Early clinical experience with ranibizumab for occult and minimally classic neovascular membranes in age-related macular degeneration.

BACKGROUND: In large randomized multicenter trials, ranibizumab has shown its therapeutic efficacy for exudative age-related macular degeneration (AMD). The aim of this paper is to report the real-life clinical experience with this treatment for occult and minimally classic membranes without pigment epithelium detachment. METHODS: We conducted a retrospective chart review of 37 patients with occult and minimally classic neovascular membranes in AMD, without pigment epithelium detachment. RESULTS: The mean visual improvement of 2 lines at 3, 6 and 9 months corresponds well with the results of the large trials. A mean number of 5 reinjections was reached by month 8. It may potentially exceed the mean 5.5 injections of the PrONTO study (prospective optical coherence tomography imaging of patients with neovascular AMD treated with intraocular ranibizumab). At months 6-8 recurrence was frequently observed. CONCLUSION: The early experience of ranibizumab in clinical practice brings similarly good results as the large-scale trials. However, interrupting the treatment too early may be a disadvantage.

Preserved decision making ability in early multiple sclerosis.

BACKGROUND: The purpose of this study was to assess decision making in patients with multiple sclerosis (MS) at the earliest clinically detectable time point of the disease. METHODS: Patients with definite MS (n = 109) or with clinically isolated syndrome (CIS, n = 56), a disease duration of 3 months to 5 years, and no or only minor neurological impairment (Expanded Disability Status Scale [EDSS] score 0-2.5) were compared to 50 healthy controls using the Iowa Gambling Task (IGT). RESULTS: The performance of definite MS, CIS patients, and controls was comparable for the two main outcomes of the IGT (learning index: p = 0.7; total score: p = 0.6). The IGT learning index was influenced by the educational level and the co-occurrence of minor depression. CIS and MS patients developing a relapse during an observation period of 15 months dated from IGT testing demonstrated a lower learning index in the IGT than patients who had no exacerbation (p = 0.02). When controlling for age, gender and education, the difference between relapsing and non-relapsing patients was at the limit of significance (p = 0.06). CONCLUSION: Decision making in a task mimicking real life decisions is generally preserved in early MS patients as compared to controls. A possible consequence of MS relapsing activity in the impairment of decision making ability is also suspected in the early phase of MS.

Early diagnosis of invasive candidiasis with mannan antigenemia and antimannan antibodies.

Late treatment of invasive candidiasis (IC) results in severe complications and high mortality. New tools are needed for early diagnosis. We conducted a retrospective study to assess the diagnostic utility of mannan antigenemia (Mn) and antimannan antibodies (anti-Mn) in neutropenic cancer patients at high risk for candidiasis. Twenty-eight patients with IC (based on European Organization for Research and Treatment of Cancer and Mycoses Study Group definitions) and 25 controls were studied. Mn and anti-Mn were positive (> or = 0.25 ng/mL and > or = 5 AU/mL, respectively) in 25/28 (89%) patients with candidiasis and in 4/25 (16%) controls: sensitivity, 89%; specificity, 84%; positive predictive value, 86%; negative predictive value, 88%. In patients with hepatosplenic lesions, assessing Mn/anti-Mn shortened the median time of diagnosis of candidiasis when compared with imaging (9 versus 25 days after fever onset as first sign of infection; P < 0.001). Candidiasis was diagnosed before neutrophil recovery in 78% and 11% of cases with Mn/anti-Mn and radiology, respectively (P < 0.001). Mn and anti-Mn may be useful for early noninvasive diagnosis of IC.

Early processing in the human lateral occipital complex is highly responsive to illusory contours but not to salient regions.

Human electrophysiological studies support a model whereby sensitivity to so-called illusory contour stimuli is first seen within the lateral occipital complex. A challenge to this model posits that the lateral occipital complex is a general site for crude region-based segmentation, based on findings of equivalent hemodynamic activations in the lateral occipital complex to illusory contour and so-called salient region stimuli, a stimulus class that lacks the classic bounding contours of illusory contours. Using high-density electrical mapping of visual evoked potentials, we show that early lateral occipital cortex activity is substantially stronger to illusory contour than to salient region stimuli, whereas later lateral occipital complex activity is stronger to salient region than to illusory contour stimuli. Our results suggest that equivalent hemodynamic activity to illusory contour and salient region stimuli probably reflects temporally integrated responses, a result of the poor temporal resolution of hemodynamic imaging. The temporal precision of visual evoked potentials is critical for establishing viable models of completion processes and visual scene analysis. We propose that crude spatial segmentation analyses, which are insensitive to illusory contours, occur first within dorsal visual regions, not the lateral occipital complex, and that initial illusory contour sensitivity is a function of the lateral occipital complex.

