[Heart transplantation and the subsequent treatment of AL amyloidosis].
Severe damage to the heart caused by AL amyloid deposits is a contraindication of high-dose chemotherapy with autologous haematopoietic stem cell transplantation. Severe heart damage caused by AL amyloid results in frequent life-threatening complications, even during the course of the classical chemotherapy treatment and it often makes keeping to the treatment schedule impossible. Scheduling heart transplantation before the treatment of AL amyloidosis will significantly improve the patients overall condition and enable them to undergo the intensive AL amyloidosis treatment with the hope that a long-term complete remission may be achieved. Transplantations of heart damaged by AL amyloid deposits were conducted in three patients; two men, age 48 and 54, and one woman, age 63. In the interval of 3-6 months from the heart transplantation before the scheduled AL amyloidosis treatment was initiated, an examination of bone marrow, the concentration of monoclonal immunoglobulin and free light chains was carried out. Both men had more than 10% of plasma cells in the bone marrow after the heart transplantation and the concentrations of the λ free light chains were pathologically increased. During the first-line therapy, autologous haematopoietic stem cells were harvested from peripheral blood after mobilizaton with granulocyte growth factor (filgrastim) at the dose of 5 µg/kg twice a day. During the administration of filgrastim until the end of the haematopoietic stem cell harvest, the combined immunosuppressive treatment was reduced and a corticosteroid dose was compensatory increased. The prophylactic antiviral drug valganciclovir was discontinued during the haematopoietic stem cell harvest. High-dose chemotherapy (melphalan 100 mg/m2) with autologous haematopoietic stem cell transplantation followed. In the interval from administering melphalan until the rise in neutrophil count over 2 x 109/l, antiviral prophylaxis was discontinued again, the immunosuppressive drug doses were reduced and corticoid doses were slightly increased. High-dose chemotherapy with melphalan at the of 100 mg/m2 was tolerated without major complications and without mucositis; however, in neither of the male patients did it lead to a complete haematological remission. Consequently, the second-line therapy followed using bortezomib combined with dexamethasone and also with cyclophosphamide or doxorubicin. One of these two patients reached a complete haematological remission after the bortezomib therapy; the values of free light chains were normal, immunofixation was negative, and clonal plasma cells were absent in the bone marrow. In the case of the other patient, the bortezomib therapy only induced partial remission. In this case, the third-line therapy followed, applying a combination of lenalidomide, dexamethasone and cyclophosphamide. This therapy significantly reduced the values of free light chains; however, their ratio remained pathological. To conclude, the latter response can be described as a very good partial remission. Both men currently show no signs of disease activity and are in a good clinical condition 28 and 30 months after the heart transplantation. The third heart transplantation, due to severe heart damage by AL amyloid deposits, was conducted in a woman aged 63. An examination of this woman three months after the heart transplantation showed that the original pathological values of free light chains became normal. The woman had approx. 8% of clonal plasma cells before the heart transplantation. Three months after the heart transplantation the bone marrow contained only 3% of polyclonal plasma cells. In this case, the immunosuppressive treatment with corticosteroids after the heart transplantation probably induced a complete haematologic remission. The woman is in a complete AL amyloidosis remission seven months after the heart transplantation. It was beneficial to perform the heart transplantation first and to initiate the AL amyloidosis treatment no sooner than three months after the heart transplantation in patients with severe heart damage caused by AL amyloid deposits. If the patients are in a good clinical conditions, autologous haematopoietic stem cells can be harvested after the heart transplantation and high-dose chemotherapy can be offered to the patients. If this intensive treatment does not induce remission, it is necessary to apply additional alternative treatments.


NMR spectroscopy of macrophages loaded with native, oxidized or enzymatically degraded lipoproteins.
Oxidized and enzymatically modified low-density lipoproteins (oxLDL and eLDL) play a key role in early stages of atherogenesis. Their uptake by recruited macrophages leads to endolysosomal phospholipidosis or foam cell formation, respectively, each of which is preceded by highly differential lipid restructuring processes. We applied (1)H-NMR spectroscopy (NMRS) to elucidate these structural rearrangements both in consequence of lipoprotein modifications and following phagocytosis. Being specifically sensitive to the mobile lipid subset, NMRS of oxLDL and eLDL revealed a partial and total immobilization of lipids, respectively. NMRS of intact macrophages showed a sixfold increase in mobile lipids in case of loading with eLDL but no significant changes for oxLDL or native LDL. This finding reflected the disparate lipid storage in lipid droplets and in multilamellar endolysosomal clusters when loaded with either eLDL or oxLDL, respectively. Moreover, a significant shift of the degree of saturation towards mainly polyunsaturated fatty acid chains was found for the mobile lipid pool in eLDL-loaded macrophages. Additional analyses of lipid extracts by NMRS and mass spectrometry (MS) reflected these changes in lipid content and in fatty acid composition only partially. In summary, in-cell NMRS represents a unique lipidomics tool to investigate structural changes within the mobile lipid pool following atherogenic triggers that can be not detected by the analysis of lipid extracts by MS or NMRS.


Sub-5 nm porous nanocrystals: interfacial site-directed growth on graphene for efficient biocatalysis.
The direct production of macromolecular scale (sub-5 nm) porous nanocrystals with high surface area has been a considerable challenge over the past two decades. Here we report an interfacial site-directed capping agent-free growth method to directly produce porous ultrasmall (sub-5 nm), fully crystalline, macromolecular scale nanocrystals. The porous sub-5 nm Prussian blue nanocrystals exhibit uniform sizes (∼4 ± 1 nm), high surface area (∼855 m2 g-1), fast electron transfer (rate constant of ∼9.73 s-1), and outstanding sustained catalytic activity (more than 450 days). The nanocrystal-based biointerfaces enable unprecedented sub-nanomolar level recognition of hydrogen peroxide (∼0.5 nM limit of detection). This method also paves the way towards the creation of ultrasmall porous nanocrystals for efficient biocatalysis.


Cytochrome P450: the active oxidant and its spectrum.
This Forum focuses on the nature of the elusive oxidizing intermediate in P450 catalysis. The identity of this species has reemerged as a topic of contentious debate. It was recently reported that laser flash photolysis (LFP) can be used to generate P450 compound I (P450-I) quantitatively. Kinetic analyses of the reaction of the LFP-generated intermediate with substrates have been suggested to indicate that compound I is not the active oxidant in P450 catalysis. We evaluate these claims via an analysis of the UV/visible spectrum of the LFP-generated intermediate. The techniques of singular value decomposition and target testing are used to obtain the spectrum of P450-I in a model-independent manner from stopped-flow data of the reaction of P450 with m-chloroperbenzoic acid. It is shown that the LFP-generated spectrum bears no similarity to the P450-I spectrum. One may conclude that the LFP-generated intermediate is not P450-I.


Pharmacokinetics, Metabolism, and Partial Biodistribution of "Pincer Therapeutic" Nitazoxanide in Mice following Pulmonary Delivery of Inhalable Particles.
Nitazoxanide (NTZ) induces autophagy in mammalian cells and also has mycobactericidal activity, displaying a two-pronged therapeutic effect, on the host as well as the pathogen. The pharmacokinetics and biodistribution of inhaled NTZ were investigated. Particles containing NTZ in a matrix of PLGA were prepared by spray drying. HPLC and LC-MS/MS methods were developed and validated. Particles were administered as inhalations to mice. Drug concentrations in plasma and tissues were estimated at different time points. Drug loading (∼36%), entrapment efficiency (>90%), and the conversion of NTZ into metabolites in plasma and lung homogenates were assessed satisfactorily by HPLC. NTZ pharmacokinetics and biodistribution following intravenous administration or inhalation were established by LC-MS. NTZ converted into tizoxanide (99% in 30 min) and other metabolites. Pulmonary delivery of NTZ entrapped in particles increased the half-life of the drug by factors of 3, 12, and 200 in the plasma, lung tissue, and alveolar macrophages, respectively. Targeted delivery and prolonged lung retention along with dose sparing of the kidneys was observed upon pulmonary delivery as compared to intravenous administration.


Probing the Origin of Ferro-/Antiferromagnetic Exchange Interactions in Cu(II)-4f Complexes.
The mechanistic investigations between Cu(II) and the anisotropic lanthanides (Ln(III)) are not much explored to date. This is due to the complicated energy spectrum which arises due to the orbital angular momentum of anisotropic lanthanides. Interestingly, the exchange coupling J in Ln(III)-Cu(II) systems was found to be antiferromagnetic for <4f7 metal ions and ferromagnetic for ≥4f7 metal ions, while the net magnitude of JTotal strength gradually decreases moving from f1 to f13. While this is established in several examples, the reason for this intriguing trend is not rationalized. In this article, we have taken up these challenging tasks by synthesizing a family of complexes with the general molecular formula [Cu2Ln(HL)4(NO3)](NO3)2, where Ln = La (1-La), Ce (2-Ce), Pr (3-Pr), Gd (4-Gd), Tb (5-Tb), Dy (6-Dy), and Ho (7-Ho) and HL = C15H15N1O3; (2-methoxy-6-[(E)-2'-hydroxymethyl-phenyliminomethyl]-phenolate) is a monodeprotonated tridentate Schiff base ligand. Detailed dc magnetic susceptibility measurements performed for all the complexes reveal that the Cu(II) ion is coupled ferromagnetically to the respective Ln(III) ion, which has more than seven electrons in the 4f shell, while an antiferromagnetic coupling is witnessed if Ln(III) has less than seven electrons. The strength of the exchange coupling constant was quantitatively determined for representative complexes from the high-field/high-frequency electron paramagnetic resonance spectroscopy which follows the order of 4-Gd (1.50(10) cm-1) > 5-Tb (1.18(10) cm-1) > 6-Dy (0.56(10) cm-1 based on the -2JCu-Ln(SCu1→·JLnz→+SCu2→·JLnz→) spin Hamiltonian. The increased axiality in 5-Tb and 6-Dy due to the presence of 3d ions in the near vicinity of an oblate ion and the increased exchange coupling strength between Cu(II) and Tb(III) or Dy(III) is the ideal combination to stabilize magnetic bistability in these complexes in the absence of an external magnetic field with the effective energy barrier of 15.7 K (τo = 2.49 × 10-6 s) and 12.6 K (τo = 1.70 × 10-5 s), respectively. To rationalize this experimental trend, we have performed ab initio CASSCF and DFT calculations. To compute the J values, we have employed POLY_ANISO routines and utilized the computed data to establish the generic mechanism of magnetic coupling in {Cu-Ln-Cu} motifs. These mechanistic findings reveal the importance of 5d orbitals and their energy with respect to the dx2-y2 orbital of Cu(II) ions in controlling the magnetic coupling of {Cu-4f} complexes.


