Staphylococcus aureus skin/soft-tissue infections: the impact of SCCmec type and Panton-Valentine leukocidin

We assessed the role of Panton-Valentine leukocidin (PVL) and SCCmec type in community associated (CA) and healthcare associated (HC) Staphylococcus aureus (SA) skin/soft-tissue infections (STI). We prospectively monitored microbiology results (11 January 2005 to 6 January 2006), screened inpatients with SA in tissue samples or blood, and selected adults with STI. We recorded clinical/microbiological characteristics, and tested saved isolates for PVL genes (real time PCR) and SCCmec type (conventional multiplex PCR). We encountered 204 patients. MRSA strains that accounted for 70.5% CA and 66.0% HC cases, caused more abscesses (55.7% vs 29.7%; p =0.001) and were often PVL-positive (68.9% vs 4.8%; p <0.001). PVL-positive isolates caused more abscesses (72.9% vs 26.5%; p <0.001) but similar bacteremia (7.3% vs 7.1%). SCCmec IVa made up 95.8% of PVL-positive strains and accounted for 69.8% of the abscesses. SCCmec II caused higher mortality (14.8% vs 0-3.1%; p = 0.02). PVL was a predictor of abscesses (p <0.001). Predictors of bacteremia were age > or = 65 y (p =0.004), necrotizing infection (p =0.014), and head/neck location (p =0.05). These findings suggest that SCCmec type and PVL status influence STI manifestations and contribute to MRSA-MSSA differences. PVL is implicated in abscess formation but not bacteremia. Bacteremia is likely related to host condition and/or other virulence factors that were not studied.     

Singlet fission in pentacene dimers

Singlet fission (SF) has the potential to supersede the traditional solar energy conversion scheme by means of boosting the photon-to-current conversion efficiencies beyond the 30% Shockley–Queisser limit. Here, we show unambiguous and compelling evidence for unprecedented intramolecular SF within regioisomeric pentacene dimers in room-temperature solutions, with observed triplet quantum yields reaching as high as 156 ± 5%. Whereas previous studies have shown that the collision of a photoexcited chromophore with a ground-state chromophore can give rise to SF, here we demonstrate that the proximity and sufficient coupling through bond or space in pentacene dimers is enough to induce intramolecular SF where two triplets are generated on one molecule.Singlet fission (SF) is a spin-allowed process to convert one singlet excited state into two triplet excited states, namely a correlated triplet pair (1). The ability to effectively implement SF processes in solar cells could allow for more efficient harvesting of high-energy photons from the solar spectrum and allow for the design of solar cells to circumvent the Shockley–Queisser performance limit (2). Indeed, several recent studies have demonstrated remarkably efficient solar cell devices based on SF (3–6).One requirement that needs to be met to achieve SF is that the photoexcited chromophore in its singlet excited state must share its energy with a neighboring ground-state chromophore. As such, the potential of coupled chromophores to afford two triplet excited states via SF has been elucidated in, for example, a tetracene dimer with an SF yield of around 3% (3, 7). Additionally, past experiments in single-crystal, polycrystalline, and amorphous solids of pentacene have documented that the efficiency of SF relates to the electronic coupling between these two chromophores (8, 9). Hence, molecular ordering in terms of crystal packing, that is, proximity, distances, orbital overlap, etc., is decisive with respect to gaining full control over and to fine-tuning interchromophoric interactions in the solid state (10, 11). Of equal importance are the thermodynamic requirements, namely that the energy of the lowest-lying singlet absorbing state must match or exceed the energy of two triplet excited states (S₁ ≥ 2T₁) (11). In light of both aspects, hydrocarbons such as acenes––tetracene, pentacene, hexacene––and their derivatives are at the forefront of investigations toward a sound understanding and development of molecular building blocks for SF. In tetracenes, the singlet- and triplet-pair energy levels are nearly degenerate (S₁ = 2T₁), leaving no or little standard enthalpy of reaction for SF (12). In solution, the latter is, however, offset by sizable entropy rendering the process rather slow and, thus, inefficient (13). In addition, the low SF yield relates to the dimer geometry. Its nature hinders electronic coupling through space, leaving only through-bond coupling effective. The latter is, however, insufficient to enhance the SF rate (7, 14). In stark contrast, the relaxed triplet excited state in pentacenes has significantly less than half the energy of the singlet excited state. In turn, the thermodynamic SF requirement, that is (S₁ ≥ 2T₁), is fulfilled for pentacenes rendering this process exothermic and unidirectional (13). Finally, from SF in hexacenes two triplet excited states plus a certain amount of phonons are derived as the main relaxation products. In other words, the dissipated heat leads to a decrease in SF yields and rates (15).In terms of exploiting SF for improving device performances, e.g., hybrid solar cells, it is necessary to efficiently dissociate correlated triplet pairs as they are formed, to overcome triplet–triplet annihilation (5, 16). Rapid injection of electrons into fullerenes, perylene diimides, colloidal nanocrystals, semiconductor substrates, etc. suggests a viable strategy. If successful, two charge carriers might be produced per absorbed photon and the photocurrents of the device can reach external quantum efficiencies of more than 100% (5, 17, 18).A provocative debate has been ignited about the mechanism of SF at the molecular level (19, 20). Controversy exists around the electronic states that are involved in the process, the coupling among them, and the effective nuclear dynamics (14, 21–27). Two contrasting SF mechanisms have been traditionally postulated––the direct and the two-step mechanism. These mechanisms differ in the number and nature of the electronic states that are involved in the SF process. For the direct mechanism, the nonradiative relaxation of the initially populated bright state proceeds via a correlated triplet pair state of singlet character––sometimes called multiexcitonic (ME) state––which then dissociates into two separated triplet excited states (28). For the two-step mechanism, the relaxation of the bright state occurs via an intermediate charge transfer (CT) state to the ME state. As in the direct mechanism, the ME state eventually allows the two triplet excited states involved to separate and undergo separate spin relaxation (11, 21–23). Recent works have, however, challenged these traditional viewpoints on the SF mechanism and several new models have been proposed. In particular, it has been suggested (13, 29, 30) that the initial excitation produces a coherent superposition of the lowest-lying absorbing state and the ME state, with the latter splitting into two separated triplet states after decoherence. On the other hand, recent theoretical works (14, 27) have proposed a model for SF in dimers, in which the ME state is formed from the absorbing state via a superexchange mechanism involving CT states, although the kinetics of the process is one-step–like. All of the above suggests that the traditional classification of SF mechanisms as direct or two-step is presumably too simple to describe the complexity of the process.Until recently, most studies regarding SF have been carried out in the solid state (11). However, in a groundbreaking report, Friend and coworkers showed that SF could be observed in solution at room temperature for a pentacene derivative (31). Key to this discovery was the formation of an intermediate state via the collision of a singlet excited-state pentacene and a second pentacene that was in the ground state. This study broke for the first time, to our knowledge, the dogma of molecular order as a mandate for SF and demonstrated that the order and packing might not be as crucial as believed, leaving SF as an intrinsic property even in a state of disorder.In this present contribution, we report on intramolecular SF within a set of three different pentacene dimers (Fig. 1), reaching triplet quantum yields as high as 156 ± 5%, as established by means of pump–probe experiments in solution. Experimental results are complemented by theoretical calculations using high-level ab initio multireference perturbation theory methods. In the series of pentacene dimers, the two pentacenes are linked via a phenylene spacer in an ortho-, meta-, and para-arrangement to impose geometrical control, which influences through-space and through-bond couplings in the ground- and excited state. The electronic coupling element, which governs SF and triplet–triplet annihilation, is mediated through-bond in the linearly and cross-conjugated para- and meta-isomers, respectively. In the ortho-isomer, through-space coupling should dominate due to the unique spatial proximity of the pentacenes (32, 33). Through experiments, we establish a sound picture of the SF mechanism in covalently linked pentacene dimers, showing the involvement of CT states.Open in a separate windowFig. 1.(Upper) Synthesis of pentacene dimers o-2, m-2, and p-2. (Lower) SF mechanism.     