Selection of peptides and synthesis of pentameric peptabody molecules reacting specifically with ErbB-2 receptor.

The HER-2/ErbB-2 oncoprotein is overexpressed in human breast and ovarian adenocarcinomas and is clearly associated with the malignant phenotype. Although no specific ligand for this receptor has been positively identified, ErbB-2 was shown to play a central role in a network of interactions with the related ErbB-1, ErbB-3 and ErbB-4 receptors. We have selected new peptides binding to ErbB-2 extracellular domain protein (ECD) by screening 2 newly developed constrained and unconstrained random hexapeptide phage libraries. Out of 37 phage clones, which bound specifically to ErbB-2 ECD, we found 6 constrained and 10 linear different hexapeptide sequences. Among the latter, 5 consensus motifs, all with a common methionine and a positively charged residue at positions 1 and 3, respectively, were identified. Furthermore, 3 representative hexapeptides were fused to a coiled-coil pentameric recombinant protein to form the so-called peptabodies recently developed in our laboratory. The 3 peptabodies bound specifically to the ErbB-2 ECD, as determined by enzyme-linked immunosorbent assay and BIAcore analysis and to tumor cells overexpressing ErbB-2, as shown by flow cytometry. Interestingly, one of the free selected linear peptides and all 3 peptabodies inhibited the proliferation of tumor cells overexpressing ErbB-2. In conclusion, a novel type of ErbB-2-specific ligand is described that might complement presently available monoclonal antibodies.

Potential value of biliary CEA assay in early detection of colorectal adenocarcinoma liver metastases.

Elevation of the biliary CEA level in patients with liver metastases from colorectal carcinoma has been reported. The aim of this study is to determine the potential value of biliary CEA assay in the early detection of liver metastases. Biliary and serum CEA levels were determined in patients operated on for a colorectal cancer and in control groups. Among 13 patients with liver metastases from colorectal carcinomas, biliary CEA levels were markedly elevated (> 40 ng/ml) in nine, moderately elevated (5-40 ng/ml) in two and normal (arbitrarily defined as < 5 ng/ml) in two. Of 28 patients with primary colorectal carcinoma without detectable hepatic secondaries, three had marked CEA elevation in the bile, 10 had moderate CEA elevation and 15 had normal levels. Among nine patients with non-malignant hepatobiliary pathology, there was one marked biliary CEA elevation, one moderate elevation and seven normal levels. None of the 13 individuals with no identified hepatobiliary pathology had elevated biliary CEA levels. The follow-up of patients with a primary colorectal tumour, no evidence of hepatic secondaries and a biliary CEA elevation is of particular interest. If subsequent appearance of liver metastases is found in such cases, intra-operative biliary CEA assay could be considered a valuable diagnostic test. Further studies will then have to prove the possible benefit of a specific treatment for this group of patients.

Early-onset ventilator-associated pneumonia incidence in intensive care units: a surveillance-based study.

ABSTRACT: BACKGROUND: The incidence of ventilator-associated pneumonia (VAP) within the first 48 hours of intensive care unit (ICU) stay has been poorly investigated. The objective was to estimate early-onset VAP occurrence in ICUs within 48 hours after admission. METHODS: We analyzed data from prospective surveillance between 01/01/2001 and 31/12/2009 in 11 ICUs of Lyon hospitals (France). The inclusion criteria were: first ICU admission, not hospitalized before admission, invasive mechanical ventilation during first ICU day, free of antibiotics at admission, and ICU stay >=48 hours. VAP was defined according to a national protocol. Its incidence was the number of events per 1,000 invasive mechanical ventilation-days. The Poisson regression model was fitted from day 2 (D2) to D8 to incident VAP to estimate the expected VAP incidence from D0 to D1 of ICU stay. RESULTS: Totally, 367 (10.8%) of 3,387 patients in 45,760 patient-days developed VAP within the first 9 days. The predicted cumulative VAP incidence at D0 and D1 was 5.3 (2.6-9.8) and 8.3 (6.1-11.1), respectively. The predicted cumulative VAP incidence was 23.0 (20.8-25.3) at D8. The proportion of missed VAP within 48 hours from admission was 11% (9%-17%). CONCLUSIONS: Our study indicates underestimation of early-onset VAP incidence in ICUs, if only VAP occurring [greater than or equal to]48 hours is considered to be hospital-acquired. Clinicians should be encouraged to develop a strategy for early detection after ICU admission.

Number of transferred embryos: how to reduce multiple pregnancies.

