Choroidal Neovascularization and Geographic Atrophy are Potential Complications of Early Onset Large Colloid Drusen.
The authors report a case of large colloid drusen (LCD) complicated by choroidal neovascularization (CNV) and geographic atrophy (GA). A 54-year-old man was referred to the authors' department with diagnosis of early onset retinal drusen. Multimodal imaging led to a diagnosis of LCD complicated by GA in the right eye and CNV in the left eye. The patient received a single injection of intravitreal aflibercept (Eylea; Regeneron, Tarrytown, NY) in the left eye. Six months later, best-corrected visual acuity improved to 20/25, and spectral-domain optical coherence tomography still showed absence of subretinal and intraretinal fluid. GA and CNV are possible complications of LCD, and contrary to previous beliefs, it should therefore not be considered as a benign condition. Intravitreal aflibercept could be considered as a useful treatment in cases complicated by CNV. [Ophthalmic Surg Lasers Imaging Retina. 2017;48:586-590.].


Investigation of hypromellose particle size effects on drug release from sustained release hydrophilic matrix tablets.
Selected combinations of six model drugs and four hypromellose (USP 2208) viscosity grades were studied utilizing direct compression and in vitro dissolution testing. Experimental HPMC samples with differing particle size distributions (coarse, fine, narrow, bimodal) were generated by sieving. For some formulations, the impact of HPMC particle size changes was characterized by faster drug release and an apparent shift in drug release mechanism when less than 50% of the HPMC passed through a 230 mesh (63 microm) screen. Within the ranges studied, drug release from other formulations appeared to be unaffected by HPMC particle size changes.


Evaluation of white matter in patients with multiple sclerosis through diffusion tensor magnetic resonance imaging.
To study the white matter of patients with multiple sclerosis (MS) with diffusion tensor magnetic resonance (MR) imaging (DTI). Forty patients with clinical-laboratorial diagnosis of relapsing-remitting MS and 40 age- and sex-matched controls, who underwent conventional and functional (DTI) MR imaging, were included in the study. The DTI sequences resulted in maps of fractional anisotropy (FA) and regions of interest were placed on the plaques, peri-plaque regions, normal-appearing white matter (NAWM) around the plaques, contralateral normal white matter (CNWM) and normal white matter of the controls (WMC). The FA values were compared and the statistical treatment was performed with the Mann-Whitney U test. The mean FA in plaques was 0.268, in peri-plaque regions 0.365, in NAWM 0.509, in CNWM 0.552 and in WMC 0.573. Statistical significant differences in FA values were observed in plaques, peri-plaque regions and in NAWM around the plaques when compared to the white matter in the control group. There was no significant difference between the FA values of the CNWM of patients with MS and normal white matter of controls. Patients with MS show difference in the FA values of the plaques, peri-plaques and NAWM around the plaques when compared to the normal white matter of controls. As a result, DTI may be considered more efficient than conventional MR imaging for the study of patients with MS.


Interaction of triazolam and ketoconazole in P-glycoprotein-deficient mice.
The role of P-glycoprotein (P-gp) on the distribution of the benzodiazepine triazolam (TRZ) and the azole antifungal agent ketoconazole (KET), and on the TRZ-KET interaction, was studied using mdr1a(-) or mdr1a/b(-/-) mice (P-gp-deficient mice) and matched controls. TRZ and KET also were studied in Caco-2 cells in Transwell culture. After single i.p. injections of TRZ or KET in separate groups of control mice, brain concentrations of TRZ exceeded those in serum [brain/serum area under the concentration curve (AUC) ratio, 5.0], whereas brain/serum AUC ratios for KET were approximately 0.5. On the basis of single time points, brain concentrations of TRZ, or brain/serum ratios, were similar in P-gp-deficient animals compared with controls, whereas P-gp-deficient animals had significantly higher KET brain concentrations and brain/serum ratios. Coadministration of KET with TRZ increased TRZ concentrations in serum, liver, and brain, both in controls and in P-gp-deficient animals, probably attributable to impairment by KET of CYP3A-mediated clearance of TRZ. However, KET did not increase brain/serum ratios of TRZ in either group. In Caco-2 cells, basal-to-apical flux of TRZ was higher than apical-to-basal flux. However, verapamil (100 microM) did not alter flux in either direction. KET inhibited basal-to-apical transport of rho-damine-123, with a 50% inhibitory concentration of 2.7 microM. Thus, TRZ does not appear to undergo measurable blood-brain barrier efflux transport by P-gp in this animal model. KET impairs clearance of TRZ but does not increase tissue uptake. However, KET itself may be a substrate for efflux transport at the blood-brain barrier.


Electrospun Nanofibrous Mesh Based on PVA, Chitosan, and Usnic Acid for Applications in Wound Healing.
Injuries and diseases of the skin require accurate treatment using nontoxic and noninvasive biomaterials, which aim to mimic the natural structures of the body. There is a strong need to develop biodevices capable of accommodating nutrients and bioactive molecules and generating the process of vascularization. Electrospinning is a robust technique, as it can form fibrous structures for tissue engineering and wound dressings. The best way of forming such meshes for wound healing is to choose two polymers that complement each other regarding their properties. On the one hand, PVA is a water-soluble synthetic polymer widely used for the preparation of hydrogels in the field of biomedicine owing to its biocompatibility, water solubility, nontoxicity, and considerable mechanical properties. PVA is easy to subject to electrospinning and can offer strong mechanical stability of the mesh, but it is necessary to improve its biological properties. On the other hand, CS has good biological properties, including biodegradability, nontoxicity, biocompatibility, and antimicrobial properties. Still, it is harder to electrospin and does not possess as good mechanical properties as PVA. As these structures also allow the incorporation of bioactive agents due to their high surface-area-to-volume ratio, the interesting point was to incorporate usnic acid into the structure as it is a natural and suitable alternative agent for burn wounds treatment which avoids an improper or overuse of antibiotics and other invasive biomolecules. Thus, we report the fabrication of an electrospun nanofibrous mesh based on PVA, chitosan, and usnic acid with applications in wound healing. The obtained nanofibers mesh was physicochemically characterized by Fourier transform infrared spectroscopy (FT-IR) and scanning electron microscopy (SEM). In vitro biological assays were performed to evaluate the antimicrobial properties of the samples using the MIC (minimum inhibitory concentration) assay and evaluating the influence of fabricated meshes on the Staphylococcus aureus biofilm development, as well as their biocompatibility (demonstrated by fluorescence microscopy results, an XTT assay, and a glutathione (GSH) assay).


Effect of Curcumin Addition on the Adsorption and Transport of a Cationic Dye across DPPG-POPG Liposomes Probed by Second Harmonic Spectroscopy.
The effect of addition of curcumin on the adsorption and transport characteristics of a cationic dye, LDS+, across negatively charged bilayers composed of POPG and DPPG lipids were investigated by the interface selective second harmonic (SH) spectroscopic technique. Curcumin induced changes in the SH electric field signal of the LDS+ ions (E2ω (LDS+)) were observed to depend critically on the bilayer acyl chain saturation/unsaturation ratio (S/U). Following earlier works, the increase in the E2ω (LDS+) signal is attributed to the release of the Na+ counterions present in the head group region of the bilayer by curcumin and the decay of the E2ω (LDS+) signal is attributed to the bilayer intercalated state of curcumin. While the changes observed in the E2ω (LDS+) signal in the presence of POPG liposomes were consistent with our earlier study ( Varshney, G. K. et al. Langmuir , 2016 , 32 , 10415 - 10421 ), they were significantly different for DPPG liposomes, following curcumin addition. While the increase in the E2ω (LDS+) signal in the presence of POPG liposomes, is marginal (∼10-20%) and instantaneous (<1 s) followed by a rapid decay (completed within ∼100 s), in the presence of DPPG liposomes it was observed to increase slowly and at saturation shows a substantial increase (100-200%), following curcumin addition. When liposomes consisting of a mixture of POPG and DPPG lipids are used, curcumin induced kinetic characteristics of the E2ω (LDS+) signal showed a mixture of the individual kinetic characteristics observed for the unsaturated (POPG) and saturated (DPPG) liposomes. The observed kinetic trends of the E2ω (LDS+) signal following curcumin addition are explained on the basis of the relative strength of the Na+-POPG and Na+-DPPG interaction. Higher ordering of the lipid acyl chain region in DPPG liposome makes the Na+-DPPG interaction much stronger than the Na+-POPG interaction. Further, it is proposed that, in POPG-DPPG liposomes, individual domains of POPG and DPPG lipids exist at low temperature as suggested by the observed temperature dependent kinetic characteristics of the E2ω (LDS+) signal following curcumin addition. These domains are dependent on the S/U ratio and phase state of the bilayer. The gel phase was observed to be more conducive for individual domain formation. Results presented in this work not only support the notion that biological activity of curcumin is associated with its bilayer altering properties, but more interestingly it provides a qualitative insight about how bilayer phase separation can be achieved by modulating the hydrophobic interactions between the lipid acyl chains.


Occupational stress.
Stress has come to be recognized as one of the most pervasive and potent health hazards in the work environment. This paper describes recent trends in stress-related cases, reviews the changes in workers' compensation legislation and adjudication that have paved the way for the increase, and suggests means that employers, and particularly occupational health professionals, may use to manage this problem more effectively.


Fast Randomized Singular Value Thresholding for Low-Rank Optimization.
Rank minimization can be converted into tractable surrogate problems, such as Nuclear Norm Minimization (NNM) and Weighted NNM (WNNM). The problems related to NNM, or WNNM, can be solved iteratively by applying a closed-form proximal operator, called Singular Value Thresholding (SVT), or Weighted SVT, but they suffer from high computational cost of Singular Value Decomposition (SVD) at each iteration. We propose a fast and accurate approximation method for SVT, that we call fast randomized SVT (FRSVT), with which we avoid direct computation of SVD. The key idea is to extract an approximate basis for the range of the matrix from its compressed matrix. Given the basis, we compute partial singular values of the original matrix from the small factored matrix. In addition, by developping a range propagation method, our method further speeds up the extraction of approximate basis at each iteration. Our theoretical analysis shows the relationship between the approximation bound of SVD and its effect to NNM via SVT. Along with the analysis, our empirical results quantitatively and qualitatively show that our approximation rarely harms the convergence of the host algorithms. We assess the efficiency and accuracy of the proposed method on various computer vision problems, e.g., subspace clustering, weather artifact removal, and simultaneous multi-image alignment and rectification.