Bi‐allelic IARS mutations in a child with intra‐uterine growth retardation,neonatal cholestasis,and mild developmental delay

Recently, bi‐allelic mutations in cytosolic isoleucyl‐tRNA synthetase (IARS) have been described in three individuals with growth delay, hepatic dysfunction, and neurodevelopmental disabilities. Here we report an additional subject with this condition identified by whole‐exome sequencing. Our findings support the association between this disorder and neonatal cholestasis with distinct liver pathology. Furthermore, we provide functional data on two novel missense substitutions and expand the phenotype to include mild developmental delay, skin hyper‐elasticity, and hypervitaminosis D.     

Effectiveness of glycoprotein IIb/IIIa inhibitor use during primary coronary angioplasty: results of propensity analysis using the New York State Percutaneous Coronary Intervention Reporting System

Patients undergoing primary angioplasty in clinical practice experience a higher risk for adverse events than those enrolled in clinical trials. Whether glycoprotein (GP) IIb/IIIa inhibitor use during primary angioplasty is both safe and effective in real life is unknown. Therefore, we examined the pattern of GP IIb/IIIa use and its effectiveness in a large population-based cohort of 7,321 patients who underwent primary angioplasty in New York State. Propensity analysis was used to account for the nonrandomized use of GP IIb/IIIa inhibitors. Overall, 78.5% of patients who underwent primary angioplasty received GP IIb/IIIa inhibitors. In-hospital mortality was significantly lower with GP IIb/IIIa use (3% vs 6.2%, p <0.0001) after adjustment for both propensity score (odds ratio 0.57, 95% confidence interval 0.44 to 0.74, p <0.0001) and the combination of propensity score and clinical characteristics (odds ratio 0.63, 95% confidence interval 0.45 to 0.88, p = 0.006). Patients with older age and higher Mayo Clinic Risk Score (MCRS) received GP IIb/IIIa inhibitors less often. However, stratified analysis of patients with low to moderate risk (MCRS <12) versus high risk (>or=12) demonstrated that GP IIb/IIIa use lowered risk of mortality both in low- to moderate-risk (1.39% vs 3.23%, p <0.0001) and high-risk patients (16.15% vs 22.41%, p = 0.03). In conclusion, adjunct GP IIb/IIIa inhibitor use during primary angioplasty is effective and associated with improved in-hospital survival rates.     

