Dual antibacterial mechanisms of nisin Z against Gram-positive and Gram-negative bacteria.
Nisin, an amphipathic antibiotic peptide, is produced by a number of strains of Lactococcus lactis subsp. lactis. It has been employed as a food preservative as it has a high antibacterial activity with a relatively low toxicity for humans. Nisin is known to exert a high antibacterial activity against Gram-positive but not Gram-negative bacteria. However, purified nisin Z was found to show an antibacterial activity both against Gram-positive and Gram-negative bacteria. To clarify the mechanisms of activity, nisin Z and purified nisin Z were tested for their antibacterial activities in a high-salt environment. The activity of nisin Z against Staphylococcus aureus was stable even in the presence of NaCl at 100 mM, showing ca. 2log colony-forming unit (CFU) reduction. In contrast, the activity of nisin Z against Escherichia coli was highly sensitive to the same concentration of NaCl, and CFU reduction was not observed. Furthermore, purified nisin Z caused the permeabilisation both of S. aureus and E. coli cytoplasmic membranes. The permeabilisation of E. coli but not S. aureus cytoplasmic membranes was remarkably reduced in a high-salt environment. Moreover, vancomycin inhibited the nisin Z-induced permeabilisation of the S. aureus cytoplasmic membrane. These results suggest that nisin Z utilises two distinct mechanisms of antibacterial activity: a high-salt-sensitive mechanism for E. coli and a high-salt-insensitive mechanism for S. aureus.


The influence of the boat-to-chair conversion on the demetallation of the nickel(II) complex of an open-chain tetramine containing a piperazine fragment.
The nickel(II) complex with an open chain tetramine containing a piperazine fragment (1) displays an unusual resistance to demetallation in acidic solution and exhibits a lifetime of about five minutes in a solution 0.1 M in HClO4 and 7.0 M in NaClO4. Sluggishness with respect to the demetallation is ascribed to the occurrence of the boat-to-chair conformational conversion of the piperazine fragment, which implies the passage through the highly energetic half-boat transition state. The use of a high concentration of the inert electrolyte induces a 'salting out' effect on both thermodynamics (stability of metal complexes is enhanced) and kinetics (resistance to demetallation is increased).


Residual function in peripheral nerve stumps of amputees: implications for neural control of artificial limbs.
It is not known whether motor and sensory pathways associated with a missing or denervated limb remain functionally intact over periods of many months or years after amputation or chronic peripheral nerve transection injury. We examined the extent to which activity on chronically severed motor nerve fibers could be controlled by human amputees and whether distally referred tactile and proprioceptive sensations could be induced by stimulation of sensory axons in the nerve stumps. Amputees undergoing elective stump procedures were invited to participate in this study. Longitudinal intrafascicular electrodes were threaded percutaneously and implanted in severed nerves of human amputees. The electrodes were interfaced to an amplifier and stimulator system controlled by a laptop computer. Electrophysiologic tests were conducted for 2 consecutive days after recovery from the surgery. It was possible to record volitional motor nerve activity uniquely associated with missing limb movements. Electrical stimulation through the implanted electrodes elicited discrete, unitary, graded sensations of touch, joint movement, and position, referring to the missing limb. These findings indicate that both central and peripheral motor and somatosensory pathways retain significant residual connectivity and function for many years after limb amputation. This implies that peripheral nerve interfaces could be used to provide amputees with prosthetic limbs that have more natural feel and control than is possible with current myoelectric and body-powered control systems.