Different approaches for assaying melanosome transfer.
Many approaches have been tried to establish assays for melanosome transfer to keratinocytes. In this report, we describe and summarize various novel attempts to label melanosomes in search of a reliable, specific, reproducible and quantitative assay system. We tried to fluorescently label melanosomes by transfection of GFP-labeled melanosomal proteins and by incubation of melanocytes with fluorescent melanin intermediates or homologues. In most cases a weak cytoplasmic fluorescence was perceived, which was probably because of incorrect sorting or deficient incorporation of the fluorescent protein and different localization. We were able to label melanosomes via incorporation of 14C-thiouracil into melanin. Consequently, we tried to develop an assay to separate keratinocytes with transferred radioactivity from melanocytes after co-culture. Differential trypsinization and different magnetic bead separation techniques were tested with unsatisfactory results. An attempt was also made to incorporate fluorescent thiouracil, since this would allow cells to be separated by FACS. In conclusion, different methods to measure pigment transfer between donor melanocytes and acceptor keratinocytes were thoroughly examined. This information could give other researchers a head start in the search for a melanosome transfer assay with said qualities to better understand pigment transfer.


Permeation Mechanism of Potassium Ions through the Large Conductance Ca2+-Activated Potassium Channel.
The permeation of the potassium ion (K+) through the selectivity filter (SF) of the large conductance Ca2+-activated potassium (Slo1) channel remains an interesting question to study. Although the mode of K+ entering and leaving the SF has been revealed, the mechanism of K+ passing through the SF is still not clear. In the present study, the pattern of K+ permeation through the SF is investigated by chemical computation and data mining based on the molecular structure of Slo1 from Aplysia californica. Both bond configurations and the free energy of K+s inside the SF was studied using Discovery Studio software. The results suggested that, to accommodate increasing energy levels and to tolerate more K+s, 4-fold symmetric subunits of SF can only move at one direction that is perpendicular to the center axis. In addition, two configurations of chemical bonds between K+s and the SF are usually employed including the chelate configuration under low free energy and the complex configuration under high free energy conditions. Moreover, three patterns of bond configurations for multiple K+s within the SF are used to accommodate the energetic changes of the SF, and each pattern is composed of one or two subconformations. These findings likely resulted from the evolutionary optimization of the protein function of Slo1. The specific conductance and the voltage-gating of the Slo1 channel can be reinterpreted with the permeation mechanism of K+s found in the current study. The permeation mechanism of K+s through the SF can be used to understand the interaction between various toxins and the Slo1 channel, and can be employed to develop new drugs targeting relevant ion channels.


Three-dimensional matrix fiber alignment modulates cell migration and MT1-MMP utility by spatially and temporally directing protrusions.
Multiple attributes of the three-dimensional (3D) extracellular matrix (ECM) have been independently implicated as regulators of cell motility, including pore size, crosslink density, structural organization, and stiffness. However, these parameters cannot be independently varied within a complex 3D ECM protein network. We present an integrated, quantitative study of these parameters across a broad range of complex matrix configurations using self-assembling 3D collagen and show how each parameter relates to the others and to cell motility. Increasing collagen density resulted in a decrease and then an increase in both pore size and fiber alignment, which both correlated significantly with cell motility but not bulk matrix stiffness within the range tested. However, using the crosslinking enzyme Transglutaminase II to alter microstructure independently of density revealed that motility is most significantly predicted by fiber alignment. Cellular protrusion rate, protrusion orientation, speed of migration, and invasion distance showed coupled biphasic responses to increasing collagen density not predicted by 2D models or by stiffness, but instead by fiber alignment. The requirement of matrix metalloproteinase (MMP) activity was also observed to depend on microstructure, and a threshold of MMP utility was identified. Our results suggest that fiber topography guides protrusions and thereby MMP activity and motility.


An exquisite cross-control mechanism among endothelial cell fate regulators directs the plasticity and heterogeneity of lymphatic endothelial cells.
Arteriovenous-lymphatic endothelial cell fates are specified by the master regulators, namely, Notch, COUP-TFII, and Prox1. Whereas Notch is expressed in the arteries and COUP-TFII in the veins, the lymphatics express all 3 cell fate regulators. Previous studies show that lymphatic endothelial cell (LEC) fate is highly plastic and reversible, raising a new concept that all 3 endothelial cell fates may co-reside in LECs and a subtle alteration can result in a reprogramming of LEC fate. We provide a molecular basis verifying this concept by identifying a cross-control mechanism among these cell fate regulators. We found that Notch signal down-regulates Prox1 and COUP-TFII through Hey1 and Hey2 and that activated Notch receptor suppresses the lymphatic phenotypes and induces the arterial cell fate. On the contrary, Prox1 and COUP-TFII attenuate vascular endothelial growth factor signaling, known to induce Notch, by repressing vascular endothelial growth factor receptor-2 and neuropilin-1. We show that previously reported podoplanin-based LEC heterogeneity is associated with differential expression of Notch1 in human cutaneous lymphatics. We propose that the expression of the 3 cell fate regulators is controlled by an exquisite feedback mechanism working in LECs and that LEC fate is a consequence of the Prox1-directed lymphatic equilibrium among the cell fate regulators.


Effects of intraventricular infusion of corticotropin-releasing factor on VMH-lesioned obese rats.
Corticotropin-releasing factor (CRF) has been administered into the third ventricle of sham-operated and ventromedial hypothalamic (VMH)-lesioned rats in acute and chronic experiments. After a single 5-microgram injection of CRF, there was an acute reduction of food intake in both sham-operated and VMH-lesioned rats that persisted for 3 h. The effect was still present in the VMH-lesioned rats between 3 and 6 h but had dissipated in the sham-operated controls. Guanosine 5'-diphosphate (GDP) binding to mitochondria from interscapular brown adipose tissue was used as an index of thermogenic activity in this tissue. In 21-h food-deprived rats, GDP binding was significantly lower in VMH-lesioned than in sham-operated animals. Although the mean increase in sham-operated animals was increased, this was not significantly different from saline-injected controls. In the VMH-lesioned rats, however, CRF acutely increased GDP binding to values not different than those of the sham-operated controls. Serum corticosterone was significantly lower in the VMH-lesioned rats, but both groups showed a significant stimulation by CRF during a 7-day infusion of CRF (4.8 micrograms/day) into the third ventricle. Food intake was significantly depressed in the VMH-lesioned animals that received CRF, from values of 35 g/day to approximately 25 g/day. Body weight showed a slow steady decrease, having fallen by nearly 15 g at the end of the 7-day infusion period. In contrast the mean value in the VMH-lesioned controls had significantly higher in CRF-infused animals.(ABSTRACT TRUNCATED AT 250 WORDS)


Pharmacokinetics, tissue distribution and excretion of verticinone from F. hupehensis in rats.
Verticinone, the main active component in F. hupehensis, exhibits potent antitussive and expectorant effects. Here, a LC-MS method was developed and applied to study the pharmacokinetics, tissue distribution and excretion of verticinone in rats, and its plasma protein binding in vitro. A significant gender difference in the pharmacokinetics of verticinone in rats was observed, as its absolute oral bioavailability in male and female rats was 45.8% and 2.74%, respectively. The relative bioavailability of verticinone was significantly lower in female rats as compared to male, following intragastrical (i.g.) and intravenous (i.v.) administration. After successive i.g. administration of verticinone, accumulation was observed in female rats but not in the male ones. The tissue distribution study showed that verticinone had a good tissue penetrability and a high tissue affinity in most studied tissues, except brain. After a 2 mg/kg oral dose, less than 4% of the dose was excreted as unchanged parent compound in male rats, and less than 1% in female rats, which indicated that verticinone was metabolized more extensively in female rats than in male rats.


Molecular analysis of coordinated bladder and urogenital organ formation by Hedgehog signaling.
The urogenital and reproductive organs, including the external genitalia, bladder and urethra, develop as anatomically aligned organs. Descriptive and experimental embryology suggest that the cloaca, and its derivative, the urogenital sinus, contribute to the formation of these organs. However, it is unknown how the primary tissue lineages in, and adjacent to, the cloaca give rise to the above organs, nor is bladder formation understood. While it is known that sonic hedgehog (Shh) is expressed by the cloacal epithelia, the developmental programs that regulate and coordinate the formation of the urogenital and reproductive organs have not been elucidated. Here we report that Shh mutant embryos display hypoplasia of external genitalia, internal urethra (pelvic urethra) and bladder. The importance of Shh signaling in the development of bladder and external genitalia was confirmed by analyzing a variety of mutant mouse lines with defective hedgehog signaling. By genetically labeling hedgehog-responding tissue lineages adjacent to the cloaca and urogenital sinus, we defined the contribution of these tissues to the bladder and external genitalia. We discovered that development of smooth muscle myosin-positive embryonic bladder mesenchyme requires Shh signaling, and that the bladder mesenchyme and dorsal (upper) external genitalia derive from Shh-responsive peri-cloacal mesenchyme. Thus, the mesenchymal precursors for multiple urogenital structures derive from peri-cloacal mesenchyme and the coordination of urogenital organ formation from these precursors is orchestrated by Shh signals.


Meiotic prophase roles of Rec8 in crossover recombination and chromosome structure.
Rec8 is a prominent component of the meiotic prophase chromosome axis that mediates sister chromatid cohesion, homologous recombination and chromosome synapsis. Here, we explore the prophase roles of Rec8. (i) During the meiotic divisions, Rec8 phosphorylation mediates its separase-mediated cleavage. We show here that such cleavage plays no detectable role for chromosomal events of prophase. (ii) We have analyzed in detail three rec8 phospho-mutants, with 6, 24 or 29 alanine substitutions. A distinct 'separation of function' phenotype is revealed. In the mutants, axis formation and recombination initiation are normal, as is non-crossover recombination; in contrast, crossover (CO)-related events are defective. Moreover, the severities of these defects increase coordinately with the number of substitution mutations, consistent with the possibility that global phosphorylation of Rec8 is important for these effects. (iii) We have analyzed the roles of three kinases that phosphorylate Rec8 during prophase. Timed inhibition of Dbf4-dependent Cdc7 kinase confers defects concordant with rec8 phospho-mutant phenotypes. Inhibition of Hrr25 or Cdc5/polo-like kinase does not. Our results suggest that Rec8's prophase function, independently of cohesin cleavage, contributes to CO-specific events in conjunction with the maintenance of homolog bias at the leptotene/zygotene transition of meiotic prophase.


