Coronary plaque composition of culprit/target lesions according to the clinical presentation: a virtual histology intravascular ultrasound analysis

AIMS: To evaluate the plaque composition obtained by virtual histology (VH) IVUS according to the clinical presentation and to compare those data to previously published histopathology data. METHODS AND RESULTS: VH was performed on 95 de novo significant lesions (>75% stenosis) in 85 patients [28 acute coronary syndrome (ACS) patients, 30 lesions; 57 stable angina pectoris (SAP) patients, 65 lesions]. There were a higher prevalence of positive remodelling (47 vs. 22%, P=0.013), thrombus (20 vs. 1.5%, P=0.0037), and echo-lucent area (23.3 vs. 7.7%, P=0.047) in ACS patients. At the minimal lumen site, fibrous plaque area was significantly larger in ACS lesions than in SAP lesions (66.0+/-10.7 vs. 61.4+/-8.9%, P=0.034), whereas necrotic core and dense calcium plaque area were smaller in ACS lesions (Necrotic core: 6.8+/-6.0 vs. 11.0+/-8.3%, P=0.02; Dense calcium: 2.6+/-3.0 vs. 4.9+/-5.8%, P=0.03). No differences in rate of thin cap fibroatheroma, thick fibrotheroma, or for the presence of multiple necrotic core layers were observed between both groups. CONCLUSION: Plaque composition obtained by VH-IVUS shows less necrotic core and more fibrous tissue in ACS compared to SAP lesions, which is in contradiction with previously published histopathologic data.

Subcolumnar Dendritic and Axonal Organization of Spiny Stellate and Star Pyramid Neurons within a Barrel in Rat Somatosensory Cortex

Excitatory neurons at the level of cortical layer 4 in the rodent somatosensory barrel field often display a strong eccentricity in comparison with layer 4 neurons in other cortical regions. In rat, dendritic symmetry of the 2 main excitatory neuronal classes, spiny stellate and star pyramid neurons (SSNs and SPNs), was quantified by an asymmetry index, the dendrite-free angle. We carefully measured shrinkage and analyzed its influence on morphological parameters. SSNs had mostly eccentric morphology, whereas SPNs were nearly radially symmetric. Most asymmetric neurons were located near the barrel border. The axonal projections, analyzed at the level of layer 4, were mostly restricted to a single barrel except for those of 3 interbarrel projection neurons. Comparing voxel representations of dendrites and axon collaterals of the same neuron revealed a close overlap of dendritic and axonal fields, more pronounced in SSNs versus SPNs and considerably stronger in spiny L4 neurons versus extragranular pyramidal cells. These observations suggest that within a barrel dendrites and axons of individual excitatory cells are organized in subcolumns that may confer receptive field properties such as directional selectivity to higher layers, whereas the interbarrel projections challenge our view of barrels as completely independent processors of thalamic input.

Expression of zebra fish aromatase cyp19a and cyp19b genes in response to the ligands of estrogen receptor and aryl hydrocarbon receptor

