Sexual minority status, social adversity and risk for psychotic disorders-results from the GROUP study.

BACKGROUND: Lesbian, bisexual, or gay individuals (LBGs) have an increased risk for mental health problems compared to heterosexuals, but this association has sparsely been investigated for psychotic disorders. The aim of this study was: (1) to examine whether LBG sexual orientation is more prevalent in individuals with a non-affective psychotic disorder (NAPD) than in people without a psychotic disorder; and if so, (2) to explore possible mediating pathways. METHODS: Sexual orientation was assessed in the 6-year follow-up assessment of the Dutch Genetic Risk and Outcome of Psychosis study (GROUP), a case-control study with 1547 participants (582 patients with psychotic disorder, 604 siblings, and 361 controls). Binary logistic regression analyses were used to calculate the risk of patients with a psychotic disorder being LBG, compared to siblings and controls. Perceived discrimination, history of bullying, childhood trauma (CT), and sexual identity disclosure were investigated as potential mediating variables. RESULTS: The proportion of individuals with LBG orientation was 6.8% in patients (n = 40), 4.3% in siblings (n = 26), and 2.5% in controls (n = 10). The age- and gender-adjusted odds ratio of LBG for patients was 1.57 (95% CI 1.08-2.27; p = 0.019), compared to siblings and controls. Discrimination, bullying, and CT all partially mediated this association. CONCLUSIONS: Adverse social experiences related to sexual minority status may increase the risk for NAPD. Sexual identity, behavior, and difficulties need more attention in everyday clinical practice.

Imaging pulsed laser deposition oxide growth by in situ atomic force microscopy.

To visualize the topography of thin oxide films during growth, thereby enabling to study its growth behavior quasi real-time, we have designed and integrated an atomic force microscope (AFM) in a pulsed laser deposition (PLD) vacuum setup. The AFM scanner and PLD target are integrated in a single support frame, combined with a fast sample transfer method, such that in situ microscopy can be utilized after subsequent deposition pulses. The in situ microscope can be operated from room temperature up to 700 °C and at (process) pressures ranging from the vacuum base pressure of 10-6 mbar up to 1 mbar, typical PLD conditions for the growth of oxide films. The performance of this instrument is demonstrated by resolving unit cell height surface steps and surface topography under typical oxide PLD growth conditions.

The effects of nutrition-induced abnormal food metabolism in the Southern Plains woodrat (Neotoma micropus): comparisons of variations of the Western diet.

We investigated the effects of several modifications of the Western diet on a medium-sized rodent, Neotoma micropus, that lives in the area of the wildland-urban interface. We conducted a laboratory study of the response of N. micropus to high fat-high fructose (HFHF), high fat-high sucrose (HFHS), high fat-low sugar (HFLSu) and control (low fat-low sugar) diets. We found a significant increase in hepatic lipid deposition and a significant decrease in podocytes in those animals that consumed the HFHF and HFLSu diets compared to those on the HFHS and control diets. We found no significant differences in Bowman's space or hepatic collagen formation. We predict that N. micropus in the wild, with access to anthropogenic resources, will show similar effects as a result of the consumption of anthropogenic resources.

Neural response during attentional control and emotion processing predicts improvement after cognitive behavioral therapy in generalized social anxiety disorder.

BACKGROUND: Individuals with generalized social anxiety disorder (gSAD) exhibit attentional bias to salient stimuli, which is reduced in patients whose symptoms improve after treatment, indicating that mechanisms of bias mediate treatment success. Therefore, pre-treatment activity in regions implicated in attentional control over socio-emotional signals (e.g. anterior cingulate cortex, dorsolateral prefrontal cortex) may predict response to cognitive behavioral therapy (CBT), evidence-based psychotherapy for gSAD. METHOD: During functional magnetic resonance imaging, 21 participants with gSAD viewed images comprising a trio of geometric shapes (circles, rectangles or triangles) alongside a trio of faces (angry, fearful or happy) within the same field of view. Attentional control was evaluated with the instruction to 'match shapes', directing attention away from faces, which was contrasted with 'match faces', whereby attention was directed to emotional faces. RESULTS: Whole-brain voxel-wise analyses showed that symptom improvement was predicted by enhanced pre-treatment activity in the presence of emotional face distractors in the dorsal anterior cingulate cortex and dorsal medial prefrontal cortex. Additionally, CBT success was foretold by less activity in the amygdala and/or increased activity in the medial orbitofrontal gyrus during emotion processing. CONCLUSIONS: CBT response was predicted by pre-treatment activity in prefrontal regions and the amygdala. The direction of activity suggests that individuals with intact attentional control in the presence of emotional distractors, regulatory capacity over emotional faces and/or less reactivity to such faces are more likely to benefit from CBT. Findings indicate that baseline neural activity in the context of attentional control and emotion processing may serve as a step towards delineating mechanisms by which CBT exerts its effects.