H-Y antigens, testis differentiation, and spermatogenesis.
H-Y antigen defined by graft rejection and by cytotoxic T cell action ('transplantation H-Y') appears to be different from H-Y antigen that is characterized by antibodies ('serological H-Y'). Gene(s) for the transplantation H-Y were assigned to the long arm or to the centromeric region of the human Y chromosome. A regulatory gene for serological H-Y seems to be located in a distal region of the Y short arm. Various investigations suggest that serological H-Y has a molecular weight of approximately 18,000. While serological H-Y might be involved in the differentiation of the heterogametic gonad of vertebrates, transplantation H-Y may be required for normal spermatogenesis to occur in mammals.


Ventilation with negative airway pressure induces a cytokine response in isolated mouse lung.
We tested the hypothesis that, under relatively low tidal volume (VT) mechanical ventilation, continuing lung decruitment induced by negative end-expiratory pressure (NEEP) would increase the lung cytokine response, potentially contributing to lung injury. Mouse lungs were excised and randomly assigned to one of 3 different ventilatory strategies: 1) the zero end-expiratory pressure group served as a control, 2) the NEEP7 group received a NEEP of -7.5 cm H(2)O, and 3) the NEEP15 group received a NEEP of -15 cm H(2)O. In all 3 groups, a VT of 7 mL/kg was used. After 2 h of ventilation, lung lavage fluid was collected for measurements of tumor necrosis factor-alpha, monocyte chemoattractant protein-1, and lactate dehydrogenase. Increases in plateau pressure before and after mechanical ventilation were significantly greater in the NEEP15 group compared with the zero end-expiratory pressure group or NEEP7 group. Lung compliance was decreased in the NEEP15 compared with the other two groups. Concentrations of tumor necrosis factor-alpha, monocyte chemoattractant protein-1, and lactate dehydrogenase in lung lavage were larger in the NEEP15 group than in the other groups. Atelectatic lung during repeated collapse and reopening of lung units accentuates the lung cytokine response that may contribute to lung injury even during relatively low VT mechanical ventilation. Repeated closing and reopening of lung units induced by negative end-expiratory pressure resulted in lung inflammation and cell injury even under mechanical ventilation using a normal tidal volume. This finding may have clinical relevance in certain patients who are prone to atelectasis during mechanical ventilation.


[Disruption of gut immune system caused by damage of intestinal stem cells and their niche in graft-versus-host disease after allogeneic hematopoietic stem cell transplantation.]
Allogeneic hematopoietic stem cell transplantation(allo-SCT)is curative therapy for various hematological diseases. Graft-versus-host disease(GVHD)and infection remain the main problems in allo-SCT. Gastrointestinal tract is targeted by GVHD. In intestinal GVHD, intestinal stem cells and Paneth cells reside at the base of crypts are damaged by donor T cells. These damage leads to disruption of intestinal mucosal barrier and intestinal dysbiosis, resulting in more exaggerated GVHD. Recently, we and others have reported that R-Spondin1 and interleukin-22 as factors regenerated intestinal tissue homeostasis in murine model of bone marrow transplantation. It is important to understand biology of various cells targeted by intestinal GVHD and develop novel methods to protect them from GVHD damage.


Brainstem tuberculosis.
We present a case of a 38-year-old-man who presented with 1-week history of developing weakness of peripheral and cranial nerves. His MRI scan of the brain showed a large cavitating lesion at the brainstem and two further lesions of the right cerebral cortex and his CT chest showed features of old tuberculosis (TB). The identification of acid-fast bacilli was confirmed by analysis of bronchoalveolar lavage taken during bronchoscopy. He was started on anti-TB medications and repeat MRI 3 months later confirmed shrinkage of the cavitating lesion.


Metastasis from an unknown tumour.
A total of 121 patients were treated under the diagnosis: metastasis from an unknown primary tumour; 99 were irradiated. In 46 cases the primary tumour was detected from 6 months to 10 years after the primary treatment. The 3-year survival was 28.9 per cent, the 5-year 17.4 per cent and for 10 years or longer (up to 14 years) 9.1 per cent, after the primary treatment. The prognosis is correlated to the size of the metastases, their site and also their microscopic appearances.


Clinical Pattern in Hypotensive Transfusion Reactions.
Hypotensive transfusion reactions (HyTRs) may be underreported and have been associated with patients taking angiotensin-converting enzyme inhibitors (ACEIs) receiving poststorage leukoreduced blood products through negatively charged filters. Although bedside leukoreduction is no longer commonplace, HyTRs still occur and are insufficiently characterized in the prestorage leukoreduction era. We describe recently reported cases at our institution. We reviewed transfusion reaction records at Stanford Healthcare from January 2014 to April 2015. HyTRs were defined by National Health Safety Network Hemovigilance Module classification. Eleven HyTRs occurred in 10 patients. All were adults (mean age 71.7 years; range 45-92 years), 7 were male, and all underwent major surgery 0 to 2 days before the reaction. Nine patients underwent cardiac or vascular surgery, and all 10 were taking ACEIs with the last dose taken within 48 hours of the transfusion reaction in 9 patients. Nine patients were on extracorporeal circuits within 24 hours before the reaction (median duration 180 minutes; range 87-474 minutes). In 5 reactions, the implicated unit was restarted with resultant recurrent hypotension. Implicated units included 9 packed red blood cells, 1 apheresis platelet, and 1 plasma frozen within 24 hours. Contrary to what has been previously reported in the era of prestorage leukoreduction, HyTRs at our institution showed consistent patterns in patients at risk. Patients scheduled to undergo major surgery with cardiopulmonary bypass may benefit from earlier preoperative cessation of ACEIs or temporarily switching to an alternative drug class.


Avulsion fracture of the anterior superior iliac spine.
The patient was a 17-year-old adolescent male who was referred to a physical therapist for a chief complaint of anterior right hip pain. The physical therapist reviewed the patient's radiographs, which had been completed and interpreted as normal prior to referral, and determined that there were radiographic signs present that may be concerning for an avulsion fracture. Further evaluation through magnetic resonance imaging confirmed the presence of an avulsion fracture at the right anterior superior iliac spine.


Viral carcinogenesis in a pronephric cell line. An ultrastructural study.
Herpesvirus recovered from cell fractions of the spontaneous Lucké renal tumor of adult Rana pipiens were used to infect a cell line derived from pronephroi of the same species. Viruses and virus-associated structures previously found in the primary renal tumor were observed, including nuclear inclusions of capsids with single or double membranes and capsids with nucleoids often within nuclear sacs. Embedded within the clumped and marginated chromatin were 55-nm tubular elements and associated unit membrane structures. Virus-associated, 35-nm tubular elements were also seen. The cytoplasm contained single, enveloped nucleoid virus and clusters of virus within cytoplasmic vesicles. Other cytoplasmic inclusions were dense, virus-associated, 25-nm filaments, virus particles within myeloid bodies, and possible viral budding from tubular organelles.


Porous carbon anodes for a high capacity lithium-ion battery obtained by incorporating silica into benzoxazine during polymerization.
Porous carbon anodes with a controllable Vmes/Vmic ratio were synthesized through the self-assembly of poly(benzoxazine-co-resol) and the simultaneous hydrolysis of tetraethyl orthosilicate (TEOS) followed by carbonization and removal of silica. The Vmes/Vmic ratio of the carbon can be controlled in the range of approximately 1.3-32.6 through tuning the amount of TEOS. For lithium-ion battery anodes, a correlation between the electrochemical performance and Vmes/Vmic ratio has been established. A high Vmes/Vmic ratio in porous carbons is favorable for enhancing the accessibility of Li ions to active sites provided by the micropores and for achieving good lithium storage performance. The obtained porous carbon exhibits a high reversible capacity of 660 mAh g(-1) after 70 cycles at a current density of 100 mA g(-1). Moreover, at a high current density of 3000 mA g(-1), the capacity still remains at 215 mAh g(-1), showing a fast charge-discharge potential. This synthesis method relying on modified benzoxazine chemistry with the hydrolysis of TEOS may provide a new route for the development of mesoporous carbon-based electrode materials.


[Immunological activities of rat lymphocytes. III. --Isolation of differing subpopulations of lymphocytes by two techniques of T cell separation].
In previous studies we have isolated by density gradient separation a population of relatively dense T lymphocytes capable of inhibiting the mitogenic response to concanavalin A (ConA) and phytohaemagglutinin. In this study we compared two current methods of cell separation for their relative yield in T lymphocytes able or not to respond to Con A. The present results show that cells passed through nylon wool columns--in contrast to those obtained by removal of lymphocytes which bind erythrocyte-antibody-complement complex-partially lose their ability to respond to ConA. The response lost by passage through nylon wool columns can be restored by centrifugation of the T cell suspension on a gradient of "Ficoll-Hypaque". This suggests that methods of T cells purification using density gradient separation may remove the more dense suppressor cells.


Dynamics of rumor spreading in complex networks.
We derive the mean-field equations characterizing the dynamics of a rumor process that takes place on top of complex heterogeneous networks. These equations are solved numerically by means of a stochastic approach. First, we present analytical and Monte Carlo calculations for homogeneous networks and compare the results with those obtained by the numerical method. Then, we study the spreading process in detail for random scale-free networks. The time profiles for several quantities are numerically computed, which allows us to distinguish among different variants of rumor spreading algorithms. Our conclusions are directed to possible applications in replicated database maintenance, peer-to-peer communication networks, and social spreading phenomena.


Cloning and expression of the human vasoactive intestinal peptide receptor.
Vasoactive intestinal peptide (VIP) is a neuroendocrine mediator found in the central and peripheral nervous system. Distinct subsets of neural, respiratory, gastrointestinal, and immune cells bear specific high-affinity receptors for VIP, which are associated with a guanine nucleotide-binding (G) protein capable of activating adenylate cyclase. A cDNA clone (GPRN1) encoding the human VIP receptor was identified in libraries prepared from the Nalm 6 line of leukemic pre-B lymphoblasts and the HT-29 line of colon carcinoma cells. The deduced 362-amino acid polypeptide sequence encoded by GPRN1 shares a seven-transmembrane-segment hydropathicity profile with other G protein-coupled receptors. Northern blot analyses identified a 2.7-kilobase transcript of the VIP receptor in Nalm 6 and HT-29 cells as well as in tissues from rat brain, colon, heart, lung, kidney, spleen, and small intestine. COS-6 cells transfected with GPRN1 bound 125I-labeled VIP specifically with a dissociation constant (Kd) of 2.5 nM. VIP--and less effectively secretin, peptide histidine isoleucine (PHI), and glucagon competitively displaced bound 125I-VIP from transfected COS-6 cells, with potencies in the order VIP greater than secretin = PHI much greater than glucagon. VIP stimulated adenylate cyclase activity in stably transfected Chinese hamster ovary K1 cells, inducing a 3-fold increase in the intracellular level of cAMP. When the antisense orientation of the VIP receptor clone was introduced into HT-29 cells, there was a 50% suppression of the specific binding of 125I-VIP and of the VIP-induced increase in cAMP level, relative to untransfected cells. The VIP receptor cloned exhibits less than or equal to 24% homology with other receptors in the same superfamily and thus represents a subset of G protein-coupled receptors for peptide ligands.