Advanced imaging and digitization of preserved heart specimens using virtual reality - A primer.
Preserved congenital heart specimens are an important component of training professionals working with children and adults with congenital heart disease. They are curated in few institutions worldwide and not freely accessible. This was a proof-of-concept project to explore the use of advanced cardiac imaging modalities (computed tomography [CT] and magnetic resonance imaging [MRI]) and virtual reality (VR) simulation to assess the feasibility and identify the best method of imaging curated cardiac pathology specimens. Seven specimens in glass jars with formalin, with varied anatomic lesions, from a curated collection were imaged using MRI and high-dose CT to compare the fidelity of models created via each modality. Three-dimensional (3D) models were created and loaded into a VR headset and viewed in virtual space. Two independent physicians performed a "virtual dissection" and scored the resultant models. The highest fidelity and tissue characterization of more delicate structures was achieved with T2 spoiled gradient-echo sequences on MRI (median score of 4 out of 5). CT (median score of 3), while excellent for external anatomy, lost some fidelity with delicate internal anatomy, even at high-radiation doses. No specimens were damaged. We believe that in vitro heart specimens can be easily scanned with high fidelity at a relatively low cost, without causing damage, using high-dose CT and MRI. The ability to "walk through" different chambers of the heart makes the understanding of anatomy easy and intuitive. VR and 3D printing are technologies that could be easily adapted to digitize preserved heart specimens, making it globally accessible for teaching and training purposes.


The regulation of corticosteroid receptors in response to chronic social defeat.
Our previous studies demonstrated that chronic social defeat (CSD) up-regulated expression of the serotonin transporter (SERT) and norepinephrine transporter (NET) in the brain, which was mediated by corticosteroid receptors. In the present study we first analyzed the alterations of corticosteroid receptors in different brain regions after the CSD paradigm. The results showed that CSD significantly reduced glucocorticoid receptor (GR) protein levels in the CA1 and dentate gyrus of the hippocampus, as well as in central and basolateral nuclei of the amygdala, which was accompanied by the translocation of GR from cytoplasm to nuclei. CSD also markedly reduced GR mRNA levels and MR immunoreactivity in the CA1, CA3 and dentate gyrus areas of the hippocampus. Conversely, CSD pronouncedly enhanced GR mRNA and protein levels in the dorsal raphe nucleus and locus coeruleus relative to the control. As an extension of our previous studies, in situ hybridization and immunohistochemical staining demonstrated that CSD regimen caused a notable increase of SERT mRNA levels in the dorsal raphe nucleus and increased SERT immunoreactivities in CA1 and CA3 of the hippocampus, as well as those in the basolateral nuclei of the amygdala. Likewise, CSD regimen resulted in an evident enhancement of NET immunoreactivity in the CA1 of the hippocampus and in the basolateral nuclei of the amygdala. Our current findings suggest that GR expressional alterations in response to CSD are complex and brain region-specific, which may correspond to their different functions in these regions.


Placebo and nocebo effects on itch: effects, mechanisms, and predictors.
Placebo and nocebo effects have been extensively studied in the field of pain and more recently also on itch. In accordance with placebo research on pain, expectancy learning via verbal suggestion or conditioning has shown to induce placebo and nocebo effects on itch, in which the combination of both procedures seems most promising. Moreover, itch can also be transferred 'contagiously' in which suggestion and social behavioural learning seem to play a role. With regard to predictors of placebo and nocebo responding on itch and contagious itch, preliminary evidence suggests a role for individual psychological characteristics and personality traits regarding negative outcome expectancies. Although findings on placebo and nocebo effects on itch seem comparable to pain, we have only just begun to understand the underlying mechanisms and predictors of placebo and nocebo effects on itch.


Tip-enhanced coherent anti-stokes Raman scattering for vibrational nanoimaging.
An electric field enhanced by a metallic nanoprobe has locally induced coherent anti-Stokes Raman scattering (CARS) of adenine molecules in a nanometric DNA network structure. Owing to the third-order nonlinearity, the excitation of the CARS polarization is extremely confined to the end of the tip apex, resulting in a spatial resolution far beyond the diffraction limit of light. Our tip-enhanced CARS microscope visualized the DNA network structure at a specific vibrational frequency (approximately 1337 cm(-1)) corresponding to the ring-breathing mode of diazole of adenine molecules.


