Functional advantages of building nanosystems using multiple molecular components.

Over half of all the natural nanomachines in living organisms are multimeric and likely exploit the self-assembly of their components to provide functional benefits. However, the advantages and disadvantages of building nanosystems using multiple molecular components remain relatively unexplored at the thermodynamic, kinetic and functional levels. In this study we used theory and a simple DNA-based model that forms the same nanostructures with different numbers of components to advance our knowledge in this area. Despite its lower assembly rate, we found that a system built with three components may undergo a more cooperative assembly transition from less preorganized components, which facilitates the emergence of functionalities. Using simple variations of its components, we also found that trimeric nanosystems display a much higher level of programmability than their dimeric counterparts because they can assemble with various levels of cooperativity, self-inhibition and time-dependent properties. We show here how two simple strategies (for example, cutting and adding components) can be employed to efficiently programme the regulatory function of a more complex, artificially selected, RNA-cleaving catalytic nanosystem.

Azacitidine-induced pyoderma gangrenosum at injection sites in a patient with myelodysplastic syndrome.

Pyoderma gangrenosum (pg) is a rare neutrophilic dermatosis characterized by painful necrotic ulceration affecting preferentially the lower extremities. Diagnosis is challenging, and a thorough workup (including biopsy) is required. In this case report, we describe a 67-year-old patient with a diagnosis of myelodysplastic syndrome (mds) who developed fever and pg two days after the first cycle of subcutaneous azacitidine (Vidaza; Celgene Corporation, Summit, NJ, USA). On physical examination, the patient had four erythematous plaques at sites of subcutaneous injections of azacitidine on the arms, as well as three other plaques in proximity. A skin biopsy demonstrated a dense neutrophilic interstitial infiltrate in the dermis. After the diagnosis of pg, prednisone 1 mg/kg was started and the fever subsided rapidly. This was followed by the resolution of the cutaneous lesions. Changing the route of administration of azacitidine from subcutaneous to intravenous and adding a daily dose of prednisone during the treatment allowed the patient to receive a total of 10 cycles of azacitidine. This is the second case reported in the literature. Because azacitidine is frequently used in mds and acute myeloid leukemia, clinicians should be aware of this rare cutaneous adverse event. Our approach can be used to avoid the recurrence of pg when continuing azacitidine treatment.

Validation study of the s classification for melanoma patients with positive sentinel nodes: the Montreal experience.

BACKGROUND: Standard of care is to perform a complete lymph node dissection (CLND) in melanoma patients with positive sentinel lymph nodes (SLNs). However, less than 20% will have metastases in non-SLNs. The S classification was described to predict the non-SLN status, hoping to identify a subset of patients who can be spared the CLND. We tried to validate the feasibility and usefulness of this classification. MATERIALS AND METHODS: We performed a retrospective chart review. All melanoma cases between 1996 and 2006 were included, and 359 patients with SLN biopsies were identified. All pathology slides were reviewed with an emphasis on the S classification. RESULTS: There were 365 SLN biopsies performed. A total of 82 patients (22.8%) had positive SLNs, while 277 patients (77.2%) had negative SLNs. There were 22 patients classified as SI, 18 as SII, 37 as SIII, and 5 were unclassified. On CLND, only 10 patients (12.2%) had positive non-SLNs. None of these were classified as SI while 2 patients (11%) were classified as SII and 8 (22%) as SIII. The S category was found to be a predictor of non-SLN status, and this reached statistical significance (P = 0.044). On univariate analysis, only an increasing Breslow depth and ulceration were predictive of a non-SI status. CONCLUSION: Our results suggest that the S classification is easily feasible and predicts the status of non-SLNs. No patient with SI status was found to have additional non-SLN positive nodes. A larger-scale, prospective trial should be done to confirm these results and possibly spare patients the morbidity of CLND with a positive SLN.

The type I diabetes association of the IL2RA locus.

To confirm and fine map previous reports of association, the Type I Diabetes (T1D) Genetics Consortium (T1DGC) assembled a large collection of DNA samples from affected sib-pair (ASP) families with T1D (5003 affected individuals) and genotyped polymorphic markers. One of these loci, involving the IL2RA gene, had been reported to be due to three independent effects. The T1DGC genotyped 69 single-nucleotide polymorphisms (SNPs) that span approximately 88 kb from the 5' flanking to 3' flanking region of the IL2RA locus. The most highly associated SNP reported earlier (ss52580101) was not included in the genotyping list; however, a 5-SNP (rs3134883, rs3118470, rs7072793, rs4749955 and rs12251307) haplotype (H5) was identified that strongly tagged its minor allele with r(2)=0.869 (95% CI, 0.850-0.885). This haplotype was significantly protective (P=3.2 x 10(-5)) in the T1D ASP families, with an odds ratio virtually identical to that reported for ss52580101. The SNP marking the second independent locus, (rs11594656) showed no association in the T1DGC set and the third (rs2104286) could not be distinguished, by conditional regression, from H5. Instead, the most significant independent effect was detected from the 5' flanking IL2RA SNP rs4749955, which remained significant after regression for H5. Thus, we confirm independent effects at the IL2RA locus.

Disseminated Histoplasma capsulatum infection presenting with panniculitis and focal myositis in rheumatoid arthritis treated with etanercept.