The use of the cryoplasty technique in the treatment of infrapopliteal lesions for Critical Limb Ischemia patients in a routine hospital setting: one-year outcome of the Cryoplasty CLIMB Registry.
It was the objective of the Cryoplasty CLIMB to evaluate the effectiveness of the PolarCath device in a standard clinical practice in the treatment of infrapopliteal lesions in critical limb ischemia patients. Between May 2007 and July 2008, 100 patients (72 years, 67%male) with CLI were enrolled in the trial for the treatment of 100 infrapopliteal stenoses or occlusions. The mean lesion length and diameter stenosis were 54.9+/-55.8 mm and 91.3+/-8.3%. Primary endpoint was defined as 12-month primary patency based on duplex. Secondary endopoints were immediate success and 12-month limb salvage and survival rate. Multiple cryoplasty cycles were performed in 56 cases (2.1 inflations per patient) and in 4 the use of a different size balloon was required. The immediate technical success rate was 95.0% and the stent rate was 17.0%. The 12 month primary patency, limb salvage and survival rates were 55.9+/-7.4%, 93.8+/-2.5% and 81.8+/-3.9%, respectively. Stratification for lesion length did not show significant outcome differences for lesions < or =50.0 mm and those >50.0 mm neither for primary patency (P=0.94), nor for limb salvage (P=0.32). The cryoplasty technique is effective for the treatment of infrapopliteal lesions in CLI patients. The results seem to be within the range of those of conventional PTA. Especially for shorter lesion (<50.0 mm), the wide-spread use of cryoplasty is not recommended. For lesions with a minimal length of 50.0 mm, the results are encouraging.


Mass output and particle size distribution of glucocorticosteroids emitted from different inhalation devices depending on various inspiratory parameters.
Efficient inhalation therapy depends on successful delivery of the drug to the lung. The efficacy of drug delivery is not only influenced by the characteristics of the inhalation device, but also by the patient's handling of the device and by the inspiratory maneuver achieved through the device. We analyzed the output characteristics of three different chlorofluorocarbon (CFC)-free breath-actuated inhalers for inhaled glucocorticosteroids (BUD Turbohaler, FP Diskus/Accuhaler and HFA-BDP Autohaler, respectively). Mass output and particle size distribution of drug aerosol delivered by the inhalers were determined depending on different inhalation parameters in vitro using an Andersen cascade impactor. We found that, beside the peak inspiratory flow (PIF), other factors such as flow acceleration and inhalation volume also have significant effects on aerosol generation with respect to mass output and particle size distribution. Thus, these parameters should be taken into account when a suitable device for an individual patient is to be selected. The dependency on inspiratory parameters was most pronounced for the dry powder inhalers. The Turbohaler showed by far the highest variance in particle output (fine particle fraction ranging from 3.4% to 22.1% of label claim), whereas the Diskus was less dependent on variations in inhalation (10.6% to 18.5% of label claim). The most constant aerosol output was found for the Autohaler, which also released the highest fine particle fraction (43.1% to 56.6% of label claim).


The congrid eel genus Bathycongrus of Taiwan, with descriptions of three new species (Anguilliformes: Congridae).
Ten species of the congrid eel genus Bathycongrus are recognized from Taiwanese waters. Diagnoses and full descriptions of eight species are provided in present work. Three species are described as new. Bathycongrus bimaculatus sp. nov. is a small species with a pale body color, two black patches on dorsal fin, and 109-111 total vertebrae. Bathycongrus graciliceps sp. nov. is a moderately elongate species with a small, slender head and long trunk, and 163 total vertebrae. Bathycongrus castlei sp. nov. is a slender species with a relatively short trunk, dorsal half of body deep brownish, and 160-162 total vertebrae. Two rare species, B. bleekeri Fowler, 1934 and B. macroporis (Kotthaus, 1968), are newly reported from Taiwan. A key to all species in Taiwan is provided.


Chromosome stability is maintained by short intercentromeric distance in functionally dicentric human Robertsonian translocations.
While the formation of a dicentric chromosome often leads to chromosome instability, human dicentric Robertsonian translocations usually remain stable. To investigate the basis for this stability, we have examined the centromeres of 15 structurally dicentric rob(13q14q) Robertsonian translocations using immunofluorescence and fluorescence in situ hybridization (FISH). The immunofluorescence detection of centromere protein C (CENP-C) was used as a marker for centromere function as CENP-C seems to play an essential role in kinetochore structure and stability and was previously shown to be absent from inactive centromeres. In all 15 translocation-containing cell lines, CENP-C was confined to only one of the centromeres of the translocation in a fraction of the cells analyzed. This suggests that centromere inactivation commonly occurs on dicentric Robertsonian translocations and may serve as one mechanism allowing for their stability. However, in the majority of the translocations (12 out of 15), a portion of the cells analyzed displayed CENP-C immunofluorescence at both centromeres, suggesting that both centromeres were active and that the translocation was functionally dicentric. The percentage of cells with CENP-C at both centromeres ranged from 2% to 82%. These results support the hypothesis that the close proximity of two functional centromeres on Robertsonian translocations allows them to remain stable.


Studies on hantavirus infection in small mammals captured in southern and central highland area of Vietnam.
To investigate the distribution of hantaviruses among animals in Southern and Central Highland area of Vietnam, a total of 1311 serum samples were obtained from rats and Asian house shrews (Suncus murinus) captured at 11 locations between 2006 and 2009. A total of 1066 serum samples from rats were examined for IgG antibodies against Hantaan virus, and there were 30 antibody-positive serum samples from rats that had been captured mainly in a port area and urban area in Ho Chi Minh City (HCMC) (2.8%). All of the antibody-positive rats were Rattus norvegicus, and they had Seoul virus (SEOV) genome in their lungs. SEOV sequences detected from rats captured in Southern Vietnam belonged to the same lineage as those from rats captured at Haiphong Port and a market area in Hanoi City. SEOV strain CSG5 was isolated from a rat captured at Saigon Harbor. Strain CSG5 showed a cross-neutralization pattern almost the same as that of a representative strain of SEOV. A total of 245 Asian house shrews were captured in the Central Highland area and near HCMC. Sera were examined for IgG antibodies against Thottapalayam virus (TPMV), and 32 (13.1%) of the antibody-positive shrews were mainly from the Central Highland area and showed a neutralizing antibody against TPMV. These results indicated that SEOV is distributed among R. norvegicus inhabiting harbor and urban areas of Southern Vietnam and that TPMV or an antigenically related virus is distributed among Asian house shrews in Central Highland area.


PROTECTIVE ROLE OF CARNITINE SYNERGIZED WITH VITAMIN E AGAINST ISOPROTERENOL INDUCED CARDIAC INFARCTION IN RATS.
The current study aimed to evaluate the role of carnitine in combination with vitamin E in protection against myocardial infarction induced by isoproterenol (ISO) in rats. Rats were grouped into 5 (each 10 rats): Group I. Control fed a standard diet. Group III: Rats were injected with vitamin E (100 IU/kg bw, i.p) daily. Group IV: Rats were given carnitine (20 mg/kg bw, i.p) daily. Group V: Rats were injected with both vitamin E (100 IU/kg bw, i.p) and carnitine (20 mg/kg bw, i.p) daily. On 7th, 8th, and 9th day, rats in groups (II-V) were injection i.p with ISO (55mg/kg b.w for successive three days). The treatment with carnitine and vitamin E were continuous for 21 days. Canirine combined with vitamin E significantly increased coronary flow (CF) (P<0.001) in rats injected with ISO. The recovery of rate pressure product (RPP) and left ventricular developed pressure (LVDP) were significantly improved in treated rats in comparison to untreated. The rats administrated with ISO resulted in a significant elevation of serum enzymes (CK-MB and LDH) compared with control group (p<0.001). However, it returned to about normal. ISO administration resulted in a significant elevation in the levels of malondialdehyde (MDA) and nitric oxide (NO) as compared with control (p<0.001) and a significant reduction in the activities of GSPxase and GSRase (p<0.001) compared with control group. The levels of cardiac inflammatory markers interleukine-6 (IL-6) and tumor necrosis factor (TNF-α) were markedly elevated in rats injected with ISO compared with control group. Vitamin E combined with carnitine reversed these effects. However, pretreatment with vitamin E or carnitine or combined together showed a significant reduction in MDA and NO (p<0.001) and a significant elevation in the activities of GSPxase and GSRase (p<0.001) as compared to ISO injected group. The combined effect was more significant than individual ones. Vitamin E combined with carnitine exerts potential protective effect against MI through suppression of inflammatory mediators and enhancement of antioxidant activity.


Definition of a fluorescence in-situ hybridization score identifies high- and low-level FGFR1 amplification types in squamous cell lung cancer.
We recently reported fibroblast growth factor receptor-type 1 (FGFR1) amplification to be associated with therapeutically tractable FGFR1 dependency in squamous cell lung cancer. This makes FGFR1 a novel target for directed therapy in these tumors. To reproducibly identify patients for clinical studies, we developed a standardized reading and evaluation strategy for FGFR1 fluorescence in-situ hybridization (FISH) and propose evaluation criteria, describe different patterns of low- and high-level amplifications and report on the prevalence of FGFR1 amplifications in pulmonary carcinomas. A total of 420 lung cancer patients including 307 squamous carcinomas, 100 adenocarcinomas of the lung and 13 carcinomas of other types were analyzed for FGFR1 amplification using a dual color FISH. We found heterogeneous and different patterns of gene copy numbers. FGFR1 amplifications were observed in 20% of pulmonary squamous carcinomas but not in adenocarcinomas. High-level amplification (as defined by an FGFR1/centromer 8 (CEN8) ratio ≥2.0, or average number of FGFR1 signals per tumor cell nucleus ≥6, or the percentage of tumor cells containing ≥15 FGFR1 signals or large clusters ≥10%) was detected at a frequency of 16% and low-level amplification (as defined by ≥5 FGFR1 signals in ≥50% of tumor cells) at a frequency of 4%. We conclude that FGFR1 amplification is one of the most frequent therapeutically tractable genetic lesions in pulmonary carcinomas. Standardized reporting of FGFR1 amplification in squamous carcinomas of the lung will become increasingly important to correlate therapeutic responses with FGFR1 inhibitors in clinical studies. Thus, our reading and evaluation strategy might serve as a basis for identifying patients for ongoing and upcoming clinical trials.