Incidence of SARS-CoV-2 infection in health care workers from Northern Italy based on antibody status: immune protection from secondary infection- A retrospective observational case-controlled study.
The protection from SARS-CoV-2 infection induced by SARS-CoV-2 anti-S1 and anti-S2 IgG antibody positivity resulting from natural infection was evaluated. The frequency of SARS-CoV-2 infection (as determined by virus RNA detection) was evaluated in a group of 1,460 seropositive and a control group of 8,150 seronegative healthcare workers in three Centres of Northern Italy in the period June-November 2020. Neutralizing serum titers were analyzed in seropositive subjects with or without secondary SARS-CoV-2 infection. During the 6-month survey, 1.78% seropositive subjects developed secondary SARS-CoV-2 infection while 6.63% seronegative controls developed primary infection (odds ratio: 0.26; 95% confidence interval: 0.17-0.38). Secondary infection was associated with low or absent serum neutralizing titer (p<0.01) and was mildly symptomatic in 45.8% cases vs 71.4% symptomatic primary infections (odds ratio: 0.34; 95% confidence interval: 0.16-0.78). Immunity from natural infection appears protective from secondary infection; therefore, vaccination of seronegative subjects might be prioritized.


Recyclable magnetic superhydrophobic straw soot sponge for highly efficient oil/water separation.
A simple and low-cost route to fabricate durable superhydrophobic magnetic polyurethane sponge was obtained by immersing a polyurethane sponge in a colloidal suspension of straw soot and magnetic nanoparticles. The as prepared sponge was used for separation of oil/water mixture. XRD, FT-IR, VSM, SEM and contact angle measurement analysis were used for characterization the materials. The effects of different stabilizer or surfactants (cetyltrimethylammonium bromide (CTAB), sodium dodecyl sulfate (SDS) and polyethylene glycol 6000 (PEG 6000)) on the morphology and geometrical structure of magnetic nanoparticles were investigated. For increasing the hydrophobic property of the surface, the sponge was further modified using PDMS. Results indicated that this matter can promote interfacial interactions between the sponge surface and oil. The prepared sponge showed excellent superhydrophobicity with water contact angle as high as 154°. Experiments showed that the amount of the absorbed oil was about 30 times of sponges own weight, it has our 30 times recyclability and the advantage of magnetic separation.


Primary signet-ring cell carcinoma of the urinary bladder.
Primary signet-ring cell carcinoma is an uncommon malignancy arising in the urinary bladder. The authors report 12 cases collected at their institution. Median age for the ten men and two women was 58 years; the most frequent presentation was hematuria. In two of nine cases no mucosal lesion was cystoscopically visible. Eleven tumors were of nonurachal origin and one of urachal. At diagnosis, one tumor was stage B, two stage C, seven stage D, and two stages unknown. Nine of 12 patients were dead of disease (range, 1-16 months; median, 9 months), 1 alive with metastatic disease, 1 alive and well, and 1 dead of an unrelated cause. From a literature review, the authors accepted 35 cases that met their criteria and combined them with their 12 cases for statistical analysis. Prognosis was worse with a pure diffuse versus a mixed tumor (P = 0.004) and for nonurachal versus urachal origin (P = 0.005). The difference in five-year survival rates between stages B and D disease (P less than 0.05) was also statistically significant.


CdS-Based Catalysts Derived from TMeQ[6]/[CdxCly]n--Based Frameworks for Oxidation Benzylamine.
The anion-induced outer surface interaction of Q[n]s is an important driving force in the construction of Q[n]-based supramolecular frameworks. In this work, a symmetric tetramethyl-substituted cucurbit[6]uril (TMeQ[6]) is selected as the basic structural block. Using the anion-induced outer surface interaction of Q[n]s derived from [CdxCly]n- anions formed by Cd2+ cations in a HCl medium, four different TMeQ[6]-[CdxCly]n--based supramolecular frameworks are constructed. Three of the most common TMeQ[6]-[CdxCly]n--based supramolecular frameworks are selected for further vulcanization, and three different CdS/TMeQ[6]-based framework catalysts with different structures and properties are obtained. The catalytic activities of these three CdS/TMeQ[6]-based framework catalysts are investigated by the coupling photocatalytic reaction of aminobenzyl, and the results showed that the catalytic activities of the three catalysts are all higher than that of pure CdS. Therefore, this work establishes that it is possible to establish a method for synthesizing the Q[n]-based framework-supported catalysts by first synthesizing TMeQ[6]-[CdxCly]n--based supramolecular frameworks and then forming Q[n]-based framework supported catalysts by sulfurization or reduction.


