and proliferation in response to bacteria and virus-derived antigens. We show that the functional impairment of CD4 T cells, including the reduced capacity to proliferate and to produce IFN-γ and IL-2, was restricted to bacteria-specific and not virus-specific CD4 T cells. High levels of endotoxins were found in the plasma of patients with CVID, suggesting that CD4 T cell dysfunction might be caused by bacterial translocation. Of note, endotoxemia was associated with significantly higher expression of programmed death 1 (PD-1) on CD4 T cells. The blockade of the PD-1-PD-L1/2 axis in vitro restored CD4 T cell proliferation capacity, thus indicating that PD-1 signaling negatively regulates CD4 T cell functions. Finally, we showed that intravenous immunoglobulin G (IVIG) treatment significantly reduced endotoxemia and the percentage of PD-1(+) CD4 T cells, and restored bacteria-specific CD4 T cell cytokine production and proliferation. In conclusion, the present study demonstrates that the CD4 T cell exhaustion and functional impairment observed in CVID patients is associated with bacterial translocation and that IVIG treatment resolves bacterial translocation and restores CD4 T cell functions.

MHC class II/ESO tetramer-based generation of in vitro primed anti-tumor T-helper lines for adoptive cell therapy of cancer.

Generation of tumor-antigen specific CD4(+) T-helper (T(H)) lines through in vitro priming is of interest for adoptive cell therapy of cancer, but the development of this approach has been limited by the lack of appropriate tools to identify and isolate low frequency tumor antigen-specific CD4(+) T cells. Here, we have used recently developed MHC class II/peptide tetramers incorporating an immunodominant peptide from NY-ESO-1 (ESO), a tumor antigen frequently expressed in different human solid and hematologic cancers, to implement an in vitro priming platform allowing the generation of ESO-specific T(H) lines. We isolated phenotypically defined CD4(+) T-cell subpopulations from circulating lymphocytes of DR52b(+) healthy donors by flow cytometry cell sorting and stimulated them in vitro with peptide ESO(119-143), autologous APC and IL-2. We assessed the frequency of ESO-specific cells in the cultures by staining with DR52b/ESO(119-143) tetramers (ESO-tetramers) and TCR repertoire of ESO-tetramer(+) cells by co-staining with TCR variable β chain (BV) specific antibodies. We isolated ESO-tetramer(+) cells by flow cytometry cell sorting and expanded them with PHA, APC and IL-2 to generate ESO-specific T(H) lines. We characterized the lines for antigen recognition, by stimulation with ESO peptide or recombinant protein, cytokine production, by intracellular staining using specific antibodies, and alloreactivity, by stimulation with allo-APC. Using this approach, we could consistently generate ESO-tetramer(+) T(H) lines from conventional CD4(+)CD25(-) naïve and central memory populations, but not from effector memory populations or CD4(+)CD25(+) Treg. In vitro primed T(H) lines recognized ESO with affinities comparable to ESO-tetramer(+) cells from patients immunized with an ESO vaccine and used a similar TCR repertoire. In this study, using MHC class II/ESO tetramers, we have implemented an in vitro priming platform allowing the generation of ESO-monospecific polyclonal T(H) lines from non-immune individuals. This is an approach that is of potential interest for adoptive cell therapy of patients bearing ESO-expressing cancers.

A case of dissection of intracranial cerebral arteries with segmental mediolytic "arteritis".

The intravital diagnosis of intracranial arterial dissection is not always possible due to atypic and non-specific clinical and radiological presentations. The postmortem pathological examination of cerebral blood vessels is therefore necessary to establish or confirm the presence of a dissecting aneurysm of intracranial arteries. Most of the described cases showed no significant underlying vascular pathology. Here we present the case of a 24-year-old women who died 5 days after admission to the hospital for a rapidly developing right-sided hemisyndrome. Neuroradiological examination had revealed ill-defined bifrontal hypodense lesions and angiographic findings were compatible with a dissection of the left extracranial internal carotid artery with embolic subocclusion of both anterior cerebral arteries. The pathological evaluation ruled out a thromboembolic occlusion of cerebral arteries and an extracranial internal carotid artery dissection but showed an extended dissecting process of variable age in the anterior circulation of the circle of Willis. The dissected vessels showed pathological changes characteristic of segmental mediolytic "arteritis" [Slavin and Gonzalez-Vitale 1976]. To our knowledge this is the first report on intracranial arteries being affected by this pathologic entity. Our case illustrates the importance of a postmortem examination of dissecting aneurysms of intracranial arteries. Careful serial section studies of dissected intracranial arteries in young subjects should be performed and may allow for a better understanding of the vascular pathology underlying the dissection processus.