Epidermal growth factor receptor as a therapeutic target in glioblastoma.

Glioblastoma represents one of the most challenging problems in neurooncology. Among key elements driving its behavior is the transmembrane epidermal growth factor receptor family, with the first member epidermal growth factor receptor (EGFR) centered in most studies. Engagement of the extracellular domain with a ligand activates the intracellular tyrosine kinase (TK) domain of EGFR, leading to autophosphorylation and signal transduction that controls proliferation, gene transcription, and apoptosis. Oncogenic missense mutations, deletions, and insertions in the EGFR gene are preferentially located in the extracellular domain in glioblastoma and cause constitutive activation of the receptor. The mutant EGFR may also transactivate other cell surface molecules, such as additional members of the EGFR family and the platelet-derived growth factor receptor, which ignite signaling cascades that synergize with the EGFR-initiated cascade. Because of the cell surface location and increased expression of the receptor along with its important biological function, EGFR has triggered much effort for designing targeted therapy. These approaches include TK inhibition, monoclonal antibody, vaccine, and RNA-based downregulation of the receptor. Treatment success requires that the drug penetrates the blood-brain barrier and has low systemic toxicity but high selectivity for the tumor. While the blockade of EGFR-dependent processes resulted in experimental and clinical treatment success, cells capable of using alternative signaling ultimately escape this strategy. A combination of interventions targeting tumor-specific cell surface regulators along with convergent downstream signaling pathways will likely enhance efficacy. Studies on EGFR in glioblastoma have revealed much information about the complexity of gliomagenesis and also facilitated the development of strategies for targeting drivers of tumor growth and combination therapies with increasing complexity.

The impact of intraspecific variation in a fish predator on the evolution of phenotypic plasticity and investment in sex in Daphnia ambigua.

Theory predicts that the evolution of phenotypic plasticity depends upon cues that indicate environmental change. Predators typically induce plastic responses in prey. However, variation among populations of predators alters the frequency of predation and, possibly, the evolution of plasticity. We compared responses to predator cues in Daphnia ambigua from lakes where alewife (Alosa pseudoharengus) either do (anadromous) or do not (landlocked) migrate between marine and freshwater. In 'anadromous' lakes, Daphnia are abundant each spring but eliminated by alewives in summer, whereas Daphnia are constantly under the threat of predation in 'landlocked' lakes. Daphnia from 'anadromous' lakes grew faster, matured earlier and larger, produced more offspring and invested more in sex than Daphnia from landlocked lakes. We observed several significant lake type-by-predator treatment interactions. These interactions, whereby the differences between lakes were greater in predator-conditioned water, agree with theory and argue that Daphnia plasticity has been influenced by variation in alewives.

Development of an oncolytic herpes simplex virus using a tumor-specific HIF-responsive promoter.

We exploited the differential activation of hypoxia-inducible factor (HIF)-dependent gene expression in tumors versus normal tissue for the design of a targeted oncolytic herpes simplex virus type-1 (HSV-1). A gene that is essential for viral replication, infected cell polypeptide 4 (ICP4), was placed under the regulation of an HIF-responsive promoter and then introduced into the thymidine kinase locus (U(L)23) of HSV d120, which contains partial deletions in the two endogenous ICP4 genes. Recombinant HIF-HSV was isolated and their derivation from d120 was verified by expression of a truncated, non-functional form of ICP4 protein. Disruption of the U(L)23 locus was confirmed by loss of thymidine kinase expression and resistance to acyclovir. Unexpectedly, HIF-HSV expressed ICP4 and induced tumor cell lysis at similar levels under normoxia and hypoxia. The lack of HIF-dependent ICP4 transgene expression by HIF-HSV was due to two factors that have not previously been reported-reversion of the ICP4 gene region to its wild-type configuration and increased HIF-transcriptional activity under normoxia when cells were infected with any strain of HSV-1. The findings that an oncolytic HSV-1 is genetically unstable and can activate a tumor-related promoter in a non-specific manner have important implications for any proposed use of this virus in cancer therapy.