Many endocrine-disrupting chemicals act via estrogen receptor (ER) or aryl hydrocarbon receptor (AhR). To investigate the interference between ER and AhR, we studied the effects of 17beta-estradiol (E2) and 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) on the expression of zebra fish cyp19a (zfcyp19a) and cyp19b (zfcyp19b) genes, encoding aromatase P450, an important steroidogenic enzyme. In vivo (mRNA quantification in exposed zebra fish larvae) and in vitro (activity of zfcyp19-luciferase reporter genes in cell cultures in response to chemicals and zebra fish transcription factors) assays were used. None of the treatments affected zfcyp19a, excluding the slight upregulation by E2 observed in vitro. Strong upregulation of zfcyp19b by E2 in both assays was downregulated by TCDD. This effect could be rescued by the addition of an AhR antagonist. Antiestrogenic effect of TCDD on the zfcyp19b expression in the brain was also observed on the protein level, assessed by immunohistochemistry. TCDD alone did not affect zfcyp19b expression in vivo or promoter activity in the presence of zebra fish AhR2 and AhR nuclear translocator 2b (ARNT2b) in vitro. However, in the presence of zebra fish ERalpha, AhR2, and ARNT2b, TCDD led to a slight upregulation of promoter activity, which was eliminated by either an ER or AhR antagonist. Studies with mutated reporter gene constructs indicated that both mechanisms of TCDD action in vitro were independent of dioxin-responsive elements (DREs) predicted in the promoter. This study shows the usefulness of in vivo zebra fish larvae and in vitro zfcyp19b reporter gene assays for evaluation of estrogenic chemical actions, provides data on the functionality of DREs predicted in zfcyp19 promoters and shows the effects of cross talk between ER and AhR on zfcyp19b expression. The antiestrogenic effect of TCDD demonstrated raises further concerns about the neuroendocrine effects of AhR ligands.

Characterization of Giardia lamblia WB C6 clones resistant to nitazoxanide and to metronidazole

OBJECTIVES: The characterization of Giardia lamblia WB C6 strains resistant to metronidazole and to the nitro-thiazole nitazoxanide [2-acetolyloxy-N-(5-nitro 2-thiazolyl) benzamide] as the parent compound of thiazolides, a novel class of anti-infective drugs with a broad spectrum of activities against a wide variety of helminths, protozoa and enteric bacteria. METHODS: Issuing from G. lamblia WB C6, we have generated two strains exhibiting resistance to nitazoxanide (strain C4) and to metronidazole (strain C5) and determined their susceptibilities to both drugs. Using quantitative RT-PCR, we have analysed the expression of genes that are potentially involved in resistance formation, namely genes encoding pyruvate oxidoreductases (POR1 and POR2), nitroreductase (NR), protein disulphide isomerases (PDI2 and PDI4) and variant surface proteins (VSPs; TSA417). We have cloned and expressed PDI2 and PDI4 in Escherichia coli. Using an enzyme assay based on the polymerization of insulin, we have determined the activities of both enzymes in the presence and absence of nitazoxanide. RESULTS: Whereas C4 was cross-resistant to nitazoxanide and to metronidazole, C5 was resistant only to metronidazole. Transcript levels of the potential targets for nitro-drugs POR1, POR2 and NR were only slightly modified, PDI2 transcript levels were increased in both resistant strains and PDI4 levels in C4. This correlated with the findings that the functional activities of recombinant PDI2 and PDI4 were inhibited by nitazoxanide. Moreover, drastic changes were observed in VSP gene expression. CONCLUSIONS: These results suggest that resistance formation in Giardia against nitazoxanide and metronidazole is linked, and possibly mediated by, altered gene expression in drug-resistant strains compared with non-resistant strains of Giardia.

A call for uniform reporting standards in studies assessing endovascular treatment for chronic ischaemia of lower limb arteries

Endovascular therapy is a rapidly evolving field for the treatment of patients with peripheral arterial disease, and a magnitude of studies reporting on various modern revascularization concepts have been recently published. Thus, studies assessing the efficacy of endovascular therapy of peripheral arteries do not operate with uniformly defined endpoints, rendering a direct comparison of studies difficult. The purpose of this consensus statement is to highlight differences in the terminology used in the current literature and to propose some standardized criteria that must be considered when reporting results of endovascular revascularization for chronic ischaemia of lower limb arteries.