African tick-bite fever: a new entity in the differential diagnosis of multiple eschars in travelers. Description of five cases imported from South Africa to Switzerland.

African tick-bite fever (ATBF) is a newly described spotted fever rickettsiosis that frequently presents with multiple eschars in travelers returning from sub-Saharan Africa and, to a lesser extent, from the West Indies. It is caused by the bite of an infected Amblyomma tick, whose hunting habits explain the typical presence of multiple inoculation skin lesions and the occurrence of clustered cases. The etiological agent of ATBF is Rickettsia africae, an emerging tick-borne pathogenic bacterium. We describe herein a cluster of five cases of ATBF occurring in Swiss travelers returning from South Africa. The co-incidental infections in these five patients and the presence of multiple inoculation eschars, two features pathognomonic of this rickettsial disease, suggested the diagnosis of ATBF. Indeed, the presence of at least one inoculation eschar is observed in 53-100% of cases and multiple eschars in 21-54%. Two patients presented regional lymphadenitis and one a mild local lymphangitis. Though a cutaneous rash is described in 15-46% of cases, no rash was observed in our series. ATBF was confirmed by serology. Thus, ATBF has recently emerged as one of the most important causes of flu-like illness in travelers returning from Southern Africa. The presence of one or multiple eschars of inoculation is an important clinical clue to the diagnosis. It can be confirmed by serology or by PCR of a biopsy of the eschar. Culture can also be done in reference laboratories. Dermatologists and primary care physicians should know this clinical entity, since an inexpensive and efficient treatment is available.

Delay of extubation in neonates and children after cardiac surgery: impact of ventilator-associated pneumonia.

OBJECTIVE: This study was undertaken to determine the delay of extubation attributable to ventilator-associated pneumonia (VAP) in comparison to other complications and complexity of surgery after repair of congenital heart lesions in neonates and children. METHODS: Cohort study in a pediatric intensive care unit of a tertiary referral center. All patients who had cardiac operations during a 22-month period and who survived surgery were eligible (n = 272, median age 1.3 years). Primary outcome was time to successful extubation. Primary variable of interest was VAP Surgical procedures were classified according to complexity. Cox proportional hazards models were calculated to adjust for confounding. Potential confounders comprised other known risk factors for delayed extubation. RESULTS: Median time to extubation was 3 days. VAP occurred in 26 patients (9.6%). The rate of VAP was not associated with complexity of surgery (P = 0.22), or cardiopulmonary bypass (P = 0.23). The adjusted analysis revealed as further factors associated with delayed extubation: other respiratory complications (n = 28, chylothorax, airway stenosis, diaphragm paresis), prolonged inotropic support (n = 48, 17.6%), and the need for secondary surgery (n = 51, 18.8%; e.g., re-operation, secondary closure of thorax). Older age promoted early extubation. The median delay of extubation attributable to VAP was 3.7 days (hazards ratio HR = 0.29, 95% CI 0.18-0.49), exceeding the effect size of secondary surgery (HR = 0.48) and other respiratory complications (HR = 0.50). CONCLUSION: VAP accounts for a major delay of extubation in pediatric cardiac surgery.

Cardiomyopathie de tako-tsubo: une entité clinique rare et méconnue [Tako-tsubo cardiomyopathy: a rare and badly known clinical entity]

Tako-tsubo cardiomyopathy or "transient left ventricular (LV) apical ballooning" clinically presents like acute myocardial infarction without angiographic stenosis on coronary angiogram and a transient (reversible) LV apical ballooning. We discuss here about a 56-year-old woman complains of first constrictive chest pain with ST elevation in leads V2-V6 and minimal enzymatic release. Coronary angiogram demonstrates vessels without stenosis and the left ventriculogram an extensive LV apical wall motion abnormalities. LV dysfunction will only be transient since 24 hours after admission echographic images demonstrate quite complete recovery of LV systolic function. The pain disappears 12 hours after admission and the creatine kinase level normalize after 48 hours.