Alemtuzumab with rapid steroid taper in simultaneous kidney and pancreas transplantation: comparison to induction with antithymocyte globulin.

We compared our experience with alemtuzumab induction and rapid steroid taper (RST) in simultaneous kidney and pancreas transplantation (SKPT) with a historic control group who received rabbit antithymocyte globulin (r-ATG) induction with RST. 74 SKPTs performed at our center between January 2005 to November 2008 who underwent immunosuppression with RST in combination with r-ATG induction (n = 33; 1.5 mg/kg x 4 for a total dose of 6 mg/kg) or alemtuzumab induction (n = 41; 30 mg single dose). Maintenance immunosuppression consisted of tacrolimus and mycophenolate mofetil. Steroids were discontinued after postoperative day 4. Recipient and transplant characteristics were similar between the 2 groups, with 82% of the r-ATG and 80% of the alemtuzumab group steroid free at 1 year. The rate of clinical acute rejection episodes was 12% in the r-ATG group and 15% in the alemtuzumab group. The rates of cytomegalovirus (CMV) infection, BK nephropathy, and graft survival were similar between the 2 groups. There was no difference in mean serum creatinine, calculated GFR, or fasting blood sugar at 1 year between the 2 groups, whereas glycosylated hemoglobin (HbA1c) was lower at 1 year in the alemtuzumab (5.3 +/- 0.4) versus the r-ATG group (5.6 +/- 0.4; P = .0021). Induction with r-ATG or alemtuzumab with RST was safe and effective in SKPT. The incidences of acute rejection episodes, CMV infection, and BK nephropathy were similar. Mean HbA1C at 1 year was lower among the alemtuzumab group. Further long-term follow-up is needed to confirm these results.

Second-generation HIF-activated oncolytic adenoviruses with improved replication, oncolytic, and antitumor efficacy.

There is a need to develop more potent oncolytic adenoviruses (Ads) that show increased antitumor activity in patients. The HYPR-Ads are targeted oncolytic Ads that specifically kill tumor cells, which express active hypoxia-inducible factor (HIF). While therapeutically efficacious, the HYPR-Ads showed attenuated replication and oncolytic activity. To overcome these deficiencies and improve antitumor efficacy, we created new HIF-activated oncolytic Ads, HIF-Ad and HIF-Ad-IL4, which have two key changes: (i) a modified HIF-responsive promoter to regulate the E1A replication gene and (ii) insertion of the E3 gene region. The HIF-Ads showed conditional activation of E1A expression under hypoxia. Importantly, the HIF-Ads show hypoxia-dependent replication, oncolytic and cellular release activities, and potent antitumor efficacy, all of which are significantly greater than that of the HYPR-Ads. Notably, HIF-Ad-IL4 treatment led to regressions in tumor size by 70% and extensive tumor infiltration by leukocytes resulting in an antitumor efficacy that is up to six-fold greater than that of the HYPR-Ads, HIF-Ad and wild-type Ad treatment. These studies show that treatment with an HIF-activated oncolytic Ad leads to a measurable therapeutic response. The novel design of the HIF-Ads represents a significant improvement compared with first-generation oncolytic Ads and has great potential to increase the efficacy of this cancer therapy.

The clinical utility of MRI in patients with neurodevelopmental disorders of unknown origin.

INTRODUCTION: Neuroimaging of the brain in the diagnostic work-up of patients with neurodevelopmental disorders is a matter of continuing debate. Recommendations range from performing brain imaging in all patients with neurodevelopmental disorders to performing an MRI only in those with indication on clinical examinations. Important indications for neuroimaging are head size abnormalities and focal neurological findings. METHODS: Patients with neurodevelopmental disorders of unknown origin (n = 410), referred to a specialized tertiary diagnostic center for neurodevelopmental disorders were included in a retrospective analysis. A 1-day work-up, including an MRI of the brain was performed. Studied were the: (i) yield of MRI scans of the brain and (ii) associations of specific clinical symptoms/signs with abnormal and diagnostic MRI scans. RESULTS: (i) In 30.7% of the 410 patients with neurodevelopmental disorders (n = 126), abnormal MRI scans were observed, leading to an etiological diagnosis in 5.4% of the patients (n = 22). (ii) Pyramidal disorders (P = 0.001), epilepsy (P = 0.04) and an abnormal head circumference (P = 0.02) were associated with an abnormal MRI scan. The presence of one of the following neurological symptoms/signs: movement disorders, pyramidal disorders, epilepsy, or an abnormal head circumference was associated with a diagnostic MRI scan (P < 0.001) (diagnostic MRI % in neurological versus no neurological symptoms/signs, 13.0% versus 1.9%). CONCLUSION: Neuroimaging of the brain in a tertiary care center for patients with neurodevelopmental disorders of unknown origin is useful, especially in case of neurological symptoms/signs.