Antigen-antibody crossed electrophoresis (Laurell) applied to the study of the antigenic structure of Candida albicans.
By means of the antigen-antibody crossed electrophoresis procedure of Laurell, 68 antigens were demonstrated in Candida albicans. This is about four times the number of antigens described earlier by means of classical immunoelectrophoresis. The procedures for obtaining this result are described, including the preparation of antigen, the immunization of rabbits, and the method of N. M. G. Harboe for the production of purified and concentrated rabbit antibodies suitable for quantitative immunoelectrophoresis. The immunoplates were stained by means of the sensitive Coomassie brilliant blue R. The various quantitative immunoelectrophoretic methods offer considerable possibilities for qualitative and quantitative characterization of antigens, even in complex mixtures, and are therefore well suited for the investigation of microbial antigens.


[Prevalence of acute symptomatic seizure after intracerebral hemorrhage].
Introduсtion: Acute symptomatic seizure (ASS) is a most frequently complication after a stroke. Seizures could be associated with the worse outcome. Nowadays the prophylactic antiepileptic treatment after the stroke is not advisable. However this question have to be discussed in a particular groups of patients. The aim: To study the prevalence of ASS in the particular groups of patients after intracerebral hemorrhage as well as to determine the predictors of the sizure occurrence in these groups of patients. Materials and methods: The retrospective analysis of the clinical features of intracerebral hemorrhage for 305 patients was performed. Among them there were 127 patients with aneurysmal subarachnoid hemorrhage as well as 178 patients were with nonaneurysmal intracerebral hemorrhage. Results: In 12 patients from 127 with subarachnoid hemorrhage were occurred onset seizures. 4 patients from 12 with subarachnoid hemorrhage died (28.5% of all deaths in the group of patients with subarachnoid hemorrhage (SAH)). In the group of patients with seizures 10 of them had aneurysm in anterior part of Willi's Circle. In 11 patients from 178 with nonaneurysmal intracerebral hemorrhage occurred onset seizures. Only one patient from 72 with medial localization of intracerebral hemorrhage had seizures. Conclusions: Prevalence of ASS after intracerebral hemorrhage reaches 7.5%, in the group of patients with SAH - 9.5%, in the group of patients with intracerebral nonaneurysmal hemorrhage - 6.25%. Initial seizures at the onset of subarachnoid hemorrhage is an unfavorable prognostic criteria and is associated with higher mortality. Localization of aneurysm in anterior part of Willi's Circle and lateral localisation of intracerebral hemorrhage are associated with a higher risk of the ASS development.


Non-Coding RNA in the Pathogenesis, Progression and Treatment of Hypertension.
Hypertension is a complex, multifactorial disease that involves the coexistence of multiple risk factors, environmental factors and physiological systems. The complexities extend to the treatment and management of hypertension, which are still the pursuit of many researchers. In the last two decades, various genes have emerged as possible biomarkers and have become the target for investigations of specialized drug design based on its risk factors and the primary cause. Owing to the growing technology of microarrays and next-generation sequencing, the non-protein-coding RNAs (ncRNAs) have increasingly gained attention, and their status of redundancy has flipped to importance in normal cellular processes, as well as in disease progression. The ncRNA molecules make up a significant portion of the human genome, and their role in diseases continues to be uncovered. Specifically, the cellular role of these ncRNAs has played a part in the pathogenesis of hypertension and its progression to heart failure. This review explores the function of the ncRNAs, their types and biology, the current update of their association with hypertension pathology and the potential new therapeutic regime for hypertension.


Single-image phase retrieval for hard X-ray grating interferometry.
A single-image method is proposed for quantitative phase retrieval in hard X-ray grating interferometry. This novel method assumes a quasi-homogeneous sample, with a constant ratio between the real and imaginary parts of its complex refractive index. The method is first theoretically derived and presented, and then validated by synchrotron radiation experiments. Compared with the phase-stepping method, the presented approach abandons grating scanning and multiple image acquisition, and is therefore advantageous in terms of its simplified acquisition procedure and reduced data-collection times, which are especially important for applications such as in vivo imaging and phase tomography. Moreover, the sample's phase image, instead of its first derivative, is directly retrieved. In particular, the stripe artifacts encountered in the integrated phase images are significantly suppressed. The improved quality of the retrieved phase images can be beneficial for image interpretation and subsequent processing. Owing to its requirement for a single image and its robustness against noise, the present method is expected to find use in potential investigations in diverse applications.


Evidence for a base-paired region of hepatitis B virus pregenome encapsidation signal which influences the patterns of precore mutations abolishing HBe protein expression.
In two natural HBe-minus hepatitis B virus mutants, expression of HBe protein was abrogated by a nonsense mutation at precore codon 28 and a frameshift mutation at codon 29, respectively. Both mutants contained an additional nucleotide substitution(s) which was found by transfection experiments to be required for efficient packaging of pregenomic RNA. The observed mutational profiles were consistent with the presence of a base-paired region of the pregenome encapsidation signal overlapping the HBe-coding sequence. Results obtained with artificial mutants with significant changes in the primary sequence suggested that base pairing is required but insufficient for efficient pregenome packaging. However, the predicted first four base pairs of the stem are dispensable.


Removal of silicone oil droplets adhering to the posterior surface of an intraocular lens (IOL).
We report a rare case of silicone oil droplets adhering to the posterior surface of an intraocular lens (IOL) after removal of silicone oil for a patient with retinal reattachment, who had a history of pseudophakic rhegmatogenous retinal detachment. A 45-year-old male with a history of cataract surgeries of both eyes developed pseudophakic retinal detachment in his left eye. He received surgeries of scleral buckle and standard 3-port pars plana vitrectomy with silicon oil tamponade. With retinal attachment for 7 months, he underwent removal of silicone oil in the left eye. However, a big silicone oil droplet was found on the posterior surface of the IOL with complaints of distorted micropsia and poor vision, a month later. Pars plana vitrectomy using a 20-gauge vitreous cutter, which was supposed to have a higher cleaning capability compared with a smaller size device, was performed to aspirate the main part of the big oil droplet. The residual dispersed smaller droplets at the center of the visual axis were swept peripherally using a 27-gauge bending tip cannula. Fortunately, the patient regained his vision of 20/20 without distortion and micropsia in his left eye. This was a rare case where silicone oil droplets were found adhering to the posterior surface of an IOL after removing silicone oil a month later. We used a 20-gauge vitrectomy system to remove large oil droplets and swept smaller ones off the visual axis to improve the vision and visual quality.


Cyclic voltammetric measurements of growth of Aspergillus terreus.
A detailed study using the cyclic voltammogram was done on the live cells of Aspergillus terreus. The peak current values were obtained for different days of growth and plotted against time. The response of cyclic voltammogram showed the phases of the growth of the fungus. The growth curve obtained matched well with the conventional methodology, which assesses the increase of dry weight of the organisms against time. The electrochemical method is more advantageous because it is easy to assess and consumes less time. Further the electrochemical method clearly shows the decline phase which is generally not very defined in the conventional method of assessment of the growth curve. It was confirmed by further experiments that the metabolites were responsible for the anodic peak and not the biomass. Further work is in progress in order to analyze the metabolite(s) that is/are responsible for the anodic peak.


[Geographical distribution of fluoride in the public water supply in the province of Tucumán, Argentina].
This work studied the geographical distribution of fluoride content in the public water supply in the province of Tucumán, Argentina. A total of 1,210 samples were collected in 190 localities of the 17 departments of the province during the 2008-2012 period. The analytical determination was performed using the SPADNS method and QGis 2.16 was used for processing the information. The fluoride content requirements in the studied localities were determined according to the Argentine Food Code. The results showed that 94% of population studied consumed water with fluoride concentrations below the recommended limits, 5% were exposed to fluoride concentrations above the required maximum limit and 1% consumed water at optimal fluoride concentrations. The maps showed a heterogeneous geographical distribution of fluorides, in which areas with deficit, excess and recommended values of fluorides can be differentiated; in some departments an inverse relationship between the density of the hydrological network and fluoride concentration can be observed. In the capital of the province, the average value found was 0.32 mg/l, presenting a homogeneous geographical distribution. The information obtained is indispensable for the proper management of fluoride, so as to improve public health through policy.


Cyclical Thinning of Black Phosphorus with High Spatial Resolution for Heterostructure Devices.
A high spatial resolution, cyclical thinning method for realizing black phosphorus (BP) heterostructures is reported. This process utilizes a cyclic technique involving BP surface oxidation and vacuum annealing to create BP flakes as thin as 1.6 nm. The process also utilizes a spatially patternable mask created by evaporating Al that oxidizes to form Al2O3, which stabilizes the unetched BP regions and enables the formation of lateral heterostructures with spatial resolution as small as 150 nm. This thinning/patterning technique has also been used to create the first-ever lateral heterostructure BP metal oxide semiconductor field-effect transistor (MOSFET), in which half of a BP flake was thinned in order to increase its band gap. This heterostructure MOSFET showed an ON/OFF current ratio improvement of 1000× compared to homojunction MOSFETs.


On the mechanism of central hypotensive action of clonidine.
The hypotensive effect of clonidine in anaesthetised (pentobarbitone) cat has been analysed with the help of pharmacological tools. Application of clonidine (0.1%) to the exposed ventral surface of medulla oblongata produced hypotension (28.6%) and bradycardia (18%). Similar application of glycine (5%) and GABA (10%) also lowered the blood pressure of cat by 20.3% and 29.3%, respectively. The hypotension as well as the bradycardia owing to clonidine were significantly (p less than 0.01) blocked by similar prior application of atropine methylnitrate (1%) and hemicholinium-3 (HC3, 1%), whereas HC3 pretreatment only insignificantly blocked the hypotension produced by glycine (p greater than 0.80) and GABA (p less than 0.70). Topical application of atropine (1%) also blocked (p less than 0.05) the hypotensive effect of clonidine. Intravenous administration of clonidine (50 microgram/kg) produced hypotension (34.6%) after an initial hypertensive response and bradycardia (38.8%). The hypotension was significantly (p less than 0.01) blocked by pretreatment of the cat with intracerebroventricular atropine (4 mg) or HC3 (0.5 mg). Topical application of atropine (1%) to the ventral surface of medulla also significantly (p less than 0.05) reduced the hypotension and bradycardia resulting from intravenous administration of clonidine. It is concluded that an intact cholinergic link in the brainstem is essential for the hypotensive effect of clonidine.