Mothers adjust egg size to helper number in a cooperatively breeding cichlid

Mothers should adjust the size of propagules to the selective forces to which these offspring will be exposed. Usually, a larger propagule size is favored when young are exposed to high mortality risk or conspecific competition. Here we test 2 predictions on how egg size should vary with these selective agents. When offspring are cared for by parents and/or alloparents, protection may reduce the predation risk to young, which may allow mothers to invest less per single offspring. In the cooperatively breeding cichlid Neolamprologus pulcher, brood care helpers protect group offspring and reduce the latters' mortality rate. Therefore, females are expected to reduce their investment per egg when more helpers are present. In a first experiment, we tested this prediction by manipulating the helper number. In N. pulcher, helpers compete for dispersal opportunities with similar-sized individuals of neighboring groups. If the expected future competition pressure on young is high, females should increase their investment per offspring to give them a head start. In a second experiment, we tested whether females produce larger eggs when perceived neighbor density is high. Females indeed reduced egg size with increasing helper number. However, we did not detect an effect of local density on egg size, although females took longer to produce the next clutch when local density was high. We argue that females can use the energy saved by adjusting egg size to reduced predation risk to enhance future reproductive output. Adaptive adjustment of offspring size to helper number may be an important, as yet unrecognized, strategy of cooperative breeders.

Characteristics, determinants, and clinical relevance of CD4 T cell recovery to <500 cells/microL in HIV type 1-infected individuals receiving potent antiretroviral therapy

BACKGROUND: The CD4 T cell count recovery in human immunodeficiency virus type 1 (HIV-1)-infected individuals receiving potent antiretroviral therapy (ART) shows high variability. We studied the determinants and the clinical relevance of incomplete CD4 T cell restoration. METHODS: Longitudinal CD4 T cell count was analyzed in 293 participants of the Swiss HIV Cohort Study who had had a plasma HIV-1 RNA load <1000 copies/mL for > or =5 years. CD4 T cell recovery was stratified by CD4 T cell count 5 years after initiation of ART (> or =500 cells/microL was defined as a complete response, and <500 cells/microL was defined as an incomplete response). Determinants of incomplete responses and clinical events were evaluated using logistic regression and survival analyses. RESULTS: The median CD4 T cell count increased from 180 cells/microL at baseline to 576 cells/microL 5 years after ART initiation. A total of 35.8% of patients were incomplete responders, of whom 47.6% reached a CD4 T cell plateau <500 cells/microL. Centers for Disease Control and Prevention HIV-1 disease category B and/or C events occurred in 21% of incomplete responders and in 14.4% of complete responders (P>.05). Older age (adjusted odds ratio [aOR], 1.71 per 10-year increase; 95% confidence interval [CI], 1.21-2.43), lower baseline CD4 T cell count (aOR, 0.37 per 100-cell increase; 95% CI, 0.28-0.49), and longer duration of HIV infection (aOR, 2.39 per 10-year increase; 95% CI, 1.19-4.81) were significantly associated with a CD4 T cell count <500 cells/microL at 5 years. The median increases in CD4 T cell count after 3-6 months of ART were smaller in incomplete responders (P<.001) and predicted, in conjunction with baseline CD4 T cell count and age, incomplete response with 80% sensitivity and 72% specificity. CONCLUSION: Individuals with incomplete CD4 T cell recovery to <500 cells/microL had more advanced HIV-1 infection at baseline. CD4 T cell changes during the first 3-6 months of ART already reflect the capacity of the immune system to replenish depleted CD4 T lymphocytes.

A randomized clinical trial of mupirocin in the eradication of Staphylococcus aureus nasal carriage in human immunodeficiency virus disease

Seventy-six human immunodeficiency virus (HIV)-infected patients with Staphylococcus aureus nasal carriage were randomized to treatment groups receiving intranasal mupirocin or placebo twice daily for 5 days. Nasal cultures for S. aureus were obtained at 1, 2, 6, and 10 weeks after therapy. At 1 week, 88% of mupirocin-treated patients had negative nasal cultures compared with 8% in placebo patients (P<.001). The percentage of mupirocin-treated patients with persistently negative nasal cultures decreased over time (63%, 45%, and 29% at 2, 6, and 10 weeks, respectively) but remained significantly greater than the placebo group (3% at 2, 6, and 10 weeks). In mupirocin-treated patients, most (16/19) instances of nasal recolonization were with pretreatment strains (determined by means of by pulsed field gel electrophoresis); mupirocin resistance was not observed. Five days of treatment with mupirocin eliminated S. aureus nasal carriage in HIV-infected patients for several weeks; however, since the effect waned over time, intermittent dosing regimens should be considered for long-term eradication.