A randomised comparison of bilateral recession versus unilateral recession-resection as surgery for infantile esotropia.

OBJECTIVE: Infantile esotropia, a common form of strabismus, is treated either by bilateral recession (BR) or by unilateral recession-resection (RR). Differences in degree of alignment achieved by these two procedures have not previously been examined in a randomised controlled trial. DESIGN: Controlled, randomised multicentre trial. SETTING: 12 university clinics. PARTICIPANTS AND INTERVENTION: 124 patients were randomly assigned to either BR or RR. Standardised protocol prescribed that the total relocation of the muscles, in millimetres, was calculated by dividing the preoperative latent angle of strabismus at distance, in degrees, by 1.6. MAIN OUTCOME MEASURE: Alignment assessed as the variation of the postoperative angle of strabismus during alternating cover. RESULTS: The mean preoperative latent angle of strabismus at distance fixation was +17.2 degrees (SD 4.4) for BR and +17.5 degrees (4.0) for RR. The mean postoperative angle of strabismus at distance was +2.3 degrees (5.1) for BR and +2.9 degrees (3.5) for RR (p = 0.46 for reduction in the angle and p = 0.22 for the within-group variation). The mean reduction in the angle of strabismus was 1.41 degrees (0.45) per millimetre of muscle relocation for RR and 1.47 (0.50) for BR (p = 0.50 for reduction in the angle). Alignment was associated with postoperative binocular vision (p = 0.001) in both groups. CONCLUSIONS: No statistically significant difference was found between BR and RR as surgery for infantile esotropia.

A controlled comparison of brachial artery flow mediated dilation (FMD) and digital pulse amplitude tonometry (PAT) in the assessment of endothelial function in systemic lupus erythematosus.

The utility of flow mediated dilation (FMD) a measure of endothelial function is limited by operator dependence. Pulse amplitude tonometry (PAT) is a novel, less operator-dependent technique to assess endothelial function. This study compares PAT to FMD in SLE and controls. Thirty women with SLE and 31 controls were enrolled. Medications, cardiovascular disease and risk factors, SLE activity (SLAM-R) and damage (SLICC-DI) were recorded. FMD and PAT were performed simultaneously. Endothelium-independent function was assessed with nitroglycerin. Average age was 48.3 +/- 10.1 years, SLE duration 16.2 years, SLAM-R 8.3 and SLICC-DI 1.0. Framingham Risk Scores were < or =2% in most subjects. There were no differences between SLE cases and controls in FMD, PAT or response to nitroglycerin. This study found no association between FMD and PAT in SLE or controls. In the 17 SLE cases with a history of Raynaud's, correlation between FMD and PAT was 0.50 (P = 0.04). There was no difference in endothelial function assessed by FMD or PAT in SLE cases versus controls. FMD did not correlate with PAT except in SLE cases with a history of Raynaud's. Correlation between FMD and PAT may be stronger in populations with greater variation in endothelial function and more cardiovascular risk factors.

Molecular changes in the polymerase genes (PA and PB1) associated with high pathogenicity of H5N1 influenza virus in mallard ducks.