Predictive factors of adrenal insufficiency in patients admitted to acute medical wards: a case control study.

BACKGROUND: Adrenal insufficiency is a rare and potentially lethal disease if untreated. Several clinical signs and biological markers are associated with glucocorticoid failure but the importance of these factors for diagnosing adrenal insufficiency is not known. In this study, we aimed to assess the prevalence of and the factors associated with adrenal insufficiency among patients admitted to an acute internal medicine ward. METHODS: Retrospective, case-control study including all patients with high-dose (250 μg) ACTH-stimulation tests for suspected adrenal insufficiency performed between 2008 and 2010 in an acute internal medicine ward (n = 281). Cortisol values <550 nmol/l upon ACTH-stimulation test were considered diagnostic for adrenal insufficiency. Area under the ROC curve (AROC), sensitivity, specificity, negative and positive predictive values for adrenal insufficiency were assessed for thirteen symptoms, signs and biological variables. RESULTS: 32 patients (11.4%) presented adrenal insufficiency; the others served as controls. Among all clinical and biological parameters studied, history of glucocorticoid withdrawal was the only independent factor significantly associated with patients with adrenal insufficiency (Odds Ratio: 6.71, 95% CI: 3.08 -14.62). Using a logistic regression, a model with four significant and independent variable was obtained, regrouping history of glucocorticoid withdrawal (OR 7.38, 95% CI [3.18 ; 17.11], p-value <0.001), nausea (OR 3.37, 95% CI [1.03 ; 11.00], p-value 0.044), eosinophilia (OR 17.6, 95% CI [1.02; 302.3], p-value 0.048) and hyperkalemia (OR 2.41, 95% CI [0.87; 6.69], p-value 0.092). The AROC (95% CI) was 0.75 (0.70; 0.80) for this model, with 6.3 (0.8 - 20.8) for sensitivity and 99.2 (97.1 - 99.9) for specificity. CONCLUSIONS: 11.4% of patients with suspected adrenal insufficient admitted to acute medical ward actually do present with adrenal insufficiency, defined by an abnormal response to high-dose (250 μg) ACTH-stimulation test. A history of glucocorticoid withdrawal was the strongest factor predicting the potential adrenal failure. The combination of a history of glucocorticoid withdrawal, nausea, eosinophilia and hyperkaliemia might be of interest to suspect adrenal insufficiency.

Genes mirror geography within Europe.

Understanding the genetic structure of human populations is of fundamental interest to medical, forensic and anthropological sciences. Advances in high-throughput genotyping technology have markedly improved our understanding of global patterns of human genetic variation and suggest the potential to use large samples to uncover variation among closely spaced populations. Here we characterize genetic variation in a sample of 3,000 European individuals genotyped at over half a million variable DNA sites in the human genome. Despite low average levels of genetic differentiation among Europeans, we find a close correspondence between genetic and geographic distances; indeed, a geographical map of Europe arises naturally as an efficient two-dimensional summary of genetic variation in Europeans. The results emphasize that when mapping the genetic basis of a disease phenotype, spurious associations can arise if genetic structure is not properly accounted for. In addition, the results are relevant to the prospects of genetic ancestry testing; an individual's DNA can be used to infer their geographic origin with surprising accuracy-often to within a few hundred kilometres.

Spread spectrum magnetic resonance imaging.

We propose a novel compressed sensing technique to accelerate the magnetic resonance imaging (MRI) acquisition process. The method, coined spread spectrum MRI or simply s(2)MRI, consists of premodulating the signal of interest by a linear chirp before random k-space under-sampling, and then reconstructing the signal with nonlinear algorithms that promote sparsity. The effectiveness of the procedure is theoretically underpinned by the optimization of the coherence between the sparsity and sensing bases. The proposed technique is thoroughly studied by means of numerical simulations, as well as phantom and in vivo experiments on a 7T scanner. Our results suggest that s(2)MRI performs better than state-of-the-art variable density k-space under-sampling approaches.