Recent Advances in Nanoporous Membranes for Water Purification.
Nanoporous materials exhibit wide applications in the fields of electrocatalysis, nanodevice fabrication, energy, and environmental science, as well as analytical science. In this review, we present a summary of recent studies on nanoporous membranes for water purification application. The types and fabrication strategies of various nanoporous membranes are first introduced, and then the fabricated nanoporous membranes for removing various water pollutants, such as salt, metallic ions, anions, nanoparticles, organic chemicals, and biological substrates, are demonstrated and discussed. This work will be valuable for readers to understand the design and fabrication of various nanoporous membranes, and their potential purification mechanisms towards different water pollutants. In addition, it will be helpful for developing new nanoporous materials for quick, economic, and high-performance water purification.


Forced translocation of a polymer: Dynamical scaling versus molecular dynamics simulation.
We suggest a theoretical description of the force-induced translocation dynamics of a polymer chain through a nanopore. Our consideration is based on the tensile (Pincus) blob picture of a pulled chain and the notion of a propagating front of tensile force along the chain backbone, suggested by Sakaue [Phys. Rev. E 76, 021803 (2007); Phys. Rev. E 81, 041808 (2010); Eur. Phys. J. E 34, 135 (2011)]. The driving force is associated with a chemical potential gradient that acts on each chain segment inside the pore. Depending on its strength, different regimes of polymer motion (named after the typical chain conformation: trumpet, stem-trumpet, etc.) occur. Assuming that the local driving and drag forces are equal (i.e., in a quasistatic approximation), we derive an equation of motion for the tensile front position X(t). We show that the scaling law for the average translocation time 〈τ〉 changes from <τ> ∼ N2ν/f1/ν to <τ> ∼ N^1+ν/f (for the free-draining case) as the dimensionless force f[over ̃]R=aNνf/T (where a, N, ν, f, and T are the Kuhn segment length, the chain length, the Flory exponent, the driving force, and the temperature, respectively) increases. These and other predictions are tested by molecular-dynamics simulation. Data from our computer experiment indicate indeed that the translocation scaling exponent α grows with the pulling force f[over ̃]R, albeit the observed exponent α stays systematically smaller than the theoretically predicted value. This might be associated with fluctuations that are neglected in the quasistatic approximation.


Precursor Supply for Erythromycin Biosynthesis: Engineering of Propionate Assimilation Pathway Based on Propionylation Modification.
Erythromycin is necessary in medical treatment and known to be biosynthesized with propionyl-CoA as direct precursor. Oversupply of propionyl-CoA induced hyperpropionylation, which was demonstrated as harmful for erythromycin synthesis in Saccharopolyspora erythraea. Herein, we identified three propionyl-CoA synthetases regulated by propionylation, and one propionyl-CoA synthetase SACE_1780 revealed resistance to propionylation. A practical strategy for raising the precursor (propionyl-CoA) supply bypassing the feedback inhibition caused by propionylation was developed through two approaches: deletion of the propionyltransferase AcuA, and SACE_1780 overexpression. The constructed Δ acuA strain presented a 10% increase in erythromycin yield; SACE_1780 overexpression strain produced 33% higher erythromycin yield than the wildtype strain NRRL2338 and 22% higher erythromycin yield than the industrial high yield Ab strain. These findings uncover the role of protein acylation in precursor supply for antibiotics biosynthesis and provide efficient post-translational modification-metabolic engineering strategy (named as PTM-ME) in synthetic biology for improvement of secondary metabolites.


Lectins from the Red Marine Algal Species Bryothamnion seaforthii and Bryothamnion triquetrum as Tools to Differentiate Human Colon Carcinoma Cells.
The carbohydrate-binding activity of the algal lectins from the closely related red marine algal species Bryothamnion triquetrum (BTL) and Bryothamnion seaforthii (BSL) was used to differentiate human colon carcinoma cell variants with respect to their cell membrane glyco-receptors. These lectins interacted with the cells tested in a dose-dependent manner. Moreover, the fluorescence spectra of both lectins clearly differentiated the cells used as shown by FACS profiles. Furthermore, as observed by confocal microscopy, BTL and BSL bound to cell surface glycoproteins underwent intense internalization, which makes them possible tools in targeting strategies.


Which mothers receive a post partum home visit in Queensland, Australia? A cross-sectional retrospective study.
Although home visiting in the early post partum period appears to have increased, there are limited data defining which women receive a visit and none that include Queensland. We aimed to investigate patterns of post partum home visiting in the public and private sectors in Queensland. Data were collected via a retrospective cross-sectional survey of women birthing in Queensland between 1 February and 31 May 2010 at 4 months post partum (n = 6948). Logistic regression was used to assess associations between receiving a home visit and sociodemographic, clinical and hospital variables. Analyses were stratified by public and private birthing sector because of significant differences between sectors. Public sector women were more likely to receive a visit from a nurse or midwife (from the hospital or child health sector) within 10 days of hospital discharge (67.2%) than private sector women (7.2%). Length of hospital stay was associated with home visiting in both sectors. Some vulnerable subpopulations in both sectors were more likely to be visited, whereas others were not. Home visiting in Queensland varies markedly between the public and private sector and is less common in some vulnerable populations. Further consideration to improving the equity of community post partum care in Queensland is needed.


Sensitization of lanthanide luminescence by two different Pt-->Ln energy transfer pathways in PtLn3 heterotetranuclear complexes with 5-ethynyl-2,2'-bipyridine.
Reactions of 5-[2-(trimethylsilyl)-1-ethynyl]-2,2'-bipyridine (Me3SiC-Cbpy) with Pt(bpy)C12 (bpy = 2,2'-bipyridine) and Pt(bpyC[triple bond]C-C[triple bond]Cbpy)Cl2 (bpyC[triple bond]C-C[triple bond]Cbpy=bis(2,2'-bipyridin-5-yl)butadiyne) induced isolation of Pt(bpy)(C[triple bond]Cbpy)2 (1) and Pt(bpyC[triple bond]C-C[triple bond]Cbpy)(C[triple bond]Cbpy)2 (5), respectively. Incorporating Ln(hfac)3(H2O)2 (hfac = hexafluoroacetylacetone) with 1 or 5 gave the corresponding PtLn2 (Ln = Nd (2), Eu (3), Yb (4)) or PtLn3 arrays (Ln=Nd (6), Eu (7), Gd (8), Yb (9)). With excitation at 360 < or = lamda(ex)0 < or =480 nm, which is the MLCT absorption region of the Pt(2,2'-bipyridyl)(acetylide)2 chromophore, sensitized lanthanide luminescence is successfully attained by efficient Pt-->Ln energy transfer from the Pt(II) antenna chromophores. In contrast with quite efficient Pt-->Ln energy transfer in the Pt-C[triple bond]Cbpy-Ln(Pt...Ln = 8.6 A) array, energy transfer transmitted across the Pt-bpyC[triple bond]C-C[triple bond]Cbpy-Ln(Pt...Ln = 13.3 A) array is less efficient owing to the much longer Pt...Ln separation in the latter.


Ligand-specific contribution of the N terminus and E2-loop to pharmacological properties of the histamine H1-receptor.
There are species differences between human histamine H(1) receptor (hH(1)R) and guinea pig (gp) histamine H(1) receptor (gpH(1)R) for phenylhistamines and histaprodifens. Several studies showed participation of the second extracellular loop (E2-loop) in ligand binding for some G protein-coupled receptors (GPCRs). Because there are large species differences in the amino acid sequence between hH(1)R and gpH(1)R for the N terminus and E2-loop, we generated chimeric hH(1)Rs with gp E2-loop (h(gpE2)H(1)R) and gp N terminus and gp E2-loop (h(gpNgpE2)H(1)R). hH(1)R, gpH(1)R, and chimeras were expressed in Sf9 insect cells. [(3)H]Mepyramine binding assays and steady-state GTPase assays were performed. In the series hH(1)R > h(gpE2)H(1)R > h(gpNgpE2)H(1)R, we observed a significant decrease in potency of histamine 1 in the GTPase assay. For phenoprodifen 5 and the chiral phenoprodifens 6R and 6S, a significant decrease in affinity and potency was found in the series hH(1)R > h(gpE2)H(1)R > h(gpNgpE2)H(1)R. In addition, we constructed new active-state H(1)R models based on the crystal structure of the human beta(2)-adrenergic receptor (hbeta(2)AR). Compared with the H(1)R active-state models based on the crystal structure of bovine rhodopsin, the E2-loop differs in its contact to the ligand bound in the binding pocket. In the bovine rhodopsin-based model, the backbone carbonyl of Lys187 (gpH(1)R) interacts with large histaprodifens in the binding pocket, but in the hbeta(2)AR-based model, Lys187 (gpH(1)R) is located distantly from the binding pocket. In conclusion, the differences in N terminus and E2-loop between hH(1)R and gpH(1)R exert an influence on affinity and/or potency for histamine and phenoprodifens 5, 6R, and 6S.


Increased vasopressin expression in the BNST accompanies paternally induced territoriality in male and female California mouse offspring.
While developmental consequences of parental investment on species-typical social behaviors has been extensively characterized in same-sex parent-offspring interactions, the impact of opposite-sex relationships is less clear. In the bi-parental California mouse (Peromyscus californicus), paternal retrieval behavior induces territorial aggression and the expression of arginine vasopressin (AVP) in adult male offspring. Although similar patterns of territorially emerge among females, the sexually dimorphic AVP system has not been considered since it is generally thought to regulate male-typical behavior. However, we recently demonstrated that male and female P. californicus offspring experience increases in plasma testosterone following paternal retrieval. Since AVP expression is androgen-dependent during development, we postulate that increases in AVP expression may accompany territoriality in female, as well as male offspring. To explore this aim, adult P. californicus offspring that received either high or low levels of paternal care (retrievals) during early development were tested for territoriality and immunohistochemical analysis of AVP within the bed nucleus of the stria terminalis (BNST), paraventricular nucleus (PVN), and supraoptic nucleus (SON). Consistent with previous studies, high care offspring were more aggressive than low care offspring. Moreover, high care offspring had significantly more AVP immunoreactive (AVP-ir) cells within the BNST than low care offspring. This pattern was observed within female as well as male offspring, suggesting an equally salient role for paternal care on female offspring physiology. Regardless of early social experience, sex differences in AVP persisted in the BNST, with males having greater expression than females.


Clinical profile of recurrent vesicular palmoplantar dermatitis in children and adolescents.
Previously known as dyshidrosis, recurrent vesicular palmoplantar dermatitis (RVPD) is presented as severe eruption of nonerythematous, symmetrical vesicles or bullae located along the lateral sides of fingers, on the palmar or plantar areas, and developing into a chronic and recurrent condition. Although very frequently observed on the hands, there are no specific studies about such eczema in children and adolescents. To report on the RVPD clinical profile in children and adolescents, and monitor the association of RVPD with seasonal variations, hyperhidrosis, atopy and nickel sulfate. Eighteen patients affected by RVPD were submitted to clinical and laboratory assessment through anamnesis, physical exam, mycological exam, patch test, complete blood count and serum IgE levels. Seven patients (38.9%) reported increased frequency of eruptions during the summer months; 12 patients (66.7%) presented hyperhidrosis; in 14 cases (77.8%), atopic factors were determined; reaction to nickel sulfate was positive in three patients (16.7%). RVPD onset may occur at an early age, developing into a chronic and recurrent infection. Hyperhidrosis and atopic status was established in the clinical profile and no connection between nickel sulfate and RVPD was observed.