Keeping It Organized: Multicompartment Constructs to Mimic Tissue Heterogeneity.
Tissue engineering aims at replicating tissues and organs to develop applications in vivo and in vitro. In vivo, by engineering artificial constructs using functional materials and cells to provide both physiological form and function. In vitro, by engineering three-dimensional (3D) models to support drug discovery and enable understanding of fundamental biology. 3D culture constructs mimic cell-cell and cell-matrix interactions and use biomaterials seeking to increase the resemblance of engineered tissues with its in vivo homologues. Native tissues, however, include complex architectures, with compartmentalized regions of different properties containing different types of cells that can be captured by multicompartment constructs. Recent advances in fabrication technologies, such as micropatterning, microfluidics or 3D bioprinting, have enabled compartmentalized structures with defined compositions and properties that are essential in creating 3D cell-laden multiphasic complex architectures. This review focuses on advances in engineered multicompartment constructs that mimic tissue heterogeneity. It includes multiphasic 3D implantable scaffolds and in vitro models, including systems that incorporate different regions emulating in vivo tissues, highlighting the emergence and relevance of 3D bioprinting in the future of biological research and medicine.


Distribution and diversity of glycocin biosynthesis gene clusters beyond Firmicutes.
Glycocins are the ribosomally synthesized glycosylated bacteriocins discovered and characterized in Firmicutes, only. These peptides have antimicrobial activity against several pathogenic bacteria, including Streptococcus pyogenes , methicillin-resistant Staphylococcus aureus and food-spoilage bacteria Listeria monocytogenes. Glycocins exhibit immunostimulatory properties and make a promising source of new antibiotics and food preservatives akin to Nisin. Biochemical studies of Sublancin, Glycocin F, Pallidocin and ASM1 prove that the nested disulfide-bonds are essential for their bioactivities. Using in silico approach of genome mining coupled with manual curation, here we identify 220 new putative glycocin biosynthesis gene clusters (PGBCs) spread across 153 bacterial species belonging to seven different bacterial phyla. Based on gene composition, we have grouped these PGBCs into five distinct conserved cluster Types I-V. All experimentally identified glycocins belong to Type I PGBCs. From protein sequence based phylograms, tanglegrams, global similarity heat-maps and cumulative mutual information analysis, it appears that glycocins may have originated from closely related bacteriocins, whereas recruitment of cognate glycosyltransferases (GTs) might be an independent event. Analysis further suggests that GTs may have coevolved with glycocins in cluster-specific manner to define distinctive donor specificities of GTs or to contribute to glycocin diversity across these clusters. We further identify 162 hitherto unreported PGBCs wherein the corresponding product glycocins have three or less than three cysteines. Secondary structure predictions suggest that these putative glycocins may not form di-nested disulfide-bonds. Therefore, production of such glycocins in heterologous host Escherichia coli is feasible and may provide novel antimicrobial spectrum and or mechanism of action for varied applications.


Topographical changes along the neural fold associated with neurulation in the hamster and mouse.
The topography of the ectoderm was examined by scanning electron microscopy during neurulation in hamster and mouse embryos. Stages from the appearance of the neural folds to closure of the posterior neuropore were studied. Progressive development of a zone of altered cellular morphology was observed along the crests of the neural folds. This zone evolved from an abrupt transition between surface and neural regions of the ectoderm to a narrow band of flattened cells which exhibited numerous membranous "ruffles" in the mouse, or blebs and presumably degenerating cells in the hamster, immediately prior to contact between the folds. These alterations were more prominent along the anterior than the posterior portions of the folds. Contact of the folds occurred first between the flattened cells with subsequent union of the surface cells. Stages of neural crest cell formation was observed subjacent to the zone of alterations in histological sections. It is suggested that the observed surface alterations may reflect changes in the membrane properties of the altered cells which are correlated with both neural crest formation and initial adhesion between the folds.