Protein kinase C alpha modulates microvascular reactivity in the human coronary and skeletal microcirculation

BACKGROUND: Cardioplegic arrest (CP) and cardiopulmonary bypass (CPB) can lead to dysfunction in the coronary and skeletal microcirculation leading to impaired tissue perfusion. alpha-Adrenergic signaling pathways acting on these microcirculatory beds are thought to involve protein kinase C (PKC). We investigate here the role of the conventional PKCs in microvascular function in the setting of CP/CPB. METHODS: Atrial and skeletal muscle was harvested from 30 patients undergoing cardiac surgery before and after CP/CPB. Microvessels were used for Western blotting and immunofluorescent staining against conventional PKCs. Microvascular constriction was assessed in pre- and post-CP/CPB samples in response to alpha-adrenergic stimulation with phenylephrine, with and without a PKC-alpha inhibitor or PKC-alpha activator. PKC activity was assessed in isolated microvessels. RESULTS: Western blotting and immunostaining demonstrated only PKC-alpha in coronary and skeletal microvessels. CP/CPB diminished contractile responses to phenylephrine in coronary and skeletal samples. Inhibition of PKC-alpha reduced phenylephrine induced vasoconstriction in coronary and skeletal microvessels, whereas activation of PKC-alpha-augmented phenylephrine induced responses. PKC activity was decreased in coronary microvessels and to an even greater degree in skeletal microvessels after CP/CPB. CONCLUSIONS: PKC-alpha is the predominant conventional PKC present in the human coronary and skeletal microcirculation. It likely plays a key role in alpha-adrenergic signaling in microvessels and in the vasomotor dysfunction after CP/CPB.     

Germline LEMD3 mutations are rare in sporadic patients with isolated melorheostosis

To further explore the allelic heterogeneity within the group of LEMD3-related disorders, we have screened a larger series of patients including 5 probands with osteopoikilosis or Buschke-Ollendorff syndrome (BOS), 2 families with the co-occurrence of melorheostosis and BOS, and 12 unrelated patients with isolated melorheostosis. Seven novel LEMD3 mutations were identified, all predicted to result in loss-of-function of the protein. We confirm that loss-of-function mutations in the LEMD3 gene can result in either osteopoikilosis or BOS. However, LEMD3 germline mutations were only found in two melorheostosis patients belonging to a different BOS family and one sporadic patient with melorheostosis. The additional presence of osteopoikilosis lesions in these patients seemed to distinguish them from the group of sporadic melorheostosis patients where no germline LEMD3 mutation was identified. Somatic mosaicism for a LEMD3 mutation in the latter group was also not observed, and therefore we must conclude that the genetic defect in the majority of sporadic and isolated melorheostosis remains unknown.     

Does paternal antigen-induced secretion of interleukin-10 by T regulatory cells mediate the birth order effect?

Childhood allergy constitutes a significant burden of disease in the Western world. The prevalence of this condition is highest in first born children, an as yet unresolved phenomenon called the "birth order effect". The hygiene hypothesis attempted to explain this differential risk by stating that less exposure to microbial agents at an early age of first born children would result in reduced activation of the immune system and subsequent polarization towards a Th2 phenotype. However, no conclusive evidence for or against the hygiene hypothesis has been found so far. Another, not necessarily conflicting, theory states that the birth order effect is already established during prenatal life and that the fetal-maternal interaction changes during successive pregnancies. Combining this theory with research on preeclampsia, another disease originating in pregnancy and also related to birth order, could suggest clues about the mechanisms underlying the birth order effect. Recent research on preeclampsia showed that preeclamptic women have higher levels of pro-inflammatory IL-6 and lower paternal antigen-induced secretion of IL-10 compared to normal pregnant women, indicating a lower number or lower functional activity of T regulatory (Treg) cells. These Treg cells play an important role in maintaining tolerance to fetal antigens in pregnancy and they are found in high numbers at the maternal-fetal interface. We hypothesize that nulliparous women have a lower activity of Treg cells specific to paternal antigens compared to parous women, either in peripheral blood or in the decidua (maternal part of the fetal-maternal interface). If this hypothesis is true, this would mean that the allergen suppressor mechanism of Treg cells is sub-optimal in first born children. This would explain at least a part of the mechanism of the birth order effect and would give us directions for developing preventive measures to prevent possibly 30% of future childhood allergies.     

The expanding panorama of split hand foot malformation

The split hand/foot malformation is a developmental defect of the extremities resulting from errors in the initiation and maintenance of the apical ectodermal ridge. The phenotype is genetically heterogeneous, and it can be identified either as an isolated phenotypic manifestation or as a constituent component of a malformation syndrome. This overview describes the clinical phenotype, related animal models, and the evolving genetic heterogeneity of the malformation.