Granulomatosis-associated common variable immunodeficiency disorder: a case-control study versus sarcoidosis.

The aim of the present study was to investigate to what extent interstitial lung disease (ILD) in common variable immunodeficiency disorder (CVID)-associated granulomatous disease (GD) is similar to pulmonary sarcoidosis 20 patients with CVID/GD were included in a retrospective study conducted by the Groupe Sarcoïdose Francophone. Medical records were centralised. Patients were compared with 60 controls with sarcoidosis. Clinical examination showed more frequent crackles in patients than controls (45% versus 1.7%, respectively; p<0.001). On thoracic computed tomography scans, nodules (often multiple and with smooth margins), air bronchograms and halo signs were more frequent in patients than controls (80% versus 42%, respectively; p=0.004) as well as bronchiectasis (65% versus 23%, respectively; p<0.001). The micronodule distribution was perilymphatic in 100% of controls and in 42% of patients (p<0.001). Bronchoalveolar lavage analysis showed lower T-cell CD4/CD8 ratios in patients than in controls (mean±sd 1.6±1.1 versus 5.3±4, respectively; p<0.01). On pathological analysis, nodules and consolidations corresponded to granulomatous lesions with or without lymphocytic disorders in most cases. Mortality was higher in patients than controls (30% versus 0%, respectively) and resulted from common variable immunodeficiency complications. ILD in CVID/GD presents a specific clinical picture and evolution that are markedly different from those of sarcoidosis.

Variable phenotypic expressivity in a Swiss family with autosomal dominant retinitis pigmentosa due to a T494M mutation in the PRPF3 gene.

PURPOSE: To characterize the clinical, psychophysical, and electrophysiological phenotypes in a five-generation Swiss family with dominantly inherited retinitis pigmentosa caused by a T494M mutation in the Precursor mRNA-Processing factor 3 (PRPF3) gene, and to relate the phenotype to the underlying genetic mutation. METHODS: Eleven affected patients were ascertained for phenotypic and genotypic characterization. Ophthalmologic evaluations included color vision testing, Goldmann perimetry, and digital fundus photography. Some patients had autofluorescence imaging, Optical Coherence Tomography, and ISCEV-standard full-field electroretinography. All affected patients had genetic testing. RESULTS: The age of onset of night blindness and the severity of the progression of the disease varied between members of the family. Some patients reported early onset of night blindness at age three, with subsequent severe deterioration of visual acuity, which was 0.4 in the best eye after their fifties. The second group of patients had a later onset of night blindness, in the mid-twenties, with a milder disease progression and a visual acuity of 0.8 at age 70. Fundus autofluorescence imaging and electrophysiological and visual field abnormalities also showed some degree of varying phenotypes. The autofluorescence imaging showed a large high-density ring bilaterally. Myopia (range: -0.75 to -8) was found in 10/11 affected subjects. Fundus findings showed areas of atrophy along the arcades. A T494M change was found in exon 11 of the PRPF3 gene. The change segregates with the disease in the family. CONCLUSIONS: A mutation in the PRPF3 gene is rare compared to other genes causing autosomal dominant retinitis pigmentosa (ADRP). Although a T494M change has been reported, the family in our study is the first with variable expressivity. Mutations in the PRPF3 gene can cause a variable ADRP phenotype, unlike in the previously described Danish, English, and Japanese families. Our report, based on one of the largest affected pedigree, provides a better understanding as to the phenotype/genotype description of ADRP caused by a PRPF3 mutation.

Plant defense against herbivory: progress in identifying synergism, redundancy, and antagonism between resistance traits.

Plants respond to herbivore attack through a complex and variable system of defense, involving different physical barriers, toxic chemicals, and recruitment of natural enemies. To fully understand the relative role of each type of defense, their synergisms, redundancies, or antagonisms between traits, a variety of methods of enquiry, commonly used in plant physiology and ecology, have been employed. By overexpressing or silencing genes of interest, it is possible to understand the specific role of a particular defensive molecule or mode of action. We argue, however, that these types of experiments alone are not enough to holistically understand the physiological as well as ecological role of plant defenses. We thus advocate for the use of a combination of methods, including genetic modification, quantitative genetics, and phylogenetically controlled comparative studies.