Assessment of DLPNO-MP2 Approximations in Double-Hybrid DFT.
The unfavorable scaling (N5) of the conventional second-order Møller-Plesset theory (MP2) typically prevents the application of double-hybrid (DH) density functionals to large systems with more than 100 atoms. A prominent approach to reduce the computational demand of electron correlation methods is the domain-based local pair natural orbital (DLPNO) approximation that is successfully used in the framework of DLPNO-CCSD(T). Its extension to MP2 [Pinski P.; Riplinger, C.; Valeev, E. F.; Neese, F. J. Chem. Phys. 2015, 143, 034108.] paved the way for DLPNO-based DH (DLPNO-DH) methods. In this work, we assess the accuracy of the DLPNO-DH approximation compared to conventional DHs on a large number of 7925 data points for thermochemistry and 239 data points for structural features, including main-group and transition-metal systems. It is shown that DLPNO-DH-DFT can be applied successfully to perform energy calculations and geometry optimizations for large molecules at a drastically reduced computational cost. Furthermore, PNO space extrapolation is shown to be applicable, similar to its DLPNO-CCSD(T) counterpart, to reduce the remaining error.


Religiousness as a Predictor of Suicide: An Analysis of 162 European Regions.
Research on religion as a protective factor has been marked by four recurrent limitations: (1) an overemphasis on the United States, a nation where religiosity is relatively high; (2) a neglect of highly secularized zones of the world, where religiousness may be too weak to affect suicide; (3) restriction of religiousness to religious affiliation, a construct which may miss capturing other dimensions of religiousness such as the importance of religion in one's life; and (4) an overwhelming use of the nation as a unit of analysis, which masks variation in religiousness within nations. The present article addresses these limitations by performing a cross-national test of the following hypothesis: The greater the strength of subjective religiousness, the lower the suicide rate, using small units of analysis for a secularized area of the world. All data refer to 162 regions within 22 European nations. Data were extracted from two large databases, EUROSTAT and the European Social Surveys (ESS Round 4), and merged using NUTS-2 (Nomenclature of Statistical Territorial Units) regions as the unit of analysis. Controls are incorporated for level of economic development, education, and measures of economic strain. The results of a multiple regression analysis demonstrated that controlling for the other constructs in the model, religiousness is associated with lower suicide rates, confirming the hypothesis. Even in secularized European nations, where there is a relatively weak moral community to reinforce religion, religiousness acts as a protective factor against suicide. Future work is needed to explore the relationship in other culture zones of the world.


Male factors in ART outcome prediction.
Paternal influences on reproduction are significant causing about half of the infertile couples to turn to assisted reproductive techniques. Due to the increasing proportion of infertile couples adopting to conceive by in vitro fertilisation (IVF), predicting outcomes is of ever increasing importance. Since pregnancy rates following IVF are still quite low, prognostic information is very helpful in clinical decisions. Although significant research has been done on the maternal influence, male factor infertility is relatively understudied. To date, potential predictors include: method of fertilisation, age, reactive oxygen species, sperm quality parameters and DNA fragmentation. Predictors under investigation which show promising signs, even though there is no clear cut consensus on the predictive value to date include: folate and homocysteine, anti müllerian hormone measurement, environmental factors, body mass index, smoking, male age, stress, some subsets of antisperm antibodies and epigenetic features.


Inhibition of hepatocellular carcinoma by metabolic normalization.
In two different mouse liver cancer models, we recently showed that a switch from oxidative phosphorylation (Oxphos) to glycolysis (the Warburg effect) is invariably accompanied by a marked decline in fatty acid oxidation (FAO) and a reciprocal increase in the activity of pyruvate dehydrogenase (PDH), which links glycolysis to the TCA cycle. We now show that short-term implementation of either medium-chain (MC) or long-chain (LC) high fat diets (HFDs) nearly doubled the survival of mice with c-Myc oncoprotein-driven hepatocellular carcinoma (HCC). Mechanistically, HFDs forced tumors to become more reliant on fatty acids as an energy source, thus normalizing both FAO and PDH activities. More generally, both MC- and LC-HFDs partially or completely normalized the expression of 682 tumor-dysregulated transcripts, a substantial fraction of which are involved in cell cycle control, proliferation and metabolism. That these same transcripts were responsive to HFDs in livers strongly suggested that the changes were the cause of tumor inhibition rather than its consequence. In seven different human cancer cohorts, patients with tumors containing high ratios of FAO-related:glycolysis-related transcripts had prolonged survival relative to those with low ratios. Furthermore, in 13 human cancer types, the expression patterns of transcripts encoding enzymes participating in FAO and/or cholesterol biosynthesis also correlated with significantly prolonged survival. Collectively, our results support the idea that the survival benefits of HFDs are due to a reversal of the Warburg effect and other tumor-associated metabolic and cell cycle abnormalities. They also suggest that short-term dietary manipulation, either alone or in combination with more traditional chemotherapeutic regimens, might be employed as a relatively non-toxic and cost-effective means of enhancing survival in certain cancer types.


Antenatal ultrasonic evaluation of acardiac monsters.
Acardiac monster represents a rare but serious complication of monozygotic twin pregnancy. Antenatal recognition is important because of accompanying obstetrical problems, including polyhydramnios, dystocia, and uterine rupture. While pathologic findings are varied, characteristic sonographic findings allow accurate prenatal diagnosis. Acardia must be distinguished from sacrococcygeal teratoma, omphalocele and macerated fetus.


Combination PROP: A Case Report of a Hybrid Flexible and Traditional Partial Removable Dental Prosthesis.
The need for partial removable dental prostheses (PRDP) is increasing as the over-65 partially edentulous population grows. The use of flexible materials in the fabrication of these prostheses has captured a large portion of the market once occupied by traditional cast metal PRDPs. While there are some clinical advantages to the use of flexible PRDPs, there are also disadvantages and contraindications that must be considered. This paper describes a clinical case in which a patient's dentition is restored with a hybrid partial removable dental prosthesis consisting of a traditional metal framework and flexible denture base and clasps. This design can result in achieving the benefits of each type of prosthesis in an effort to satisfy the needs of the patient.


Misunderstandings and controversies about the insulin-secreting properties of antidiabetic sulfonylureas.
After 60 years of use in the treatment of type 2 diabetes, hypoglycemic sulfonylureas remain a recommended option in current therapeutic charts. Their binding to sulfonylurea receptor-1, the regulatory subunit of ATP-sensitive potassium channels in the plasma membrane of pancreatic β-cells, leads to closure of the channels, membrane depolarization and influx of Ca2+ through voltage-gated calcium channels. The resulting increase in cytosolic Ca2+ triggers exocytosis of insulin granules. Sulfonylureas and glucose thus produce the same triggering signal but, unlike sulfonylureas, glucose does so via acceleration of β-cell metabolism. Glucose metabolism also produces amplifying signals that approximately double the secretory response to triggering Ca2+. One persistent misunderstanding about sulfonylureas is the alleged glucose-independence of their effects. It is correct that high concentrations of these drugs can induce insulin secretion in low glucose and cause hypoglycemic episodes in treated patients. Conversely, that untoward effect is erroneously considered as evidence that their therapeutic action is independent of glucose. Another evolving controversy about the action of sulfonylureas in β-cells is whether, like glucose, they also produce intracellular amplifying signals able to augment the efficacy of Ca2+ on exocytosis. The aims of this review are to dissipate the misunderstanding and discuss the controversy. Reasons why proposed amplifying effects of sulfonylureas are unlikely to be relevant for their action in vivo will be presented. Possible interactions of sulfonylureas and glucagon-like peptide-1 in β-cells will be discussed. Mechanisms whereby the ambient glucose concentration modulates the insulin-secreting action of therapeutic concentrations of sulfonylureas will be explained.


Multiparity, Brain Atrophy, and Cognitive Decline.
Multiparity - grand multiparity (i.e., five or more childbirths) in particular - has been reported to have an association with increased risk of Alzheimer's disease (AD) dementia or related cognitive decline in women. However, the pathological links underlying this relationship are still unknown. This study was conducted to examine the relationships of multiparity with cerebral amyloid-beta (Aβ) deposition, brain atrophy, and white matter hyperintensities (WMHs). In this study, total of 237 older women with 148 cognitively normal and 89 mild cognitive impairment from the Korean Brain Aging Study for Early Diagnosis and Prediction of Alzheimer's Disease (KBASE) were included. Participants underwent clinical and neuropsychological assessments in addition to 11C-labeled Pittsburgh Compound B positron emission tomography, and magnetic resonance imaging. The associations of parity with Aβ deposition, hippocampal volume, cortical volume, WMH volume and mini-mental status examination (MMSE) score were examined. Participants with grand multiparity showed significantly reduced adjusted hippocampal volume, spatial pattern of atrophy for recognition of AD volume and spatial pattern of atrophy for recognition of brain aging volume even after controlling for potential confounders. Furthermore, MMSE score was also significantly lower in this group. In contrast, grand multiparity did not show any association with global Aβ retention, Aβ positivity rate, or WMH volume, regardless of covariates. Our findings suggest that grand multiparity contributes to cognitive decline or increased dementia risk in older women by aggravating amyloid-independent hippocampal or cortical atrophy.


Effect of lentiviral shRNA of Nogo receptor on rat cortex neuron axon outgrowth.
Axon growth is crucial for injured neural tissue to recover; however it is difficult to achieve in general. Axon outgrowth is inhibited by the activation of the Nogo receptor (NgR) by one of three different ligands. The present study aimed to suppress the inhibitory effect of the three inhibitory proteins to facilitate axon outgrowth. A lentiviral vector, siNgR199 (that has the capacity to interfere with the gene of NgR expression), was constructed for suppressing the gene transcription of NgR. Rat cortex neurons and oligodendrocytes were prepared to observe the effect of siNgR199 on facilitating axon outgrowth. After transfection, the lentiviral siRNA of NgR remained in target neurons for almost two weeks whereas the conventional siRNA of NgR remained in neurons less than five days. Lentivirus-mediated delivery of exogenous small interfering RNA (siNgR199) targeting NgR significantly reduced the expression of this receptor and promoted axon outgrowth. In contrast, provision of naked siRNA targeting NgR (NgRsiRNA) showed less inhibitory effect on NgR protein expression and did not affect axon outgrowth. Lentiviral siRNA of NgR effectively suppresses the expression of NgR in cultured neurons that facilitates the axon outgrowth. The data implicate that lentiviral siRNA of NgR has therapeutic potential in facilitating the recovery of injured neural tissue.