The highly pathogenic (HP) influenza viruses H5 and H7 are usually nonpathogenic in mallard ducks. However, the currently circulating HP H5N1 viruses acquired a different phenotype and are able to cause mortality in mallards. To establish the molecular basis of this phenotype, we cloned the human A/Vietnam/1203/04 (H5N1) influenza virus isolate that is highly pathogenic in ferrets, mice, and mallards and found it to be a heterogeneous mixture. Large-plaque isolates were highly pathogenic to ducks, mice, and ferrets, whereas small-plaque isolates were nonpathogenic in these species. Sequence analysis of the entire genome revealed that the small-plaque and the large-plaque isolates differed in the coding of five amino acids. There were two differences in the hemagglutinin (HA) gene (K52T and A544V), one in the PA gene (T515A), and two in the PB1 gene (K207R and Y436H). We inserted the amino acid changes into the wild-type reverse genetic virus construct to assess their effects on pathogenicity in vivo. The HA gene mutations and the PB1 gene K207R mutation did not alter the HP phenotype of the large-plaque virus, whereas constructs with the PA (T515A) and PB1 (Y436H) gene mutations were nonpathogenic in orally inoculated ducks. The PB1 (Y436H) construct was not efficiently transmitted in ducks, whereas the PA (T515A) construct replicated as well as the wild-type virus did and was transmitted efficiently. These results show that the PA and PB1 genes of HP H5N1 influenza viruses are associated with lethality in ducks. The mechanisms of lethality and the perpetuation of this lethal phenotype in ducks in nature remain to be determined.

Oculodentodigital dysplasia with mandibular retrognathism and absence of syndactyly: a case report with a novel mutation in the connexin 43 gene.

Oculodentodigital dysplasia (ODDD) is a rare, autosomal dominant pleiotropic disorder, caused by mutations in the Connexin 43 (Cx43 or GJA1) gene. Described here is the case of a 10-year-old girl with enamel hypoplasia, typical facies and mental delay, initially thought to be related to an unknown metabolic disorder. Careful clinical re-evaluation revealed a type of ODDD, characterised by the predominance of facial and ophthalmological involvement with mandibular retrognathism, and by the absence of cutaneous hand or foot syndactyly. A novel single-sequence variation (Nt460A>G) in exon 2, resulting in the substitution of alanine for threonine at amino acid 154, was found. These findings confirm once again the highly variable phenotypic expression caused by Cx43 mutations.

Changing epidemiology and ecology of highly pathogenic avian H5N1 influenza viruses.

The H5N1 virus currently circulating is continuing to evolve, and it has already resulted in the extension of its host and geographical range. It is likely that H5N1 will become a global problem for the poultry industry. How many of the recent H5N1 changes observed have been induced by changing patterns in poultry raising? A change in attitude on the use of high-quality vaccines is a change that would drastically help in the control of the current epidemic in the poultry industry. This article provides an overview of the changing properties that have been observed during the current H5N1 outbreaks.

Integrated care for MS patients.

PURPOSE: The problem of complex healthcare to MS patients, together with the rising prevalence of MS and escalating costs, has caused healthcare policy makers to consider innovative approaches to controlling costs and improving the quality of care. An integrated care approach may provide a means for better coordination and delivery of care. The aim is to review recent integrated care initiatives and their significance for MS patients. METHOD: A literature search was conducted to trace relevant literature on integrated care for MS patients published between 1995 and 2003. RESULTS: Although integrated care appears to offer potential for eliminating fragmentation and discontinuity in healthcare for MS patients, there are few published studies which have evaluated its implementation with MS patients. CONCLUSIONS: Even though the potential advantages of integrated care are well known, the applicability of this approach for MS patients has still to be demonstrated.

Acute rejection risk in kidney transplant recipients on steroid-avoidance immunosuppression receiving induction with either antithymocyte globulin or basiliximab.

Immunosuppression with rapid discontinuation of corticosteroids, usually with induction therapy, is safe in kidney transplant recipients. In 89 patients, we induced immunosuppression with basiliximab or rabbit antithymocyte globulin (17 and 72 patients, respectively). Selection criteria for basiliximab were age (>or=65 years), history (malignancy; chronic infection), and type 1 diabetes mellitus (eligible for pancreas transplant). Steroids were administered through posttransplantation day 4 (five doses); maintenance immunosuppression was with tacrolimus and mycophenolate mofetil. At last follow-up (average, 286 days), most patients were steroid-free (antithymocyte globulin, 90%; basiliximab, 88%). Protocol biopsies were performed at 1, 4, and 12 months posttransplantation. The overall risk of biopsy-proven acute rejection was 12%. At 6 months posttransplantation, acute rejection-free survival was 93% for antithymocyte globulin, 65% for basiliximab (P<.001). Median time to biopsy-proven acute rejection was 27 and 71 days, respectively. The low incidence of biopsy-proven acute rejection with steroid-avoidance immunosuppression may be further reduced with antithymocyte globulin.