Identification of a mammalian mitochondrial porphyrin transporter.
The movement of anionic porphyrins (for example, haem) across intracellular membranes is crucial to many biological processes, but their mitochondrial translocation and coordination with haem biosynthesis is not understood. Transport of porphyrins into isolated mitochondria is energy-dependent, as expected for the movement of anions into a negatively charged environment. ATP-binding cassette transporters actively facilitate the transmembrane movement of substances. We found that the mitochondrial ATP-binding cassette transporter ABCB6 is upregulated (messenger RNA and protein in human and mouse cells) by elevation of cellular porphyrins and postulated that ABCB6 has a function in porphyrin transport. We also predicted that ABCB6 is functionally linked to haem biosynthesis, because its mRNA is found in both human bone marrow and CD71+ early erythroid cells (by database searching), and because our results show that ABCB6 is highly expressed in human fetal liver, and Abcb6 in mouse embryonic liver. Here we demonstrate that ABCB6 is uniquely located in the outer mitochondrial membrane and is required for mitochondrial porphyrin uptake. After ABCB6 is upregulated in response to increased intracellular porphyrin, mitochondrial porphyrin uptake activates de novo porphyrin biosynthesis. This process is blocked when the Abcb6 gene is silenced. Our results challenge previous assumptions about the intracellular movement of porphyrins and the factors controlling haem biosynthesis.


Core-shell microspherical Ti(1-x)Zr(x)O2 solid solution photocatalysts directly from ultrasonic spray pyrolysis.
A series of Ti(1-x)Zr(x)O(2) solid solutions photocatalysts (x = 0.000, 0.045, 0.090, 0.135, and 0.180) was directly obtained by an ultrasonic spray pyrolysis method. Compared with previous methods for solid solutions, our preparation was very fast. The resulting samples were characterized by X-ray diffraction, scanning electron microscopy, transmission electron microscopy, high-resolution transmission electron microscopy, nitrogen adsorption, and UV-vis diffuse reflectance spectroscopy. The characterizations revealed core-shell spherical structures of the resulting solid solutions. We evaluated photocatalytic activities of the solid solutions on degradation of rhodamine B in aqueous solution under simulated solar light. It was found that Ti(0.91)Zr(0.09)O(2) solid solution exhibited the highest photocatalytic activity among all the as-prepared samples. Its activity was much higher than that of P25. The formation mechanism of core-shell spherical structures was proposed. Moreover, we successfully extended this method to prepare microspheres of ceria and ceria-zirconia solid solutions. We think this general method may be easily scaled up for industrial production of microspherical solid solutions photocatalysts and catalysts.


The relationship of urgent hospital admissions for respiratory illnesses to photochemical air pollution levels in Montreal.
The relationship between the number of daily urgent hospital admissions for respiratory illnesses (31 hospitals) and ambient air pollution in Montreal, Canada, was investigated for warm periods between 1984 and 1988. Air pollutants included 1-hr and 8-hr maximum ozone, estimated particulate matter < or = 10 microns in aerometric diameter (PM10), and estimated sulfate (SO4(2-) fraction of PM10. Regression analyses controlled for seasonal and day-of-week trends, autocorrelation, temperature, and relative humidity. For July and August periods, there was a statistically significant (P < 0.01) univariate relationship of all respiratory admissions to 8-hr maximum ozone, which became nonsignificant when coregressed with temperature. Levels of ozone which never exceeded the U.S. National Ambient Air Quality Standard (NAAQS) of 120 ppb and high intercorrelations between ozone, particulates, and temperature may explain this finding. Asthma admissions in the May-October periods increased by 2.7% over mean levels for each 12 micrograms/m3 increase in PM10 levels 3 days prior to the admission day (95% confidence interval, 0.7 to 4.8%). In the July and August periods, hospital admissions for respiratory illnesses excluding asthma were 9.6% higher (95% confidence interval, 0.5 to 18.7%) when estimated SO4(2-) had exceeded 8.1 micrograms/m3 4 days prior to the admission day compared to days when SO4(2-) was at or below this level. There were no significant (P < 0.05) associations of a reference group of nonrespiratory admissions to air pollution after controlling for weather. The above results were found despite levels of PM10 which never exceeded the NAAQS of 150 micrograms/m3. The associations found are relevant to public health, since hospital admissions are expected to be accompanied by considerably more frequent occurrences of less serious outcomes. The present findings suggest that particulate air pollution during photochemically active periods is related to respiratory morbidity in Montreal.


Statistics and Properties of Low-Frequency Vibrational Modes in Structural Glasses.
Low-frequency vibrational modes play a central role in determining various basic properties of glasses, yet their statistical and mechanical properties are not fully understood. Using extensive numerical simulations of several model glasses in three dimensions, we show that in systems of linear size L sufficiently smaller than a crossover size L_{D}, the low-frequency tail of the density of states follows D(ω)∼ω^{4} up to the vicinity of the lowest Goldstone mode frequency. We find that the sample-to-sample statistics of the minimal vibrational frequency in systems of size L<L_{D} is Weibullian, with scaling exponents in excellent agreement with the ω^{4} law. We further show that the lowest-frequency modes are spatially quasilocalized and that their localization and associated quartic anharmonicity are largely frequency independent. The effect of preparation protocols on the low-frequency modes is elucidated, and a number of glassy length scales are briefly discussed.


Formation of Acetylene in the Reaction of Methane with Iron Carbide Cluster Anions FeC3- under High-Temperature Conditions.
The underlying mechanism for non-oxidative methane aromatization remains controversial owing to the lack of experimental evidence for the formation of the first C-C bond. For the first time, the elementary reaction of methane with atomic clusters (FeC3- ) under high-temperature conditions to produce C-C coupling products has been characterized by mass spectrometry. With the elevation of temperature from 300 K to 610 K, the production of acetylene, the important intermediate proposed in a monofunctional mechanism of methane aromatization, was significantly enhanced, which can be well-rationalized by quantum chemistry calculations. This study narrows the gap between gas-phase and condensed-phase studies on methane conversion and suggests that the monofunctional mechanism probably operates in non-oxidative methane aromatization.


Mode of action of the Bordetella BvgA protein: transcriptional activation and repression of the Bordetella bronchiseptica bipA promoter.
The Bordetella BvgAS signal transduction system controls the transition among at least three known phenotypic phases (Bvg+, Bvg(i), and Bvg-) and the expression of a number of genes which have distinct phase-specific expression profiles. This complex regulation of gene expression along the Bvg signaling continuum is best exemplified by the gene bipA, which is expressed at a low level in the Bvg+ phase, at a maximal level in the Bvg(i) phase, and at undetectable levels in the Bvg- phase. The bipA promoter has multiple BvgA binding sites which play distinct regulatory roles. We had previously speculated that the expression profile of bipA is a consequence of the differential occupancy of the various BvgA binding sites as a result of variation in the levels of phosphorylated BvgA (BvgA-P) inside the cell. In this report, we provide in vitro evidence for this model and show that bipA expression is activated at low concentrations of BvgA-P and is repressed at high concentrations. By using independent DNA binding assays, we demonstrate that under activating conditions there is a synergistic effect on the binding of BvgA and RNA polymerase (RNAP), leading to the formation of open complexes at the promoter. We further show that, under in vitro conditions, when bipA transcription is minimal, there is competition between the binding of RNAP and BvgA-P to the bipA promoter. Our results show that the BvgA binding site IR2 plays a central role in mediating this repression.


Genetic diversity and pathogenicity differentiation of Sclerotinia sclerotiorum on rapeseed (Brassica napus L.) in Anhui Province, China.
The pathogenicity of 47 isolates of Sclerotinia sclerotiorum from oilseed rape (Brassica napus L.) in Anhui, China, was tested by detached leaf inoculation using the susceptible rape cultivar Wanyou-14. All isolates were pathogenic to the cultivar and could be grouped into 3 categories based on the lesion length on the leaves tested: weak pathogenicity type, intermediate pathogenicity type, and strong pathogenicity type. This suggested that there was differentiation in the pathogenicity among the strains tested of S. sclerotiorum. Additionally, the intraspecific DNA polymorphisms among 47 strains of S. sclerotiorum were investigated by screening 40 pairs of inter-simple sequence repeat (ISSR) primers. Unweighted pair-group method with arithmetic average cluster analysis of these ISSR data distinguished all strains from each other and revealed considerable genetic variability among them. These strains were classified into 7 clusters according to their branching in the dendrogram, and partial correlation was observed between the genetic polymorphisms and the pathogenicity of S. sclerotiorum strains.


The link between school climate and mental health among an ethnically diverse sample of middle school youth.
School climate consistently relates to adolescent adjustment across academic, socioemotional, and behavioral domains. Although past research highlights the impact of school climate on youths' experience of internalizing symptoms and violent behavior, examination of potential links with specific externalizing processes is limited. The current study examined associations between middle school students' perceived school climate and internalizing and externalizing mental health symptoms. A positive school climate was hypothesized to be inversely related to all mental health measures. Seventh grade students (N = 2768; 50% female) were recruited from 24 Texas middle schools. Participants completed baseline self-reports of perceived school climate across three dimensions (student-student relationships, student-teacher relationships, and awareness/need of reporting violence) as well as self-reports of internalizing (i.e., depression and anxiety) and externalizing (i.e., impulsivity and hostility) symptoms. Multilevel regression analyses were implemented to test all hypotheses, controlling for participant sex and race/ethnicity. Results indicated student-student relationships were negatively related to depressive symptoms, student-teacher relationships were positively related to anxiety and negatively linked to hostility, and help-seeking/reporting awareness was inversely related to all four indices of mental health. The current research underscores the impact of school climate on adolescents' psychological adjustment and emphasizes the need to address awareness and responsivity in reporting concerning school behavior.


Ferritin: an iron storage protein with diverse functions.
Ferritin is the major protein for iron storage and iron detoxification. Since non-ferrous metals, such as aluminum, beryllium and zinc, are bound both in vivo and in vitro, ferritin is implicated as a general metal ion donor and detoxicant. The role of ferritin in Al and Be toxicity is discussed. During iron release ferritin produces free radicals which are involved in phosphoprotein inactivation, lipid peroxidation and, possibly, the general aging process. Conversely, during iron loading oxidative energy in the form of electrons and protons is given off. The different subunit compositions of ferritin, termed isoferritins, are, at least in part, involved with the multifunctionality of this protein.