Because the diagnostic tools for predicting whether an early cleavage stage embryo can lead to a viable pregnancy are still elusive, transfer of more than one embryo remains quite common. However, the only way to reduce multiple pregnancies, considered as the main adverse effect of assisted reproductive technology, is to transfer a single embryo. In countries such as Switzerland and Germany, the law allows cryopreservation only at the 2-pronuclear stage. This restricts considerably the possibility of selecting the embryos to be transferred. Therefore, a good cryopreservation program at the 2-pronuclear stage is an essential tool to optimize the efficiency of in vitro fertilization (IVF). We therefore recommend the Cumulated Singleton Delivery Rate (CUSIDERA) as a measure of standard IVF efficiency. This rate averages approximately 23.5% when calculated over the last 10 years in our unit and reaches a value above 35% for patients with more than 10 zygotes. Elective single-embryo transfers and the decrease of iatrogenic multiple pregnancies in IVF remain dependent on better prognostic tools for the appropriate selection of patients, gametes, and zygotes.

Morphological scoring of human pronuclear zygotes for prediction of pregnancy outcome.

BACKGROUND: As embryo selection is not allowed by law in Switzerland, we need a single early scoring system to identify zygotes with high implantation potential and to select zygotes for fresh transfer or cryopreservation. The underlying aim is to maximize the cumulated pregnancy rate while limiting the number of multiple pregnancies. METHODS: In all, 613 fresh and 617 frozen-thawed zygotes were scored for proximity, orientation and centring of the pronuclei, cytoplasmic halo, and number and polarization of the nucleolar precursor bodies. From these individual scores, a cumulated pronuclear score (CPNS) was calculated. Correlation between CPNS and implantation was examined and compared between fresh and frozen-thawed zygotes. The effect of freezing on CPNS was also investigated. RESULTS: CPNS was positively associated with embryo implantation in both fresh and frozen zygotes. With similar CPNS, frozen zygotes presented implantation rates as high as those of fresh zygotes. Nucleolar precursor bodies pattern and cytoplasmic halo appeared as the most important factors predictive of implantation for both types of zygotes, while pronuclei position was specifically relevant for frozen-thawed zygotes. Freezing induced an alteration of most zygote parameters, resulting in a significantly lower CPNS and a lower pregnancy rate. CONCLUSIONS: CPNS may be used as a single prognostic tool for implantation of both fresh and frozen-thawed zygotes. Lower CPNS values of frozen-thawed zygotes may also be indicative of freezing damage to zygotes. Successful implantation of frozen zygotes despite lower CPNS suggests that they may recover after thawing and in vitro culture.

Winter habitat selection by two sympatric forest grouse in western Switzerland: implications for conservation

Two endangered tetraonids, the capercaillie (Tetrao urogallus) and the hazel grouse (Bonasa bonasia rupestris), are sympatric throughout part of their distribution range in central Europe. Precise information on their specific habitat requirements is needed if the coexistence of both species in exploited forests is to be maintained. We quantified winter habitat selection for both species in the upper part (1100-1600 m) of the Jura mountains (Switzerland). No preference for altitude or exposure could be detected. Capercaillie preferred open forests (including grazed forests) with a sparse canopy dominated by spruce (Picea abies) and fir (Abies alba), and avoided dense undercanopy and understorey, especially when dominated by spruce and beech (Fagus sylvatica). By contrast, hazel grouse preferred feeding sites with a dense understorey of rowan (Sorbus aucuparia), willow (Salix sp.), beech and spruce. These preferences can be related to the feeding habits and predator avoidance behaviour of both species. Coexistence thus requires a mosaic distribution of habitat types, with a matrix of open forests (30% canopy cover) where fir is favoured, and understorey kept sparse (20%). Group-cuts of mature trees should allow regeneration patches, where a dense understorey (50% cover) should provide suitable habitats for hazel grouse

The balanced lethal system of crested newts: a ghost of sex chromosomes past?

Balanced lethal systems are more than biological curiosities: as theory predicts, they should quickly be eliminated through the joint forces of recombination and selection. That such systems might become fixed in natural populations poses a challenge to evolutionary theory. Here we address the case of a balanced lethal system fixed in crested newts and related species, which makes 50% of offspring die early in development. All adults are heteromorphic for chromosome pair 1. The two homologues (1A and 1B) have different recessive deleterious alleles fixed on a nonrecombining segment, so that heterozygotes are viable, while homozygotes are lethal. Given such a strong segregation load, how could autosomes stop recombining? We propose a role for a sex-chromosome turnover from pair 1 (putative ancestral sex chromosome) to pair 4 (currently active sex chromosome). Accordingly, 1A and 1B represent two variants (Y(A) and Y(B)) of the Y chromosome from an ancestral male-heterogametic system. We formalize a scenario in which turnovers are driven by sex ratio selection stemming from gene-environment interactions on sex determination. Individual-based simulations show that a balanced lethal system can be fixed with significant likelihood, provided the masculinizing allele on chromosome 4 appears after the elimination of the feminizing allele on chromosome 1. Our study illustrates how strikingly maladaptive traits might evolve through natural selection.