Stability/activity features of the main enzyme components of rohapect 10L.
Rohapect 10L is an enzyme cocktail commercialized for juice clarification. Here, we characterized the activity and stability of five enzymatic activities present in this cocktail: total pectinase (PE), polygalacturonase (PG), pectin lyase (PL), pectin methyl esterase (PME), and total cellulase (CE) activities. All these enzyme activities have the maximum activity and stability at pH 4, conditions near those found in most fruit juices. However, if the enzymes need to be handled under different conditions (e.g., to immobilize them), their stability becomes extremely low in some cases, just at pH values slightly higher than the optimal one. For example, at pH 10 only CE was reasonably stable at 25°C, while many other enzyme activities were rapidly almost inactivated, even at 4°C. For these cases, different additives were evaluated, and we found that polyethylene glycol was positive or very positive for all enzyme stabilities, allowing keeping reasonable activities after several hours at pH 10 and 25°C. Another additive, that is, dextran, has a small positive effect for PE, PG, and CE, and a very positive effect for PL, albeit significantly destabilizing PME. Thus, the handling and use of this extract requires some care when is performed out of optimal conditions.


Staining pattern of acid non-specific esterase in lymphocytes, plasmocytes, monocytes, and leukemic cells.
The pattern of staining for ANAE in lymphocytes, plasmocytes, monocytes and leukemic cells has been studied and the effect of NaF and E 600 on this staining reaction has been investigated. In lymphocytes the transition occasionally occurring between a dot-like (T type) and granular positivity may cause difficulties when using this reaction as a marker of resting T lymphocytes. In plasmocytes as well as in myeloma cells a number of coarse granules was present in most cells and in some cases even large blocks of the reaction product occurred. NaF and E 600 inhibits already in lower concentration (2 mM and 10 micronM respectively) the strong diffuse reaction in monocytes, the effect on other cells being negligible. Using higher concentrations the inhibitory effect of NaF (20 mM) was more pronounced in plasmocytes in comparison with T lymphocytes which on the other hand, were, in general more sensitive to E 600 (10 mM). Partially diffuse or dense granular pattern of ANAE was found in a number of hairy cells. "Lymphoblastic" leukemias in children most frequently displayed negative or fine granular reaction in a varying number of blasts and similar findings were noted in the majority of cytochemically undifferentiated leukemias in adults. In some of them, however, a similar pattern of ANAE as in myeloblastic leukemias with dispersed or partial diffuse positivity was observed. The significance of these findings is briefly discussed.


Risk Scores After Acute Coronary Syndrome.
Acute coronary syndrome (ACS) is associated with both short- and long-term unfavorable prognosis. Therefore, medical societies developed risk scores for predicting mortality and assessing decision-making regarding early aggressive treatment in patients presenting an ACS. The Thrombolysis In Myocardial Infarction and the Global Registry of Acute Coronary Events risk scores are the most extensively investigated scores for ACS. Clinical judgment is also important. Significant differences in aggressive treatment of ACS still exist with respect to gender, age, and ethnicity. The reasons for these discrepancies need to be further elucidated in future studies. Therefore, generalizability of stratifications and risk scores in certain populations should be performed with caution.


Scuba diving and pregnancy: can we determine safe limits?
No human data, investigating the effects on the fetus of diving, have been published since 1989. We investigated any potential link between diving while pregnant and fetal abnormalities by evaluating field data from retrospective study No.1 (1990/2) and prospective study No.2 (1996/2000). Some 129 women reported 157 pregnancies over 1,465 dives. Latest gestational age reported while diving was 35 weeks. One respondent reported 92 dives during a single pregnancy, with two dives to 65 m in the 1st trimester. In study No.2 >90% of women ceased diving in the 1st trimester, compared with 65% in the earlier study. Overall, the women did not conduct enough dives per pregnancy, therefore no significant correlation between diving and fetal abnormalities could be established. These data indicate women are increasingly observing the diving industry recommendation and refraining from diving while pregnant. Field studies are not likely to be useful, or the way forward, for future diving and pregnancy research. Differences in placental circulation between humans and other animals limit the applicability of animal research for pregnancy and diving studies. It is unlikely that the effect of scuba diving on the unborn human fetus will be established.