We report the case of a patient with rheumatoid arthritis (RA) on etanercept who presented with panniculitis and focal myositis as manifestations of disseminated histoplasmosis. Systematic search of the literature showed 11 additional case reports of disseminated histoplasmosis with tumour necrosis factor-alpha (TNFalpha) blockade therapy (infliximab, n = 8; etanercept, n = 3). Although disseminated histoplasmosis may manifest with classical symptoms of fever and respiratory complaints, it may also present atypically, such as with panniculitis and focal myositis. This review illustrates and emphasizes the importance of being highly suspicious for infection, including by opportunistic organisms, and to exclude such process in patients treated with a TNFalpha inhibitor when faced with unusual complications, even when an alternative aetiology appears plausible.

Dicofol residues in eggs and carcasses of captive American kestrels.

American kestrels (Falco sparverius) were fed diets containing 0 (control), 1, 3, 10, and 30 microgram/g (wet wt) of Kelthane. Residues of dicofol and its metabolites were then analyzed in the eggs and carcasses of females. Significant differences occurred among treatments for residues of both p,p'-dicofol and p,p'-dechlorodicofol (DCD) in both eggs and carcasses and for p,p'-dicholorbenzophenone (DCBP) in eggs. Residue concentrations increased with increasing treatment exposure. Residues of p,p'-dicofol, p,p'-DCD, and p,p'-DCBP in eggs were significantly correlated with eggshell quality parameters. Significant correlations also occurred among contaminants in eggs and for individual contaminants between eggs and carcasses. The lowest-observed-dietary-effect concentration for eggshell thinning was 3 microgram/g, whereas 1 microgram/g may be considered to be near a no-observable-adverse-effect concentration. Concentrations of dicofol in potential prey items and eggs of wild birds generally have been lower than dietary-effect concentrations or concentrations in tissues or eggs associated with eggshell thinning and reduced reproductive success.

Residues of petroleum hydrocarbons in tissues of sea turtles exposed to the Ixtoc I oil spill.

Sea turtles found dead when the Ixtoc I oil spill reached Texas waters were necropsied and tissues were analyzed for residues of petroleum hydrocarbons. Two of three turtles were in poor flesh, but had no apparent oil-caused lesions. There was evidence of oil in all tissues examined and indications that the exposure had been chronic. Comparisons with results of studies done on birds indicate consumption of 50,000 ppm or more of oil in the diet. Some possible mechanisms of mortality are suggested.

Quantification of petroleum-type hydrocarbons in avian tissue.

Methods were developed for the analysis of 16 hydrocarbons in avian tissue. Mechanical extraction with pentane was followed by clean-up on Florisil and Silicar. Residues were determined by gas-liquid chromatography and gas-liquid, chromatography-mass spectrometry. The method was applied to the analysis of liver, kidney, fat, and brain tissue of mallard ducks (Anas platyrhynchos) fed a mixture of hydrocarbons. Measurable concentrations of all compounds analyzed were present in all tissues except brain. Highest concentrations were in fat.

Residues of organochlorine pesticides and polychlorinated biphenyls and autopsy data for bald eagles, 1973-74.

Eighty-six bald eagles found sick or dead during 1973-74 in 24 States were analyzed for organochlorine compounds. DDE was detected in all caracasses; polychlorinated biphenyls (PCB's) were found in all but two. Seventy-five carcasses contained TDE and/or dieldrin. Four eagles had possibly lethal levels of dieldrin in the brain. Bald eagles continue to retain high residue levels of organochlorine pollutants. Illegal shooting remained the most common cause of death but accounted for a smaller percentage of the mortalities than in the two previous biennial collections.

Organochlorine pesticide and polychlorinated biphenyl residues in selected fauna from a New Jersey salt marsh--1967 vs. 1973.

More than a half million pounds of DDT were applied to control mosquitoes in salt marsh estuaries of Cape May County, New Jersey, from 1946 to 1966. The use of DDT was discontinued in the County after 1966. In 1967, mean concentrations of DDT and metabolites ranged from 0.63 to 9.05 ppm in aquatic fauna, but by 1973 mean residue levels had decreased 84 to 99 percent among nine species. DDE was still present at reduced levels in nearly all samples in 1973, but other DDT isomers had mostly disappeared. Dieldrin was detected only in clapper rails, and residue levels decreased during the period. Mean concentrations of PCB's increased in the clapper rail, remained the same in the fiddler crab and mud snail, and decreased in the sheepshead minnow, mummichog, striped killifish, and salt marsh snail. Small amounts of mirex, toxaphene, cis-chlordane (and/or trans-nonachlor), oxychlordane, and HCB were detected in a few specimens.

Residues of organochlorine pesticides and polychlorinated biphenyls and autopsy data for bald eagles, 1971-72.

Thirty-seven bald eagles found sick or dead in 18 States during 1971-72 were analyzed for organochlorine pesticides and polychlorinated biphenyls (PCB's). DDE and PCB's were detected in all bald eagle carcasses; 30 carcasses contained DDD and 28 contained dieldrin. Four eagles contained possibly lethal levels of dieldrin and nine eagles had been poisoned by thallium. Autopsies revealed that illegal shooting was the most common cause of mortality. Since 1964 when data were first collected, 8 of the 17 eagles obtained from Maryland, Virginia, South Carolina, and Florida possibly died from dieldrin poisoning; all four specimens from Maryland and Virginia were from the Chesapeake Bay Tidewater area.