Does Conversion Adversely Impact the Clinical Outcomes for Patients with Complicated Appendicitis?
Although the feasibility of laparoscopic appendectomy (LA) in complicated appendicitis (CA) has been demonstrated, LA is typically underused in CA due to its high conversion rate. However, little is known regarding the clinical course of conversion in CA. Between January 2005 and April 2012, 1699 patients older than 16 years underwent an appendectomy at our institution. Of these, 207 were confirmed to have CA, which was defined as operative findings of gangrenous or perforated appendix, with or without abscess formation. Patients were divided into the following three groups: open group (OG), laparoscopy group (LG), and converted group (CG). Perioperative outcomes were compared between the three groups. Thirty-eight patients underwent open surgery. Among the 169 patients for whom laparoscopic surgery was originally attempted, 20 (11.8%) were converted. Operation time was significantly longer and estimated blood loss was higher in the CG than in the other groups. Fewer overall complications were observed and the length of hospital stay (LOH) was shorter in the LG than in the OG and CG. However, no significant differences were observed between the OG and CG regarding the overall complication rate or LOH. Operation method was the only factor associated with postoperative morbidity in multivariate analysis. While completion by laparoscopy was associated with better outcomes than the other two procedures at all levels, open conversion did not increase the overall morbidity or LOH compared with open appendectomy. Laparoscopic approach could be a viable option even in the management of CA.


Benign adverse events following chiropractic care for neck pain are associated with worse short-term outcomes but not worse outcomes at three months.
A prospective cohort study on chiropractic patients with neck pain. To examine the association between self-reported benign adverse events after chiropractic care for neck pain and the outcome measures namely, perceived recovery, neck pain, and neck disability. Only 1 study has examined the association between adverse events and outcome in subjects with neck pain treated by chiropractors, which concluded that those receiving cervical spinal manipulation were more likely to report an adverse event compared to cervical mobilization, and those reporting an adverse event were less likely to have improved outcomes at all follow-up measurements. This was a prospective, multicenter, observational cohort study conducted in the private clinics of chiropractors throughout The Netherlands. All new, consecutive patients, between 18 and 65 years of age with neck pain of any duration, who had not undergone chiropractic or manual therapy in the prior 3 months, were eligible for recruitment. Self-reported questionnaires were administered at the first 3 visits and at 3 months. Multivariate multilevel logistic and linear regression analyses were used to evaluate the association between adverse events and recovery, neck pain, and neck disability. Outcomes were measured at the fourth visit and at 3 months. In total, 529 patients were recruited who fulfilled the inclusion criteria. The response rate at 3 months was 90%. At the fourth visit, subjects who reported a benign adverse event or "intense" adverse event after any of the first 3 visits were less likely to be recovered, and had slightly worse levels of neck pain. However, the differences in neck pain were too small to be clinically meaningful. Intense adverse events, on the other hand, were not only associated with more neck disability but also clinically relevant differences. At 3 months, adverse events were not associated with better or worse outcomes for any of the three outcome measures examined. Self-reported benign adverse events after chiropractic care for neck pain are associated with worse short-term outcomes. Intense adverse events are associated with more neck disability and clinically relevant differences at the short-term only. However, there is no association between adverse events and worse outcomes at 3 months.


Peripheral vascular malformations: imaging, treatment approaches, and therapeutic issues.
Peripheral vascular malformations are now described according to some accepted guidelines, and the principle of proper treatment (nidus ablation) is becoming clear. An appropriate classification scheme for vascular anomalies and definite indications for treatment are important to successful treatment overall. The findings from noninvasive imaging (ie, Doppler ultrasonography, computed tomography, or magnetic resonance imaging) in association with clinical findings are critical in establishing the diagnosis, evaluating the extent of the malformation, and planning appropriate treatment. Direct opacification of the nidus is useful, not only in making a correct diagnosis, but also in treating the lesion with sclerotherapy. In most cases, conservative treatment is recommended, but when a patient suffers clinical complications (eg, ulceration, pain, hemorrhage, cardiac failure, or unacceptable cosmetic consequences), the nidus sclerotherapy becomes mandatory. If the vascular malformation has blood outflow to a drainage vein during nidus opacification, flow control (with balloon occlusion, tourniquet, or embolization) is necessary to achieve sclerosant stasis within the nidus. Embolotherapy (with a coil, n-butyl cyanoacrylate, or small particles) should be used for subsequent multifaceted palliative therapy. A multi-disciplinary approach is needed in the treatment of a high-flow lesion, and a dedicated team approach is necessary for appropriate management in most cases.


Factors Associated With the Work Intention of Hospital Workers' in South Korea During the Early Stages of the COVID-19 Outbreak.
This study aims to explore factors associated with the work intention of hospital workers in the early stages of the coronavirus disease (COVID-19) outbreak in South Korea. An online self-reported survey was conducted in a tertiary hospital. Respondents were asked to report their perceived threat and perceived risk of infection, evaluation of hospital response, demographics, and job-related factors. Descriptive statistics and multivariate regression analyses were performed. A total of 441 employees participated in this study. Of respondents, 60% were willing to accept their work during an infectious disease outbreak and 12.5% were unwilling to accept the work. In addition, 8% of respondents reported that they had considered quitting their job, 54.4% reported that their job was dangerous, and 50.1% of respondents perceived the severity of COVID-19 as high. Perceived threat and effectiveness of hospital response were associated with hospital employees' intention to work. Hospital workers are at the front line of the COVID-19 outbreak. This study highlighted hospital workers' perceived effectiveness of organizational response to the outbreak, and perceived threats were found to be important factors for whether they continued to work or not in the fight against the outbreak.


Interstitial cells of Cajal in the murine gallbladder.
The presence of interstitial cells of Cajal (ICC) has been described throughout the digestive tract. In this study, we investigated whether ICC also exist in the gallbladder wall of CD1 mice. Immunofluorescent confocal microscopy was used to identify the morphology and distribution of ICC in either whole-mount flat preparations or enzyme-dispersed cells from the gallbladder of CD1 mice. Methylene blue staining and transmission electron microscopy were performed to detect the presence of ICC, and reverse transcription-polymerase chain reaction (RT-PCR) and Western blot were used to confirm the expressions of ICC-specific marker c-kit in the gallbladder tissues. The presence of c-kit-positive cells was demonstrated in both the gallbladder wall and the enzyme-dispersed cells. The ICC were distributed throughout the wall of the gallbladder and organized into a network. Under transmission electron microscopy, ICC were characterized by their well-developed perinuclear endoplasmic reticulum, abundant mitochondria, free ribosomes and intermediate filaments, and distinctive caveolae and lack of myosin filaments. The expressions of ICC-specific marker c-kit were also confirmed in the gallbladder tissue. The murine gallbladder wall contains ICC.


The role of MAGT1 in genetic syndromes.
Disturbances in magnesium homeostasis, often linked to altered expression and/or function of magnesium channels, have been implicated in a plethora of diseases. This review focuses on magnesium transporter 1 (MAGT1), as recently described changes in this gene have further extended our understanding of the role of magnesium in human health and disease. The identification of genetic changes and their functional consequences in patients with immunodeficiency revealed that magnesium and MAGT1 are key molecular players for T cell-mediated immune responses. This led to the description of XMEN (X-linked immunodeficiency with magnesium defect, Epstein Barr Virus infection, and neoplasia) syndrome, for which Mg2+ supplementation has been shown to be beneficial. Similarly, the identification of a copy-number variation (CNV) leading to dysfunctional MAGT1 in a family with atypical ATRX syndrome and skin abnormalities, suggested that the MAGT1 defect could be responsible for the cutaneous problems. On the other hand, recent genetic investigations question the previously proposed role for MAGT1 in intellectual disability. Understanding the molecular basis of the involvement of magnesium and its channels in human pathogenesis will improve opportunities for Mg2+ therapies in the clinic.


[Pregnancy presence in residual uterine horn].
The development of the 20-th week pregnancy in residual uterine horn was observed in 25 years old women in first pregnancy. The pregnant women was hospitalised in the Department of Obstetrics and Gynaecology Medical University in Lodz. The acute stomach pain was the only symptom of disease. Ultrasound examination shows the presence of 20-th alive, normal pregnancy and the presence of adjunctive uterus. The patient was operated due to the signs of hemorrhage. The rupture of the residual horn and the presence of the pregnancy in the abdominal cavity was found. The postoperative status was normal.


Long Electron Spin Coherence Times of Atomic Hydrogen Trapped in Silsesquioxane Cages.
Encapsulated atomic hydrogen in cube-shaped octasilsesquioxane (POSS) cages of the Si8O12R8 type (where R is an organic group) is one of the simplest alternative stable systems to paramagnetic endofullerenes that have been regarded as key elements of spin-based quantum technologies. Apart from common sources of decoherence such as nuclear spin and spectral diffusion, all H@POSS species studied so far suffer from additional shortening of T2 at low temperatures due to methyl group rotations. Here we eliminate this factor for the first time by studying the smallest methyl-free derivative with R = H, namely, H@T8H8. By applying dynamical decoupling methods, we measure electron spin coherence times T2 up to 280 ± 76 μs at T = 90 K and observe a linear dependence of the decoherence rate 1/T2 on trapped hydrogen concentrations, which we attribute to the spin dephasing mechanism of instantaneous diffusion and a nonuniform spatial distribution of encapsulated H atoms.


Photoinduced generation of 2,3-butanedione from riboflavin.
The volatile compound formation from riboflavin solution of a phosphate buffer (0.1 M, pH 6.5) under light for 15 h was studied by SPME-GC and SPME-GC/MS analysis. Only one major compound in the riboflavin solution was formed and increased as the light exposure time increased. The light-exposed riboflavin solution had a buttery odor. The compound of riboflavin solution under light was analyzed by gas chromatography and olfactometry. The major volatile compound eluted from the gas chromatograph had a buttery odor. The buttery odor compound was positively identified as 2,3-butanedione by a combination of gas chromatographic retention time, mass spectrum, and odor evaluation of authentic 2,3-butanedione. The addition of sodium azide, a singlet oxygen quencher, to riboflavin solution minimized the formation of the buttery odor compound. Singlet oxygen was involved in the formation of the buttery odor. The 2,3-butanedione was produced from the reaction between riboflavin and singlet oxygen. Singlet oxygen was formed from triplet oxygen by riboflavin photosensitization mechanism. This is the first reported oxidation reaction between riboflavin and singlet or triplet in food and biological systems.