Quantification of tricuspid regurgitation by live three-dimensional transthoracic echocardiographic measurements of vena contracta area.
We evaluated tricuspid regurgitation (TR) by multiple echocardiographic techniques in 93 consecutive patients who underwent standard two-dimensional (2D) and live three-dimensional (3D) transthoracic echocardiography (TTE). TR vena contracta (VC) area was obtained by 3D TTE by systematic and sequential cropping of the acquired 3D TTE dataset. Assessment of VC area by 3D TTE was compared to 2D TTE measurements of the ratio of TR regurgitant jet area to right atrial area (RJA/RAA), RJA alone, VC width, and calculated VC area. VC area from 3D TTE closely correlated with RJA/RAA and RJA alone as determined from 2D TTE measurements. Live 3D TTE color Doppler measurements of VC area can be used for quantitative assessment of TR and offer incremental value for quantification of particularly severe regurgitant lesions.


[Organic hyperinsulinism. Clinical aspects--diagnosis--therapy].
It is reported on the clinical experiences in the care of 19 patients with insulinoma. The relatively simple proof of the existence of an insulinoma which is possible by the determination of insulin is performed by the recognition of a pathognomonic insulin--blood glucose--quotient in fasting state and in the fasting test, respectively. Stimulation tests are less evident and do not lead to any further clinically relevant information. The difficulty of the diagnosis consists in the localisation of the tumour. Without clinically urgent necessity an operation without localisation of the tumour should not be performed.


Proteomic characterisation reveals active Wnt-signalling by human multipotent stromal cells as a key regulator of beta cell survival and proliferation.
Novel strategies to stimulate the expansion of beta cell mass in situ are warranted for diabetes therapy. The aim of this study was to elucidate the secretome of human bone marrow (BM)-derived multipotent stromal cells (MSCs) with documented islet regenerative paracrine function. We hypothesised that regenerative MSCs will secrete a unique combination of protein factors that augment islet regeneration. Human BM-derived MSCs were examined for glucose-lowering capacity after transplantation into streptozotocin-treated NOD/severe combined immunodeficiency (SCID) mice and segregated into samples with regenerative (MSCR) vs nonregenerative (MSCNR) capacity. Secreted proteins associated with islet regenerative function were identified using stable isotope labelling with amino acids in cell culture (SILAC)-based quantitative proteomics. To functionally validate the importance of active Wnt signalling, we stimulated the Wnt-signalling pathway in MSCNR samples during ex vivo expansion using glycogen synthase kinase 3 (GSK3) inhibition (CHIR99201), and the conditioned culture media (CM) generated was tested for the capacity to support cultured human islet cell survival and proliferation in vitro. MSCR showed increased secretion of proteins associated with cell growth, matrix remodelling, immunosuppressive and proangiogenic properties. In contrast, MSCNR uniquely secreted proteins known to promote inflammation and negatively regulate angiogenesis. Most notably, MSCR maintained Wnt signalling via Wnt5A/B (~2.5-fold increase) autocrine activity during ex vivo culture, while MSCNR repressed Wnt signalling via Dickkopf-related protein (DKK)1 (~2.5-fold increase) and DKK3 secretion. Inhibition of GSK3 activity in MSCNR samples increased the accumulation of nuclear β-catenin and generated CM that augmented beta cell survival (13% increases) and proliferation when exposed to cultured human islets. Maintenance of active Wnt signalling within human MSCs promotes the secretion of matricellular and proangiogenic proteins that formulate a niche for islet regeneration.


Exploring the Effect of Polypyridyl Ligands on the Anticancer Activity of Phosphorescent Iridium(III) Complexes: From Proteosynthesis Inhibitors to Photodynamic Therapy Agents.
A series of five kinetically inert bis-cyclometalated IrIII complexes of general formula [Ir(C^N)2 (N^N)][PF6 ] [C^N=2-phenyl-1-[4-(trifluoromethyl)benzyl]-1H-benzo[d]imidazol-κN,C; N^N=1,10-phenanthroline (phen, 1), dipyrido[3,2-d:2',3'-f]quinoxaline (dpq, 2), dipyrido[3,2-a:2',3'-c]phenazine (dppz, 3), benzo[i]dipyrido[3,2-a:2',3'-c]phenazine (dppn, 4), and dipyrido[3,2-a:2',3'-c]phenazine-10,11-imidazolone (dppz-izdo, 5)] were designed and synthesized to explore the effect of the degree of π conjugation of the polypyridyl ligand on their toxicity in cancer cells. We show that less-lipophilic complexes 1 and 2 exhibit the highest toxicity [sub-micromolar inhibitory concentration (IC50 ) values] in A2780, HeLa, and MCF-7 cancer cells, and they are markedly more efficient than clinically used platinum drugs. It is noteworthy that the investigated Ir agents display the capability to overcome acquired and inherent resistance to conventional cisplatin (in A2780cisR and MCF-7 cells, respectively). We demonstrate that the Ir complexes, unlike clinically used platinum antitumor drugs, do not kill cells through DNA-damage response. Rather, they kill cells by inhibiting protein translation by targeting preferentially the endoplasmic reticulum. Our findings also reveal that the toxic effect of the Ir complexes can be significantly potentiated by irradiation with visible light (by more than two orders of magnitude). The photopotentiation of the investigated Ir complexes can be attributed to a marked increase (≈10-30-fold) in intracellular reactive oxygen species. Collectively, these data highlight the functional diversity of antitumor metal-based drugs and the usefulness of a mechanism-based rationale for selecting candidate agents that are effective against chemoresistant tumors for further preclinical testing.


Nuclear estrogen receptor and nonhistone chromosomal proteins in hormonal independency of murine breast cancers.
The capability of nuclear binding of cytosol estrogen receptors (ERc) was studied in GR mouse mammary tumors during their alteration of hormonal dependency through serial transplantations. Nuclei from GR mouse mammary tumors were incubated with uterine cytosol receptor complexes labeled with 125I-estradiol, and the amount of receptor binding in the 0.4 M KCl nuclear extracts was determined. The originally ERc-positive-hormone-dependent (type I) tumors were capable of nuclear receptor binding, while this function was markedly reduced in the evolved hormone-independent (type II) tumors, although the ERc content in the latter was still positive. The originally hormone-independent (ERc-negative, type III) tumors, however, retained the nuclear binding capability. It appears that the hormonal independency in type III tumors is due to a lack of ER, while in type II tumors it may be attributed to the loss of nuclear binding capability for receptor complexes. Nonhistone chromosomal proteins (NHCP) were analyzed by the 2-dimensional gel electrophoretic technique. A Mr 31,000 NHCP was present in 11 of 12 type I, and four of four type III tumors. Following serial transplantation of the type I tumors, this NHCP was either markedly diminished or not observed in all 14 type II tumors examined. Although it coincides with the capability of nuclear receptor binding, the biological function of this NHCP is still undefined and warrants further investigation.


RNA-Seq Analysis of Peripheral Whole Blood from Dairy Bulls with High and Low Antibody-Mediated Immune Responses-A Preliminary Study.
Enhancing the immune response through breeding is regarded as an effective strategy for improving animal health, as dairy cattle identified as high immune responders are reported to have a decreased prevalence of economically significant diseases. The identification of differentially expressed genes (DEGs) associated with immune responses might be an effective tool for breeding healthy dairy cattle. In this study, antibody-mediated immune responses (AMIRs) were induced by the immunization of hen egg white lysozyme (HEWL) in six Chinese Holstein dairy bulls divided into high- and low-AMIR groups based on their HEWL antibody level. Then, RNA-seq was applied to explore the transcriptome of peripheral whole blood between the two comparison groups. As a result, several major upregulated and downregulated genes were identified and attributed to the regulation of locomotion, tissue development, immune response, and detoxification. In addition, the result of the KEGG pathway analysis revealed that most DEGs were enriched in pathways related to disease, inflammation, and immune response, including antigen processing and presentation, Staphylococcus aureus infection, intestinal immune network for IgA production, cytokine-cytokine receptor interaction, and complement and coagulation cascades. Moreover, six genes (BOLA-DQA5, C5, CXCL2, HBA, LTF, and COL1A1) were validated using RT-qPCR, which may provide information for genomic selection in breeding programs. These results broaden the knowledge of the immune response mechanism in dairy bulls, which has strong implications for breeding cattle with an enhanced AMIR.


Response Functions as Quantifiers of Non-Markovianity.
Quantum non-Markovianity is crucially related to the study of dynamical maps, which are usually derived for initially factorized system-bath states. We demonstrate that linear response theory also provides a way to derive dynamical maps but for initially correlated (and, in general, entangled) states. Importantly, these maps are always time-translational invariant and allow for a much simpler quantification of non-Markovianity compared to previous approaches. We apply our theory to the Caldeira-Leggett model, for which our quantifier is valid beyond linear response and can be expressed analytically. We find that a classical Brownian particle coupled to an Ohmic bath can already exhibit non-Markovian behavior, a phenomenon related to the initial state preparation procedure. Furthermore, for a peaked spectral density, we show that there is no monotonic relation between our quantifier and the system-bath coupling strength, the sharpness of the peak or the resonance frequency in the bath.


Estimating ROI activity concentration with photon-processing and photon-counting SPECT imaging systems.
Recently a new class of imaging systems, referred to as photon-processing (PP) systems, are being developed that uses real-time maximum-likelihood (ML) methods to estimate multiple attributes per detected photon and store these attributes in a list format. PP systems could have a number of potential advantages compared to systems that bin photons based on attributes such as energy, projection angle, and position, referred to as photon-counting (PC) systems. For example, PP systems do not suffer from binning-related information loss and provide the potential to extract information from attributes such as energy deposited by the detected photon. To quantify the effects of this advantage on task performance, objective evaluation studies are required. We performed this study in the context of quantitative 2-dimensional single-photon emission computed tomography (SPECT) imaging with the end task of estimating the mean activity concentration within a region of interest (ROI). We first theoretically outline the effect of null space on estimating the mean activity concentration, and argue that due to this effect, PP systems could have better estimation performance compared to PC systems with noise-free data. To evaluate the performance of PP and PC systems with noisy data, we developed a singular value decomposition (SVD)-based analytic method to estimate the activity concentration from PP systems. Using simulations, we studied the accuracy and precision of this technique in estimating the activity concentration. We used this framework to objectively compare PP and PC systems on the activity concentration estimation task. We investigated the effects of varying the size of the ROI and varying the number of bins for the attribute corresponding to the angular orientation of the detector in a continuously rotating SPECT system. The results indicate that in several cases, PP systems offer improved estimation performance compared to PC systems.