[Congenital myotonic dystrophy--the significance of a handshake]. / Congenitale myotone dystrofie--wat is er 'aan de hand'?

Three neonates, all girls, were presented immediately after birth with severe hypotonia. Two of them needed artificial ventilation because of respiratory insufficiency. All three pregnancies had been complicated by reduced fetal movements and moderate cerebral ventricular dilatation and in two of the three there was also polyhydramnios and congenital talipes. In all three infants congenital myotonic dystrophy was suspected after diagnosing myotonia in the mother. This was done by observing that none of the mothers were unable to release their grip immediately on command after shaking hands. Ophthalmological examination of the women revealed polychromatic lens crystals characteristic of myotonic dystrophy. Congenital myotonic dystrophy was confirmed by DNA analysis, as well as myotonic dystrophy in the mothers. All had an expansion of the number of cytosine-thymine-guanine(CTG)-trinucleotides in a part of the myotonic dystrophy protein-kinase gene. The first two infants died after 2 days and 15 months respectively.

Establishing pediatric immune response zones using the Cylex ImmuKnow assay.

For all transplant patients, the transplant physician must balance the risk of rejection caused by under-immunosuppression against the risk of drug toxicity, secondary infections and post-transplant lymphoproliferative disorder with over-immunosuppression. A Food and Drug Administration (FDA)-approved in vitro assay, the Cylex ImmuKnow assay, provides a global assessment of cellular immune function to help monitor the immune status of immunosuppressed patients. This assay uses the plant lectin phytohemagglutinin to stimulate lymphocytes; an ATP assay is then used to measure the degree of activation of CD4 T cells. However, the normal values for this assay were developed with healthy adult patients. In this study, we determined the normal ranges for the ImmuKnow assay in healthy children and compared those values to levels obtained in healthy adults and in stable pediatric renal transplant patients. We found that healthy children 12 yr of age and older showed immune function levels indistinguishable from adults, while healthy children under 12 had significantly lower immune function levels than adults. For adults, the ImmuKnow assay zones (in ng/mL ATP) of strong, moderate and low immune function correspond to >525, 225 to 525, and <225. In children under 12, we found the corresponding zones to be >395, 175-395 and <175 ng/mL. The median value for normal adults is 415, whereas it is only 295 for children <12 yr of age and this value decreases to 165 in stable renal transplant patients <12 yr of age (compared with 258 for stable adult renal transplant patients). Thus, this study provides critical information necessary to utilize the ImmuKnow assay with pediatric patients. In adults, the degree of immune function as assessed by the ImmuKnow assay helps to predict patients at risk for infection or rejection. If further studies in pediatric patients document the same and is true for children, then the ImmuKnow assay will provide a useful adjunct tool to prevent over- or under-immunosuppression as newly developed drugs are utilized or drug treatment is altered because of drug side effects, toxicity, concurrent illnesses or rejection.

Are ducks contributing to the endemicity of highly pathogenic H5N1 influenza virus in Asia?

Wild waterfowl are the natural reservoir of all influenza A viruses, and these viruses are usually nonpathogenic in these birds. However, since late 2002, H5N1 outbreaks in Asia have resulted in mortality among waterfowl in recreational parks, domestic flocks, and wild migratory birds. The evolutionary stasis between influenza virus and its natural host may have been disrupted, prompting us to ask whether waterfowl are resistant to H5N1 influenza virus disease and whether they can still act as a reservoir for these viruses. To better understand the biology of H5N1 viruses in ducks and attempt to answer this question, we inoculated juvenile mallards with 23 different H5N1 influenza viruses isolated in Asia between 2003 and 2004. All virus isolates replicated efficiently in inoculated ducks, and 22 were transmitted to susceptible contacts. Viruses replicated to higher levels in the trachea than in the cloaca of both inoculated and contact birds, suggesting that the digestive tract is not the main site of H5N1 influenza virus replication in ducks and that the fecal-oral route may no longer be the main transmission path. The virus isolates' pathogenicities varied from completely nonpathogenic to highly lethal and were positively correlated with tracheal virus titers. Nevertheless, the eight virus isolates that were nonpathogenic in ducks replicated and transmitted efficiently to naïve contacts, suggesting that highly pathogenic H5N1 viruses causing minimal signs of disease in ducks can propagate silently and efficiently among domestic and wild ducks in Asia and that they represent a serious threat to human and veterinary public health.