Chloride ion independence of the Bohr effect in a mutant human hemoglobin beta (V1M+H2deleted).
A mutant human hemoglobin, beta (V1M+H2 delta), has been constructed. Analysis of the oxygen binding curves obtained at pH 8.3, where the Bohr effect is inoperative, indicates that this mutation results in an additional stabilization of the T-state conformation by 0.9 kcal/mol. The crystal structure of deoxy-beta (V1M+H2 delta) has been determined to 2.2-A resolution and compared with the deoxy structure of human hemoglobin at the same resolution. In human hemoglobin, a sulfate anion is anchored to the beta-chains by a complex network of H-bonds and electrostatic interactions with the amino terminus and Lys beta 82. In the mutant hemoglobin, the shortening of the amino-terminal region of the A helix by 1 residue results in the formation of an intrachain electrostatic interaction between the amino-terminal amino and Asp beta 79. This eliminates the sulfate binding site, and the sulfate is replaced by two water molecules. At variance with human hemoglobin, the alkaline Bohr effect for beta (V1M+H2 delta) is not sensitive to the presence of Cl-. This indicates that the sulfate binding site in human hemoglobin also serves as a Cl- binding site, and that the amino-terminal Val beta 1 is essential for oxygen-linked Cl- binding to hemoglobin as well as the Cl(-)-dependent Bohr effect. Analysis of the oxygen binding curves indicates that the oxygen-linked Cl- ions are released upon binding of the first oxygen molecule.


Inherited erythermalgia: limb pain from an S4 charge-neutral Na channelopathy.
Inherited erythermalgia (also termed "erythromelalgia"), characterized by episodic burning pain in the distal extremities evoked by warmth, has been causally linked with mutations of the Na(v)1.7 sodium channel, which is preferentially expressed in nociceptors. Thus far, Na(v)1.7 mutations within intracellular linker parts of the channel have been physiologically characterized. To investigate a Na(v)1.7 erythermalgia mutation that substitutes one uncharged amino acid for another within an S4 segment. Whole-cell patch-clamp analysis was used to study biophysical properties of wild-type and mutant (F216S) Na(v)1.7 channels in mammalian cells. The F216S mutation hyperpolarizes the voltage dependence of activation by 11 mV, accelerates activation, slows deactivation, and enhances the response to slow, small depolarizations. These results provide a physiologic basis for the linkage to erythermalgia of an Na(v)1.7 mutation that substitutes one uncharged residue for another within an S4 segment of the channel. These changes should increase excitability of nociceptive dorsal root ganglion neurons in which the mutant channel is present, thus contributing to pain.


Glucocorticoids cause mandibular bone fragility and suppress osteocyte perilacunar-canalicular remodeling.
Osteocytes support dynamic, cell-intrinsic resorption and deposition of bone matrix through a process called perilacunar/canalicular remodeling (PLR). In long bones, PLR depends on MMP13 and is tightly regulated by PTH, sclerostin, TGFβ, and glucocorticoids. However, PLR is regulated differently in the cochlea, suggesting a mechanism that is anatomically distinct. Unlike long bones, the mandible derives from neural crest and exhibits unique susceptibility to medication and radiation induced osteonecrosis. Therefore, we sought to determine if PLR in the mandible is suppressed by glucocorticoids, as it is in long bone. Hemimandibles were collected from mice subcutaneously implanted with prednisolone or vehicle containing pellets for 7, 21, or 55 days (n = 8/group) for radiographic and histological analyses. Within 21 days, micro-computed tomography revealed a glucocorticoid-dependent reduction in bone volume/total volume and trabecular thickness and a significant decrease in bone mineral density after 55 days. Within 7 days, glucocorticoids strongly and persistently repressed osteocytic expression of the key PLR enzyme MMP13 in both trabecular and cortical bone of the mandible. Cathepsin K expression was significantly reduced only after 55 days of glucocorticoid treatment, at which point histological analysis revealed a glucocorticoid-dependent reduction in the lacunocanalicular surface area. In addition to reducing bone mass and suppressing PLR, glucocorticoids also reduced the stiffness of mandibular bone in flexural tests. Thus, osteocyte PLR in the neural crest-derived mandible is susceptible to glucocorticoids, just as it is in the mesodermally-derived femur, highlighting the need to further study PLR as a target of drugs, and radiation in mandibular osteonecrosis.


Accessing restoration margins--a multidisciplinary approach.
The problem of paresthesia after dental procedures has existed for years. The literature presents several simple precautions dentists can take to avoid paresthesia caused by injection in nonsurgical cases. Although the risks of complications are still extremely small (1:785,000), there has been an increase recently in the number of cases reported. Though not all instances cause total paresthesia, these incidents do involve prolonged numbness, which is of concern to both the patient and practitioner.


Bandwidth improvement for germanium photodetector using wire bonding technology.
We demonstrate an ultrahigh speed germanium photodetector by introducing gold wires into the discrete ground electrodes with standard wire bonding technology. To engineer the parasitic parameter, the physical dimension of the gold wire used for wire bonding is specially designed with an inductance of about 450 pH. Simulation and experimental results show that the bandwidth of the photodetector can be effectively extended from less than 30 GHz to over 60 GHz.


An in vitro model of intestinal infection reveals a developmentally regulated transcriptome of Toxoplasma sporozoites and a NF-κB-like signature in infected host cells.
Toxoplasmosis is a zoonotic infection affecting approximately 30% of the world's human population. After sexual reproduction in the definitive feline host, Toxoplasma oocysts, each containing 8 sporozoites, are shed into the environment where they can go on to infect humans and other warm-blooded intermediate hosts. Here, we use an in vitro model to assess host transcriptomic changes that occur in the earliest stages of such infections. We show that infection of rat intestinal epithelial cells with mature sporozoites primarily results in higher expression of genes associated with Tumor Necrosis Factor alpha (TNFα) signaling via NF-κB. Furthermore, we find that, consistent with their biology, these mature, invaded sporozoites display a transcriptome intermediate between the previously reported day 10 oocysts and that of their tachyzoite counterparts. Thus, this study uncovers novel host and pathogen factors that may be critical for the establishment of a successful intracellular niche following sporozoite-initiated infection.


Myocardial infarction, cardiac anatomy and ventricular loading.
To see whether the hypertrophic response of the surviving myocardium after infarction leads to a complete reconstitution of ventricular mass, the left coronary artery was ligated in rats and the animals killed one month later. In infarcts affecting an average of 38% of the free wall of the left ventricle, the ratio of wall thickness to chamber radius remained essentially constant. On the other hand, the ratio decreased significantly in the presence of infarcts involving an average of 60% of the ventricular wall. In addition, inadequate growth adaptations were detected in both groups of infarcts with respect to myocyte volume and length and to capillary volume and length. These defects in the regeneration of myocardial structures were associated with elevations in diastolic wall stress which were more prominent in the larger infarct group. The limited growth reaction of the myocyte and vascular compartments may be implicated in the persistence of cardiac dysfunction and failure late after infarction.


[Impulse control disorders in Parkinson's disease].
Of the patients having Parkinson's disease, up to third encounters some degree of impulse control problems and one out of seven suffers from true impulse control disorders such as pathological gambling, hypersexuality, compulsive shopping and binge eating. Dopaminergic drugs used in anti-Parkinson therapy, especially dopamine agonists, increase the risk of these disorders. Impulse control disorders are associated with a relatively more active dopamine-mediated neurotransmission of the mesolimbic and mesocortical system. Discontinuation of dopamine agonist medication can thus be considered as the first line treatment of these disorders.


Strain differences in the prealbumin serum esterases of JAX rabbits.
The serum prealbumin esterase phenotypes were determined for 431 adult rabbits representing the majority of the breeding stock of the genetically defined JAX rabbits. Uniform phenotypes were observed in 8 of the 15 strains where adequate samples were obtained. In all of the phenotypes where uniformity was observed, the Est-2F gene was lacking. Also, all 431 rabbits lacked the Est-3D allele commonly observed in Europe. A sex difference was seen in the f' zone, which was darker in females than in males when the staining process was twice the normal length of time.


Myofascial Pain: Mechanisms to Management.
More than 100 million adults in the United States have chronic pain conditions, costing more than $500 billion annually in medical care and lost productivity. They are the most common reason for seeking health care, for disability and addiction, and the highest driver of health care costs. Myofascial pain is the most common condition causing chronic pain and can be diagnosed through identifying clinical characteristics and muscle palpation. Management is focused on integrating patient training in changing lifestyle risk factors with evidence-based treatment. Understanding the cause, diagnosis, and management of myopain conditions will help prevent the impact of chronic pain.


Platelet-activating factor acetylhydrolase and transacetylase activities in human aorta and mammary artery.
Platelet-activating factor (PAF), the potent phospholipid mediator of inflammation, is involved in atherosclerosis. Platelet-activating factor-acetylhydrolase (PAF-AH), the enzyme that inactivates PAF bioactivity, possesses both acetylhydrolase and transacetylase activities. In the present study, we measured acetylhydrolase and transacetylase activities in human atherogenic aorta and nonatherogenic mammary arteries. Immunohistochemistry analysis showed PAF-AH expression in the intima and the media of the aorta and in the media of mammary arteries. Acetylhydrolase and transacetylase activities were (mean +/- SE, n = 38): acetylhydrolase of aorta, 2.8 +/- 0.5 pmol/min/mg of tissue; transacetylase of aorta, 3.3 +/- 0.7 pmol/min/mg of tissue; acetylhydrolase of mammary artery, 1.4 +/- 0.3 pmol/min/mg of tissue (P < 0.004 as compared with acetylhydrolase of aorta); transacetylase of mammary artery, 0.8 +/- 0.2 pmol/min/mg of tissue (P < 0.03 as compared with acetylhydrolase of mammary artery). Lyso-PAF accumulation and an increase in PAF bioactivity were observed in the aorta of some patients. Reverse-phase HPLC and electrospray ionization mass spectrometry analysis revealed that 1-O-hexadecyl-2 acetyl-sn glycero-3-phosphocholine accounted for 60% of the PAF bioactivity and 1-O-hexadecyl-2-butanoyl-sn-glycerol-3-phosphocholine for 40% of the PAF bioactivity. The nonatherogenic properties of mammary arteries may in part be due to low PAF formation regulated by PAF-AH activity. In atherogenic aortas, an imbalance between PAF-AH and transacetylase activity, as well as lyso-PAF accumulation, may lead to unregulated PAF formation and to progression of atherosclerosis.