Multi-Scale Computational Modeling of Spatial Calcium Handling From Nanodomain to Whole-Heart: Overview and Perspectives.
Regulation of intracellular calcium is a critical component of cardiac electrophysiology and excitation-contraction coupling. The calcium spark, the fundamental element of the intracellular calcium transient, is initiated in specialized nanodomains which co-locate the ryanodine receptors and L-type calcium channels. However, calcium homeostasis is ultimately regulated at the cellular scale, by the interaction of spatially separated but diffusively coupled nanodomains with other sub-cellular and surface-membrane calcium transport channels with strong non-linear interactions; and cardiac electrophysiology and arrhythmia mechanisms are ultimately tissue-scale phenomena, regulated by the interaction of a heterogeneous population of coupled myocytes. Recent advances in imaging modalities and image-analysis are enabling the super-resolution reconstruction of the structures responsible for regulating calcium homeostasis, including the internal structure of nanodomains themselves. Extrapolating functional and imaging data from the nanodomain to the whole-heart is non-trivial, yet essential for translational insight into disease mechanisms. Computational modeling has important roles to play in relating structural and functional data at the sub-cellular scale and translating data across the scales. This review covers recent methodological advances that enable image-based modeling of the single nanodomain and whole cardiomyocyte, as well as the development of multi-scale simulation approaches to integrate data from nanometer to whole-heart. Firstly, methods to overcome the computational challenges of simulating spatial calcium dynamics in the nanodomain are discussed, including image-based modeling at this scale. Then, recent whole-cell models, capable of capturing a range of different structures (such as the T-system and mitochondria) and cellular heterogeneity/variability are discussed at two different levels of discretization. Novel methods to integrate the models and data across the scales and simulate stochastic dynamics in tissue-scale models are then discussed, enabling elucidation of the mechanisms by which nanodomain remodeling underlies arrhythmia and contractile dysfunction. Perspectives on model differences and future directions are provided throughout.


Prefractionation of protein samples prior to two-dimensional electrophoresis.
Thousands of proteins may be visualised on a two-dimensional (2-D) gel, but only hundreds are present at levels sufficient for chemical analysis. Therefore, prefractionation of protein samples prior to 2-D polyacrylamide gel electrophoresis (PAGE) will be important for the investigation of proteins that are present at sub-picogram levels in physiological samples. We describe an approach to prefractionate protein samples prior to 2-D PAGE using the Gradiflow, which is a new (preparative) electrokinetic membrane apparatus designed to fractionate proteins in a number of different ways. We have fractionated human serum under nonreducing conditions using the 'reflux' mode, in which proteins are fractionated according to their relative mobility under controlled electrophoretic conditions, where the current is periodically reversed. We describe how fractionation occurs and present examples of enrichment of specific proteins.


An HRP study of the distribution of primary afferent neurons innervating the buccal stretch receptor in rats.
Retrograde transport of horseradish peroxidase conjugated with wheat germ agglutinin (WGA-HRP) was used to observe the ganglionic origin of primary afferent neurons innervating the buccal stretch receptor (BSR) in the rat. WGA-HRP was applied to the proximal stump of the severed nerve branch innervating the BSR. HRP-labeled cell bodies were observed only in posterolateral portion of the ipsilateral trigeminal ganglion. The diameter of these cell bodies was 25.5-52.5 microns, of which 54.9% was in the range of 31-40 microns and 36.3% larger than 41 microns. Taken together with its ontogenetic origin, the BSR is suggested to have differentiated from the mechanoreceptors in the oral mucosa or the fascia of masticatory muscles.


Perioperative complications in patients on low-molecular-weight heparin bridging therapy.
Patients taking warfarin are often given interim anticoagulation in the perioperative period. Institutional guidelines that use low-molecular-weight heparin (LMWH) 'bridging' while the international normalized ratio (INR) is sub-therapeutic are often based on the American College of Chest Physicians Anticoagulation Guidelines. This study aims to identify if patients at a tertiary referral hospital were anticoagulated in line with these guidelines, and the incidence and nature of bleeding and thromboembolic complications. A retrospective review of the Alfred Hospital General Surgical and 'Hospital at Home' databases was conducted, identifying patients who underwent elective general surgical procedures and received bridging anticoagulation with enoxaparin. Demographics, indication for anticoagulation, bleeding and thromboembolism rates were recorded. Thromboembolic risk was estimated. The study identified 108 patients. Three-quarters of all patients were anticoagulated with LMWH doses in accordance with the guidelines. Thirty of the 108 patients suffered bleeding complications. This group was younger, weighed less, received higher doses of enoxaparin and were at higher predicted risk of thromboembolism than non-bleeding patients. Wound haematoma, rectal bleeding and intra-abdominal bleeding were the most frequent complications. The peak time of bleeding was 3.5 days after surgery. Twelve patients returned to theatre, 13 were readmitted and 3 received blood transfusion. One patient suffered pulmonary emboli on the first post-operative day. LMWH bridging therapy when prescribed appropriately is associated with low rates of inpatient thromboembolism in elective general surgical patients within our institution, but an unexpectedly high rate of bleeding complications.


Impact of SARS-CoV-2 infection on neurodegenerative and neuropsychiatric diseases: a delayed pandemic?
SARS-CoV-2 was first detected in December 2019 in the Chinese city of Wuhan and has since spread across the world. At present, the virus has infected over 1.7 million people and caused over 100 000 deaths worldwide. Research is currently focused on understanding the acute infection and developing effective treatment strategies. In view of the magnitude of the epidemic, we conducted a speculative review of possible medium- and long-term neurological consequences of SARS-CoV-2 infection, with particular emphasis on neurodegenerative and neuropsychiatric diseases of neuroinflammatory origin, based on the available evidence on neurological symptoms of acute SARS-CoV-2 infection. We systematically reviewed the available evidence about the pathogenic mechanisms of SARS-CoV-2 infection, the immediate and lasting effects of the cytokine storm on the central nervous system, and the consequences of neuroinflammation for the central nervous system. SARS-CoV-2 is a neuroinvasive virus capable of triggering a cytokine storm, with persistent effects in specific populations. Although our hypothesis is highly speculative, the impact of SARS-CoV-2 infection on the onset and progression of neurodegenerative and neuropsychiatric diseases of neuroinflammatory origin should be regarded as the potential cause of a delayed pandemic that may have a major public health impact in the medium to long term. Cognitive and neuropsychological function should be closely monitored in COVID-19 survivors.


Disseminated cryptococcosis initially presenting as cellulitis in a patient suffering from nephrotic syndrome.
Cryptococcosis is considered as an opportunistic infection because it mainly occurs in immunosuppressed hosts. C. neoformans is usually acquired by the respiratory route and then may disseminate hematogenously to other places, such as meninges, bone and skin. Cutaneous involvement is a rare but important feature of disseminated cryptococcosis with a poor outcome if misdiagnosis. We reported the first case of patients with nephrotic syndrome suffering from disseminated cryptococcosis initially presented as cellulitis. A 34-year-old man developed severe cellulitis on his both lower extremities without any preceding injury and allergies. The patient had been treated with systemic corticosteroids nearly one year for nephrotic syndrome. According to the outcome of blood culture, the wound area was interpreted as bacterial cellulitis at first. However, the antimicrobial treatment made no response and the skin biopsy revealed the presence of Cryptococcus neoformans, which was subsequently confirmed by microbiological culture. Though the initiation of therapy with fluconazole 400 mg per day was immediately adopted, the patient's conditions suddenly plummeted and he died in the end. Since the poor outcome of disseminated cryptococcosis if unrecognized and untreated in time, it should be investigated rigorously as a differential diagnosis in patients with nephrotic syndrome suffering from cutaneous diseases.


Unfinished Business: The Role of Research in Family Medicine.
Although the generation of new knowledge through research is a hallmark of medical specialties, research was a low priority in family practice when it was established in 1969. Today, when a base of knowledge is crucial to the ability to lead health care change, the early relationship between family practice and research continues to influence the specialty. An examination of archival and secondary materials finds that the priority placed on research during family practice's early years was shaped by internal and external factors, including, (1) family physicians' desire to differentiate themselves from the prevailing specialty environment; (2) lack of a clear identity in family practice; (3) the non-laboratory nature of family medicine research; (4) reliance on information from other specialties; and, (5) a focus on establishing an academic presence. The low level of attention given to research during the early years of family practice has had lasting implications, as the specialty seeks to transform practice while continuing to struggle to achieve academic acceptance. A strong culture of generalist knowledge is crucial in assuring family medicine's future and strengthening its ability to improve the health of individuals, families, and communities.


Weight gain in infancy and markers of cardiometabolic health in young adulthood.
We studied whether repeatedly measured weight gain from birth up to age 2 years associated with cardiometabolic health in young adulthood. Using the data collected in the longitudinal Special Turku Coronary Risk Factor Intervention Project, we investigated in 454 healthy subjects how early weight gain in six age intervals (birth to 7 months, 7-13 months, 13-18 months, 18-24 months, and birth to 13 and 24 months) associated with measures of cardiometabolic health at age 20 years. Linear regression analyses were controlled for (1) child's sex, intervention/control group, gestational age, baseline weight and change in length for each interval, and (2) parents' education, mother's weight before pregnancy, height and weight gain during pregnancy, and father's body mass index at the 7-month visit. Weight gain after the first year of life associated directly, when adjusted for traits of the child and parents, with systolic blood pressure, waist circumference and body mass index at age 20 years. In the fully adjusted analyses, weight gain from birth to 1 year and to 2 years of age associated inversely with insulin and insulin resistance. We found no association between early growth and diastolic blood pressure or serum lipids. Early weight gain during first 2 years of life may predict later markers of cardiometabolic health.


Clinical evaluation of a chemiluminescence immunoassay for determination of immunoglobulin g avidity to human cytomegalovirus.
Clinical evaluation of a novel fully automated chemiluminescence immunoassay for determination of immunoglobulin G avidity to human cytomegalovirus (HCMV) showed 92.8% sensitivity and 84.7% specificity in detecting a recent (< or =90 days) primary HCMV infection. The assay appears useful for accurately diagnosing recent primary HCMV infections.


Repetitive motion disorders: the design of optimal rate-rest profiles.
Repetitive motion disorders of the upper extremities are the primary cause of lost time in hand-intensive industries. Typical remedies include the introduction of job aids and the redesign of the job. An alternative approach is considered here. Procedures are developed that can be used to determine the parameters of a job (e.g., the rate of work and the number and duration of the rest breaks) that minimize repetitive motion disorders and maximize productivity. It is shown that in theory the job parameters can be set so that one can achieve not only a decrease in repetitive motion disorders but also an increase in productivity. The application of the procedures to an actual manufacturing job requiring high-repetitive, high-force hand motions is discussed in detail.