Tumor necrosis factor-alpha contributes to apoptosis in hippocampal neurons during experimental group B streptococcal meningitis

To evaluate the role of tumor necrosis factor-alpha (TNF-alpha) in neuronal injury in experimental group B streptococcal meningitis, infected neonatal rats were treated with a monoclonal antibody against TNF-alpha (20 mg/kg intraperitoneally) or saline given at the time of infection. Histopathology after 24 h showed necrosis in the cortex and apoptosis in the hippocampal dentate gyrus. Treated animals had significantly less hippocampal injury than did controls (P < .001) but had similar cortical injury and cerebrospinal fluid (CSF) inflammation. The antibody was then administered directly intracisternally (170 microg) to test whether higher CSF concentrations reduced inflammation or cortical injury. Again, hippocampal apoptosis was significantly reduced (P < .01), while cortical injury and inflammation were not. Thus, TNF-alpha played a critical role in neuronal apoptosis in the hippocampus, while it was not essential for the development of inflammation and cortical injury in this model.

Antibacterial activity of beta-lactam antibiotics in experimental meningitis due to Streptococcus pneumoniae

In order to define the characteristics of the antibacterial activity of beta-lactam antibiotics in the treatment of bacterial meningitis, the relationship between cerebrospinal fluid (CSF) drug concentrations and the rate of bacterial killing was investigated for penicillin G and four new cephalosporins in an animal model of meningitis due to Streptococcus pneumoniae. All five drugs showed a significant correlation between increasing drug concentrations in CSF and increasing bactericidal rates. Minimal activity was observed in CSF at drug concentrations of approximately the broth minimal bactericidal concentration (MBC). Maximal activity occurred with CSF concentrations 10-30 times higher. In vitro tests did not reproduce the unique correlation of increasing drug concentrations and killing activity found in vivo. When evaluating new beta-lactam antibiotics for the treatment of bacterial meningitis, it is reasonable to establish a minimum standard of CSF drug concentrations of greater than or equal to 30 times the MBC against the infecting organism.

Adding cetuximab to capecitabine plus oxaliplatin (XELOX) in first-line treatment of metastatic colorectal cancer: a randomized phase II trial of the Swiss Group for Clinical Cancer Research SAKK

BACKGROUND: To determine the activity and tolerability of adding cetuximab to the oxaliplatin and capecitabine (XELOX) combination in first-line treatment of metastatic colorectal cancer (MCC). PATIENTS AND METHODS: In a multicenter two-arm phase II trial, patients were randomized to receive oxaliplatin 130 mg/m(2) on day 1 and capecitabine 1000 mg/m(2) twice daily on days 1-14 every 3 weeks alone or in combination with standard dose cetuximab. Treatment was limited to a maximum of six cycles. RESULTS: Seventy-four patients with good performance status entered the trial. Objective partial response rates after external review and radiological confirmation were 14% and 41% in the XELOX and in the XELOX + Cetuximab arm, respectively. Stable disease has been observed in 62% and 35% of the patients, with 76% disease control in both arms. Cetuximab led to skin rash in 65% of the patients. The median overall survival was 16.5 months for arm A and 20.5 months for arm B. The median time to progression was 5.8 months for arm A and 7.2 months for arm B. CONCLUSION: Differences in response rates between the treatment arms indicate that cetuximab may improve outcome with XELOX. The correct place of the cetuximab, oxaliplatin and fluoropyrimidine combinations in first-line treatment of MCC has to be assessed in phase III trials.