Surgical management of Marjolin ulcer with the anterolateral thigh free flap: a retrospective analysis.
MU is an aggressive entity, and extended surgical resection is the primary treatment. The defects from an MU extended resection need repair using free flaps, of which the ALT free flap is the most common. This study described the feasibility and application value of the ALT free flap in repairing defects after MU resection. Fifteen patients with MU had repairs with ALT free flaps and were treated by the authors' unit from June 2015 through June 2021. All defects were repaired with 1 ALT free flap except for 1 case that required 2 flaps. The average age of the 11 male and 4 female patients was 52 years (range, 36-71 years). Defect sizes ranged from 8 cm × 5.5 cm to 21 cm × 13.5 cm (mean size, 10.9 cm × 6.5 cm). Flap sizes ranged from 10 cm × 7.5 cm to 23 cm × 15.5 cm (mean size, 12.9 cm × 8.5 cm). All flaps survived completely except for 1 flap in which re-exploration was needed. The individualized ALT free flap may be selected based on the receiving area characteristics and has certain clinical application value in defect repair after MU resection.


Infant mortality and life expectancy in the Arab world.
This exercise illustrates the concept of spatial correlation, the categorizing of data for mapping, and the use of the scatter diagram. It employs the variables of infant mortality and life expectancy as applied to the Arab World, though any region can be used. The factor of oil exports is added to enhance discussion of the findings. An extra advantage of the exercise is the learning of names of countries in a relatively painless way. The exercise teaches both content and methods of interpretation, and it is adaptable to high school and college levels.


Exploring the universality of unusual conformations of the 17-membered Pt(d(G*pG*)) macrochelate ring. Dependence of conformer formation on a change in bidentate carrier ligand from an sp3 to an sp2 nitrogen donor.
Early studies on cis-PtA2(d(G*pG*)) (A2 = diamine or two amines, G = N7-platinated G) and cis-Pt(NH3)2(d(G*pG*)) models for the key cisplatin-DNA cross-link suggested that they exist exclusively or mainly as the HH1 conformer (HH1 = head-to-head G bases, with 1 denoting the normal direction of backbone propagation). These dynamic models are difficult to characterize. Employing carrier A2 ligands designed to slow dynamic interchange of conformers, we found two new conformers, DeltaHT (head-to-tail G* bases with a Delta chirality) and HH2 (with 2 denoting the backbone propagation direction opposite to normal). However, establishing that the non-HH1 conformations exist as an intrinsic feature of the 17-membered Pt(d(G*pG*)) ring requires exploring a range of different carrier ligands. Here we employ the planar aromatic sp(2) N-donor 5,5'-Me(2)bipy (5,5'-dimethyl-2,2'-bipyridine) ligand, having a shape very different from those of previously used nonplanar sp(3) N-donor bidentate carrier ligands, which often bear NH groups. The 5,5'-Me(2)bipy H6 and H6' protons project toward the d(G*pG*) moiety and hinder the dynamic motion of 5,5'-Me(2)bipyPt(d(G*pG*)). We again found HH1, HH2, and DeltaHT conformers with typical properties, supporting the conclusions that the new DeltaHT and HH2 conformers exist universally in dynamic cis-PtA2(d(G*pG*)) adducts, including cis-Pt(NH3)2(d(G*pG*)), and that the carrier ligand typically has little influence on the overall structure of the Pt(d(G*pG*)) macrocyclic ring of a given conformer. The sizes of the G H8 to H6/H6' NOE cross-peaks indicate little base canting in all 5,5'-Me(2)bipyPt(d(G*pG*)) conformers, suggesting that carrier-ligand NH groups favor the canting of one G base in the HH1 and HH2 conformers of typical cis-PtA2(d(G*pG*)) adducts.


[Death certificate and diagnosis of violent death].
Many crimes go by unpunished, be it due to the disappearance of the cadaver, or a skillful cover-up on the part of the perpetrator. Thus, the crime can be masked as an accident, a suicide, or even a natural death. In France, the writing of the death certificate confers to the doctor, an important role in their unravelling. This role rests solely on a systematic approach consisting of alerting all violent deaths, sudden deaths and suspicious deaths to the coroner's office. The coroner decides whether to hold a medico-legal autopsy according to the various facts carried to his attention.


Purified arginine permease of Candida albicans is functionally active in a reconstituted system.
We have for the first time purified arginine permease from a pathogenic yeast, Candida albicans, to homogeneity by affinity chromatography using L-arginine-linked agarose matrix as affinity column. The purified protein (PP) was of 66 kDa with no subunit structure. Two kinetically distinct binding affinities of PP were evident where high affinity binding (S1) revealed a dependence on acidic pH while pH did not have dramatic effect on low affinity (S2) binding. The specificity of L-arginine binding to PP with regard to other amino acids, structural analogues and inhibitors, was essentially similar to arginine transport observed in the intact cells of C. albicans (Rao et al., 1986). The purified arginine permease was reconstituted into proteoliposomes and its functionality was tested by imposing a valinomycin-induced membrane potential. All the characteristic features of L-arginine transport displayed by the reconstituted system were similar to those observed in intact cells. Thus homogeneous purified arginine permease was also functionally active.


E-cadherin re-expression shows in vivo evidence for mesenchymal to epithelial transition in clonal metastatic breast tumor cells.
Substantial experimental evidence has shown that dedifferentiation from an epithelial state to a mesenchymal-like state (EMT) drives tumor cell metastasis. This transition facilitates tumor cells to acquire motility and invasive features. Intriguingly, tumor cells at the metastatic site are primarily epithelial, and it is believed that they differentiate back to an epithelial state by a process called mesenchymal to epithelial transition (MET). However, there is little in vivo evidence to support the MET process. To investigate EMT and MET in vivo, we generated two epithelial (E) and two mesenchymal (M) primary clonal cell lines from a spontaneous mouse mammary tumor (Tg MMTV/neu). These cells were labeled with reporters (GFP and luciferase), and tracked in vivo during primary tumor growth and subsequent secondary metastasis. Once E cells were implanted into the mammary fat pad, E-cadherin expression progressively decreased and continued to decrease as the primary tumor enlarged over time. A greater percentage of E tumor cells expressed E-cadherin at the secondary metastatic site as compared to the corresponding primary tumor site. Collectively, these data provide direct in vivo evidence that epithelial tumor cells have metastatic potential, undergo EMT at the primary tumor site, and MET at the metastatic site.


Longitudinal Progression of Magnetic Resonance Imaging Markers and Cognition in Dutch-Type Hereditary Cerebral Amyloid Angiopathy.
Hemorrhagic and ischemic magnetic resonance imaging lesions as well as the more recently described decrease in vasomotor reactivity have been suggested as possible biomarkers for cerebral amyloid angiopathy (CAA). Analyses of these markers have been primarily cross-sectional during the symptomatic phase of the disease, with little data on their longitudinal progression, particularly in the presymptomatic phase of the disease when it may be most responsive to treatment. We used the unique opportunity provided by studying Dutch-type hereditary cerebral amyloid angiopathy (D-CAA) to determine longitudinal progression of CAA biomarkers during the presymptomatic as well as the symptomatic phase of the disease. In this longitudinal case-control study, magnetic resonance imaging markers and cognitive performance were assessed at baseline and after ≈4 years in 10 presymptomatic and 6 symptomatic D-CAA mutation carriers and 20 control subjects. These magnetic resonance imaging markers included hemorrhagic and ischemic manifestations, measurements of cerebral blood flow, and vasomotor reactivity to visual stimulation. In presymptomatic D-CAA mutations carriers, vasomotor reactivity showed a decline over time for blood-oxygen-level-dependent amplitude (P=0.011) and prolongation of time to peak (P<0.001). In contrast, no significant changes in hemorrhagic markers, ischemic markers, cerebral blood flow, and cognition were found. In symptomatic D-CAA mutation carriers, the number of intracerebral hemorrhages increased over the 4-year period (P=0.007). Our findings indicate that in the presymptomatic phase of D-CAA, cerebrovascular reactivity measured by the blood-oxygen-level-dependent amplitude and time to peak to visual stimulation progressively worsens and can thus be regarded as a disease progression marker. In the symptomatic phase, the most salient marker of progression appears to be recurrent intracerebral hemorrhage.


Self-Esteem, Social Phobia and Depression Status in Patients with Epilepsy.
The increased risk for psychiatric disorders in epilepsy can be related to a number of clinical, psychosocial and biological factors. Due to the unpredictability of seizures and the possibility that they may occur at any time and in any place, patients with epilepsy may develop social phobia and may have feelings of worthlessness and stigma. These factors decrease their psychosocial function, self-efficacy, and quality of life and even increase the suicide rate. Considering the above-mentioned scientific data, the present study was designed to investigate phobia, self-esteem and depression status in patients with epilepsy. One hundred thirty-two patients (aged 21-52 years) and age- and gender-matched control group of 61 subjects (aged 25-60 years) were included in this study. All patients in both groups were administered the Liebowitz Social Anxiety Scale (LSAS), Coopersmith Self-Esteem Inventory (CSEI), and the Beck Depression Inventory (BDI). The mean ages of the patient group and the healthy controls were 29.66±11.3 and 32.16±7.99, respectively. There was no statistical significance between the two groups in terms of age and sex (p>0.05). BDI, LSAS and CSEI scores in the patient group were statistically significantly different than in the control group (p<0.05). Our results showed that social phobia, lower self-esteem and depression are important comorbid conditions in epileptic patients. Psychiatric disorders are usually underrecognized and undertreated in patients with epilepsy. Therefore, it is very important to identify and treat the psychiatric comorbid conditions in epilepsy because of their significant burden on patients' quality of life.


Using joint activity schedules to promote peer engagement in preschoolers with autism.
We assessed the use of a joint activity schedule to increase peer engagement for preschoolers with autism. We taught 3 dyads of preschoolers with autism to follow joint activity schedules that cued both members of the pair to play a sequence of interactive games together. Results indicated that joint activity schedules increased peer engagement and the number of games completed for all dyads. Schedule following was maintained without additional prompting when activities were resequenced and when new games were introduced for 2 of the 3 dyads.