Cooperative binding of the yeast Spt10p activator to the histone upstream activating sequences is mediated through an N-terminal dimerization domain.
The yeast Spt10p activator is a putative histone acetyltransferase (HAT) possessing a sequence-specific DNA-binding domain (DBD) which binds to the upstream activation sequences (UAS elements) in the histone gene promoters. Spt10p binds to a pair of histone UAS elements with extreme positive cooperativity. The molecular basis of this cooperativity was addressed. Spt10p (640 residues) is an elongated dimer, but the isolated DBD (residues 283-396) is a monomer and binds non-cooperatively to DNA. A Spt10p fragment comprising the N-terminal domain (NTD), HAT domain and DBD (residues 1-396) binds cooperatively and is a dimer, whereas an overlapping Spt10p fragment comprising the DBD and C-terminal domains (residues 283-640) binds non-cooperatively and is a monomer. These observations imply that cooperative binding requires dimerization. The isolated NTD (residues 1-98) is a dimer and is responsible for dimerization. We propose that cooperativity involves a conformational change in the Spt10p dimer which facilitates the simultaneous recognition of two UAS elements. In vivo, deletion of the NTD results in poor growth, but does not prevent the binding at the HTA1 promoter, suggesting that dimerization is biologically important. Residues 1-396 are sufficient for normal growth, indicating that the critical functions of Spt10p reside in the N-terminal domains.


A questionnaire study on fatigue symptoms of municipal personnel.
The following questionnaire surveys were conducted on 390 male personnel who work in one of the public facilities of a certain city. 1) Fatigue surveys: Using the Fatigue Scale of Industrial Fatigue Research Committee, questionnaire investigations were carried out twice, before work and after work. 2) Health surveys: Using Cornell Medical Index, the neurotic tendency was examined. When the correlation factors of average complaints frequencies were analyzed, indoor workers showed a type of mental task before and after work, whereas outdoor workers showed a type of mental task before work, but showed a general type after work. The workers in generation below thirty-five years mainly showed a type of mental task, while complaints about physical disintegration were relatively frequent in generation above fifties. We consider such questionnaire researches at each work site will constitute a useful clue for examining and ameliorating workers' fatigued condition which may exist inordinately in daily duties.


[Dynamics of perfusion CT parameters in the early acute phase of ischemic stroke].
Perfusion computed tomography (CT) allows to evaluate brain perfusion and provides additional information about local cerebral hemodynamics in stroke patients. Twenty-seven patients underwent CT-perfusion in the early acute phase of ischemic stroke. Significant differences between ischemic lesion and contralateral hemisphere on CBF and MTT scans during the first 3 hours after stroke were revealed. In the following 24 h, the differences were seen in all perfusion parameters. CT-perfusion allows to reveal perfusion parameters associated with stroke severity and outcome that is relevant for prescription of reperfusion treatment beyond the boundaries of 3-4.5h "therapeutic window".


Activation of IL 1-dependent and IL 1-independent T cell lines by calcium ionophore and phorbol ester.
We have studied the activation of interleukin 1 (IL 1)-dependent and IL 1-independent T cell lines, specifically their capacity to produce and secrete interleukin 2 (IL 2). The IL 1-dependent T cell lymphoma LBRM33-1A5.47, which requires phytohemagglutinin (PHA) and IL 1 to produce IL 2, was compared with the IL 1-independent T cell lymphoma LBRM33-5A4 and T cell hybridomas DO-11.10/S4.4 and 3DO-54.8. The latter hybridomas do not require exogenous IL 1 to produce IL 2 in response to mitogens or ovalbumin (OVA)/I-Ad. Even though IL 1 is not required by these IL 1-independent T cell lines, we tested whether IL 1 could modulate their response but found no significant effect of exogenous IL 1. We then studied the activation of these T cell lines by the calcium ionophore A23187 and phorbol myristate acetate (PMA). In the case of the IL 1-dependent line LBRM33-1A5.47, there was a strong response when both A23187 and PMA were used simultaneously. We subsequently found that A23187 can replace PHA, and PMA can replace IL 1 in the activation of this cell line to IL 2 production. These observations suggest that the signal(s) provided by PHA and IL 1 involve at least in part a calcium flux, and activation of protein kinase C. Parallel experiments with the use of the IL 1-independent T cell lines showed a strong response to both agents when used simultaneously. A modest response observed to A23187 alone was always enhanced by the addition of PMA. No response was observed to PMA alone. IL 1-rich P388D1 supernatant could replace the enhancing effect of PMA in the response of the IL 1-independent T cell lines. We suggest that the activating signals provided by A23187 and PMA are at least part of the sequence of events that lead to production of IL 2 in either IL 1-dependent or IL 1-independent T cell lines. In IL 1-independent T cell lines, however, both of the activating signals studied may be delivered through stimulation of the Antigen-MHC T cell receptor.


PIN1 Modulates Huntingtin Levels and Aggregate Accumulation: An In vitro Model.
Huntington's disease (HD) is a dominantly inherited neurodegenerative disorder characterized by a polyglutamine expansion within the N-terminal region of huntingtin protein (HTT). Cellular mechanisms promoting mutant huntingtin (mHTT) clearance are of great interest in HD pathology as they can lower the level of the mutant protein and its toxic aggregated species, thus affecting disease onset and progression. We have previously shown that the prolyl-isomerase PIN1 represents a promising negative regulator of mHTT aggregate accumulation using a genetically precise HD mouse model, namely HdhQ111 mice. Therefore, the current study aims at underpinning the mechanism by which PIN1 affects huntingtin's aggregates. We found that PIN1 overexpression led to a reduction of mHTT aggregates in HEK293 cells, and that this could be linked to a negative regulation of mHTT half-life by PIN1. Furthermore, we show that PIN1 has the ability to stimulate the proteasome presenting evidence of a mechanism regulating this phenomenon. Our findings provide a rationale for future investigation into PIN1 with the potential for the development of novel therapeutic strategies.


Optimization of sample transfer in two-dimensional microfluidic separation systems.
Multidimensional microfluidic separation systems combining a first dimension microchannel with an array of parallel second dimension microchannels can suffer from non-uniform sample transfer between the dimensions, sample leakage, and injection plug tailing within the second dimension array. These factors can significantly reduce overall two-dimensional separation performance. In this paper, numerical and analytical models reveal an optimized chip design which combines multidimensional backbiasing and an angled channel geometry to ensure leakage-free and uniform interdimensional sample transfer, while also minimizing injected sample plug lengths. The optimized design is validated experimentally using a multidimensional chip containing five second dimension channels.


Protein and energy metabolism in starvation reconsidered.
Current concepts of the metabolic changes during starvation have been heavily influenced by recent studies on grossly obese subjects undergoing therapeutic fasting. It has been suggested that during prolonged starvation the central nervous system develops the ability to utilize ketone bodies, and that the consequent reduction in gluconeogenesis leads to an adaptive sparing of protein catabolism. However, our analysis of classical studies on starvation shows that during prolonged starvation in normal subjects the fraction of total energy expenditure derived from protein (the P ratio) remained unchanged. Although urinary nitrogen was reduced during the progress of the fast, we conclude that this is secondary to the general reduction in metabolic rate, rather than to a specific sparing of protein.


Purification, molecular cloning and functional characterization of swine phosphatidylethanolamine-binding protein 4 from seminal plasma.
Phosphatidylethanolamine-binding proteins (PEBPs) are found in various species and have multiple functions. In this study, we purified the swine homolog of human PEBP4 (sPEBP4) from swine seminal plasma, cloned the sPEBP4 cDNA and functionally characterized this protein. The molecular mass of the purified protein was calculated to be 25 kDa by SDS-polyacrylamide gel electrophoresis under reducing conditions. The full-length cDNA of sPEBP4 contains 815 bp with an open reading frame of 669 bp that encodes a protein 222 residues in length. sPEBP4 contains a putative phosphatidylethanolamine-binding domain between residues 79 and 195; however, this domain did not show lipid binding activity. The overall amino acid sequence identity of PEBP4s from swine, human, mouse, bovine and canine ranges between 56.1% and 82.4%. Immunohistochemical staining and western blotting analysis showed that sPEBP4 is secreted from epithelial cells in the epididymis to the seminal plasma. To explore the role of sPEBP4 in the seminal plasma, we tested the effect of sPEBP4 on swine sperm motility. Sperms suspended in phosphate-buffered saline began to swim after the addition of purified sPEBP4, but not when swine serum albumin was added, indicating that sPEBP4 promotes sperm motility.


Laser Tuning in van der Waals Crystals.
The great progress that optoelectronic technologies have achieved in van der Waals crystals promises the development of next-generation two-dimensional (2D) integrated optoelectronic systems (IOSs). Here, relying on the anomalous avoidance of pump-light absorption, the harvest of extremely strong Raman scattering, and the achievement of polarization inheritance by the designed optical geometry, we realized laser wavelength tuning with ultrahigh precision (0.01 nm/25 K) in layered MoS2 and WS2 by adjusting the temperature. Our results offer a potential approach for 2D laser tuning, while also building a substantial theoretical foundation, which might be of use in developing future wavelength-division-multiplexing technology in 2D IOSs.


[Reinke edema--helpful in unilateral recurrent laryngeal nerve paralysis?].
We report on a 57-year-old teacher who consulted us for her known unilateral recurrent nerve paralysis subsequent to strumectomy. Video laryngoscopic and stroboscopic examinations revealed Reinke's edema in addition to the left-sided immobile vocal fold with maintenance of good vocal function. Because of the left-sided Reinke's edema, complete glottal closure was possible although the left vocal ligament remained slack. Surgical removal of the vocal fold edema in this case would presumably result in considerable impairment of vocal function. This example illustrates that in selected cases Reinke's edema can contribute to maintenance of phonation in unilateral vocal fold paralysis. In these cases, indication for edema surgery should be very restrictive and should always take the vocal function into consideration.


The effect of GRF on the EEG sleep of normal males.
The administration of GRF in young men either before sleep onset or coinciding with sleep onset leads to an immediate significant increase in GH secretion. These increases were not associated with major alterations in sleep including slow-wave sleep.


Plasmonic hydrogen sensing with nanostructured metal hydrides.
In this review, we discuss the evolution of localized surface plasmon resonance and surface plasmon resonance hydrogen sensors based on nanostructured metal hydrides, which has accelerated significantly during the past 5 years. We put particular focus on how, conceptually, plasmonic resonances can be used to study metal-hydrogen interactions at the nanoscale, both at the ensemble and at the single-nanoparticle level. Such efforts are motivated by a fundamental interest in understanding the role of nanosizing on metal hydride formation processes in the quest to develop efficient solid-state hydrogen storage materials with fast response times, reasonable thermodynamics, and acceptable long-term stability. Therefore, a brief introduction to the thermodynamics of metal hydride formation is also given. However, plasmonic hydrogen sensors not only are of academic interest as research tool in materials science but also are predicted to find more practical use as all-optical gas detectors in industrial and medical applications, as well as in a future hydrogen economy, where hydrogen is used as a carbon free energy carrier. Therefore, the wide range of different plasmonic hydrogen sensor designs already available is reviewed together with theoretical efforts to understand their fundamentals and optimize their performance in terms of sensitivity. In this context, we also highlight important challenges to be addressed in the future to take plasmonic hydrogen sensors from the laboratory to real applications in devices, including poisoning/deactivation of the active materials, sensor lifetime, and cross-sensitivity toward other gas species.


Nanozyme and Stimulated Fluorescent Cu-Based Metal-Organic Frameworks (Cu-MOFs) Functionalized with Engineered Aptamers as a Molecular Recognition Element for Thrombin Detection in the Plasma of COVID-19 Patients.
An essential tool in the management and control of the COVID-19 pandemic is the development of a fast, selective, sensitive, and inexpensive COVID-19 biomarkers detection method. Herein, an ultrasensitive and label-free biosensing strategy was described for the colorimetric and fluorimetric detection of thrombin. A dual-mode aptasensing method based on integrating engineered ssDNA with a stimulated fluorescent enzyme-mimetic copper-based metal-organic framework (Cu-MOF) as a molecular recognition element for thrombin was investigated. Cu-MOFs displayed stimulated fluorescence and enzyme-mimetic peroxidase activities that oxidize the chromogenic colorless substance TMB to blue-colored oxTMB. The thrombin-based aptamer (ssDNA) can be immobilized on the Cu-MOF surface to form a functionalized composite, ssDNA/MOF, and quench the stimulated fluorescence emission and the enzymatic activity of the Cu-MOF. Later, addition of thrombin recovers the fluorescence and enzymatic activity of the MOF. Thus, a turn-on colorimetry/fluorimetry aptasensing probe was designed for the detection of thrombin. Based on colorimetric assay, 350 pM was recorded as the lower limit of detection (LOD), while based on the fluorescence mode, 110 fM was recorded as the LOD (when S/N = 3). The label-free aptasensing probe was used successfully for the detection of thrombin in COVID-19 patients with satisfactory recoveries, 95-98%. Since the detection time of our aptasensor is relatively rapid (45 min) and due to the low-cost precursors and easy-to-operate characteristics, we believe that it has great potential to be used in point-of-care testing (POCT).


Phase of neural excitation relative to basilar membrane motion in the organ of Corti: theoretical considerations.
Although the auditory transduction process is dependent on neural excitation of the auditory nerve in relation to motion of the basilar membrane (BM) in the organ of Corti (OC), specifics of this process are unclear. In this study, therefore, an attempt was made to estimate the phase of the neural excitation relative to the BM motion using a finite-element model of the OC at the basal turn of the gerbil, including the fluid-structure interaction with the lymph fluid. It was found that neural excitation occurs when the BM exhibits a maximum velocity toward the scala vestibuli at 10 Hz and shows a phase delay relative to the BM motion with increasing frequency up to 800 Hz. It then shows a phase advance until the frequency reaches 2 kHz. From 2 kHz, neural excitation again shows a phase delay with increasing frequency. From 800 Hz up to 2 kHz, the phase advances because the dominant force exerted on the hair bundle shifts from a velocity-dependent Couette flow-induced force to a displacement-dependent force induced by the pressure difference. The phase delay that occurs from 2 kHz is caused by the resonance process of the hair bundle of the IHC.


Hydatid cyst in head of pancreas presenting with obstructive jaundice.
We report a patient with hydatid cyst in the head of the pancreas who presented with obstructive jaundice. At operation, the cyst was compressing the common bile duct and pancreatic duct. Excision of the cyst with choledochoduodenostomy was performed.


Characterization of acute lymphoblastic leukemia progenitor cells.
Only some acute lymphoblastic leukemia (ALL) cells are thought to be capable of proliferating to maintain the leukemic clone, and these cells may be the most relevant to target with treatment regimens. We have developed a serum-free suspension culture (SC) system that supported growth of B-ALL cells from 33 patients for up to 6 weeks. ALL cells from 28 cases (85%) were expanded in this system, and growth was superior in SC than in long-term bone marrow culture. To characterize ALL progenitors, cells were sorted for expression of CD34 and CD10 or CD19 and the subfractions assayed in SC and in nonobese diabetic/severe combined immunodeficient (NOD/SCID) mice. Cells capable of long-term proliferation in vitro and NOD/SCID repopulation were derived only from the CD34(+)/CD10(-) and CD34(+)/CD19(-) subfractions, and these cells could engraft secondary recipients. The engrafted cells had the same immunophenotype and karyotype as was seen at diagnosis, suggesting they had differentiated in vivo. These results demonstrate that ALL cells capable of long-term proliferation in vitro and in vivo are CD34(+)/CD10(-)/CD19(-). This suggests that cells with a more immature phenotype, rather than committed B-lymphoid cells, may be the targets for transformation in B-ALL.


Effects of tolerance induction on the actions of interferon-gamma on porcine cardiac allografts.
It is well known that interferon-gamma (IFN-gamma) not only plays a critical role in antigen-dependent but also in antigen-independent tissue injury; however, it is not clear how tolerance induction affects the actions of IFN-gamma in the transplant setting. To address this question, we compared the effects of IFN-gamma on porcine recipients of near-syngeneic, rejecting, and tolerant heart transplants. IFN-gamma was infused continuously into the left anterior descending artery of hearts transplanted into 3 groups of major histocompatibility complex (MHC) inbred miniature swine, each treated with a 12-day course of cyclosporine A (CyA). Group 1 recipients received a MHC class I disparate heart, group 2 recipients received a near-syngeneic heart, and group 3 recipients were cotransplanted with a MHC class I disparate heart and kidney, which uniformly induces tolerance to both grafts. An additional group of animals was not transplanted but received intracoronary IFN-gamma infusion into their native hearts. IFN-gamma perfusion not only accelerated the acute rejection of MHC class I disparate hearts (mean survival time = 19 +/- 7.21 vs 38 +/- 8.19 days, P = .025), but caused near-syngeneic heart transplants, which otherwise survive indefinitely, to reject within 35 days (n = 3). In contrast, IFN-gamma perfusion had no demonstrable effects on interstitial rejection, the development of vascular lesions, or graft survival in tolerant heart plus kidney allograft recipients (n = 4) or in autologous hearts (n = 2). These results suggest that tolerance induction mitigates the damaging effects of IFN-gamma itself and that the beneficial effects of tolerance induction on acute and chronic rejection may extend to antigen-independent factors like ischemia/reperfusion injury.


Improved P1/P1' substituents for cyclic urea based HIV-1 protease inhibitors: synthesis, structure-activity relationship, and X-ray crystal structure analysis.
We present several novel P1/P1' substituents that can replace the characteristic benzyl P1/P1' moiety of the cyclic urea based HIV protease inhibitor series. These substituents typically provide 5-10-fold improvements in binding affinity compared to the unsubstituted benzyl analogs. The best substituent was the 3,4-(ethylenedioxy)benzyl group. Proper balancing of the molecule's lipophilicity facilitated the transfer of this improved binding affinity into a superior cellular antiviral activity profile. Several analogs were evaluated further for protein binding and resistance liabilities. Compound 18 (IC90 = 8.7 nM) was chosen for oral bioavailability studies based on its log P and solubility profile. A 10 mg/kg dose in dogs provided modest bioavailability with Cmax = 0.22 microg/mL. X-ray crystallographic analysis of two analogs revealed several interesting features responsible for the 3,4-(ethylenedioxy)benzyl-substituted analog's potency: (1) Comparing the two complexes revealed two distinct binding modes for each P1/P1' substituent; (2) The ethylenedioxy moieties are within 3.6 A of Pro 81 providing additional van der Waals contacts missing from the parent structure; (3) The enzyme's Arg 8 side chain moves away from the P1 substituent to accommodate the increased steric volume while maintaining a favorable hydrogen bond distance between the para oxygen substituent and the guanidine NH.


Epidemiology of suicide attempts and deaths: a population-based study in Fars, Iran (2011-16).
Suicide is a critical psychological issue worldwide with an increasing trend. This study investigated suicide comprehensively. In this cross-sectional study, we reviewed data of 28 552 suicide attempts during 2011-16, in Southern Iran. To calculate age-standardized incidence rates, population statistics were derived from the Statistical Center of Iran and the National Organization for Civil Registration. We used the standard population of World Health Organization 2012 to adjust the suicide attempts and deaths rates by age. The mean age of participants was 26.8 ± 10.6 years with the highest suicide attempts rates in the age groups of 15-24 and 25-34 years (48% and 32.5%, respectively); 58.7% were women and 52.9% were single. Case-fatality rate (CFR) was 6.27%. Annual age-standardized incidence rates of suicide attempts during the 6-year period has increased (P < 0.001), and that of deaths were not incremental (P > 0.05). Logistic regression model showed male sex, rural area, older age, psychological and somatic disorders, and family history of suicide as significant factors. In this comprehensive study, although the age-standardized mortality rate of suicide in southern Iran was lower than in other countries, the increasing trend of suicide attempts during the study period served as an alarming sign in this province.


Doing what the patient orders: maintaining integrity in the doctor-patient relationship.
No profession has undergone as much scrutiny in the past several decades as that of medicine. Indeed, one might well argue that no profession has ever undergone so much change in so short a time. An essential part of this change has been the growing insistence that competent, adult patients have the right to decide about the course of their own medical treatment. However, the familiar and widely accepted principle of patient self-determination entails a corollary that has received little attention in the growing literature on the ethics of physician-patient relations: if patients are to direct the course of their own medical treatment, then physicians are at least sometimes to be guided in their actions on behalf of patients by values that are not, and may even be incompatible with, their own values. Unless it is supposed that it would be best if physicians were simply to accommodate any and all patient requests, a possibility I consider and reject in this paper, there are bound to be numerous instances of legitimate moral conflict between the preferences of physicians and patients. In this paper, I examine the implications of this sort of moral conflict from the standpoint of the integrity of the physician....I have also considered the common practice of patient referral from the standpoint of physician integrity, and asked whether a physician who refuses to treat a patient as a matter of conscience can consistently refer the patient to another physician for the same treatment....