Advanced bioinformatics methods for practical applications in proteomics.
Mass spectrometry (MS)-based proteomics has undergone rapid advancements in recent years, creating challenging problems for bioinformatics. We focus on four aspects where bioinformatics plays a crucial role (and proteomics is needed for clinical application): peptide-spectra matching (PSM) based on the new data-independent acquisition (DIA) paradigm, resolving missing proteins (MPs), dealing with biological and technical heterogeneity in data and statistical feature selection (SFS). DIA is a brute-force strategy that provides greater width and depth but, because it indiscriminately captures spectra such that signal from multiple peptides is mixed, getting good PSMs is difficult. We consider two strategies: simplification of DIA spectra to pseudo-data-dependent acquisition spectra or, alternatively, brute-force search of each DIA spectra against known reference libraries. The MP problem arises when proteins are never (or inconsistently) detected by MS. When observed in at least one sample, imputation methods can be used to guess the approximate protein expression level. If never observed at all, network/protein complex-based contextualization provides an independent prediction platform. Data heterogeneity is a difficult problem with two dimensions: technical (batch effects), which should be removed, and biological (including demography and disease subpopulations), which should be retained. Simple normalization is seldom sufficient, while batch effect-correction algorithms may create errors. Batch effect-resistant normalization methods are a viable alternative. Finally, SFS is vital for practical applications. While many methods exist, there is no best method, and both upstream (e.g. normalization) and downstream processing (e.g. multiple-testing correction) are performance confounders. We also discuss signal detection when class effects are weak.


Anesthetic-membrane interaction: a 2H nuclear magnetic resonance study of the binding of specifically deuterated tetracaine and procaine to phosphatidylcholine.
The binding of the local anesthetics tetracaine and procaine with multilamellar dispersions of egg phosphatidylcholine has been studied by 2H nuclear magnetic resonance (NMR). The 2H-NMR line shapes of specifically deuterated local anesthetics are found to be very dependent on the attainment of a true equilibrium. The equilibrium could be most properly reached by the use of repeated freeze-thaw-vortex cycles. The data for tetracaine are consistent with the three-site exchange model proposed earlier. Tetracaine is in slow exchange between a strongly bound site and a weakly bound site and in fast exchange between the weakly bound site and free in solution. The slow exchange rate is estimated, from temperature and dilution studies, to be approximately 1.5 X 10(3) S-1 at pH 5.5 and slightly faster at pH 9.5. Comparisons of the quadrupole splitting with those seen for our earlier work in egg phosphatidylethanolamine suggest that the location of the strongly bound site in phosphatidylcholine is dependent on the anesthetic charge. This is in contrast to egg phosphatidylethanolamine, where molecular shapes appear to be the determining factor for the location of the anesthetic. Procaine bound very weakly to the model membranes, to yield only a broad resonance and no quadrupole splitting. It appears that procaine, unlike tetracaine, is not bound by the ordered acyl chains.


Thailand's response to the HIV epidemic: yesterday, today, and tomorrow.
Thailand's comprehensive national response to the HIV/AIDS epidemic has been extensively documented since the beginning of epidemic. Substantial progress in the fight against HIV/AIDS has been made because awareness of the problem was raised. Top-level political commitment and multisectoral strategies mobilized funds and human resources to implement the control program at all levels. Behavioral change resulting in increased condom use in brothels on a national scale rose from virtually nil to more than 95%. This was accompanied by a 90% reduction of the sexually transmitted disease rate. In parallel, the rate of new HIV infections dropped by 80%. Despite these achievements, there remains an urgent need to continue efforts to ensure universal and unfailing condom use. Further, Thailand needs to establish pragmatic innovative approaches to reduce transmission, especially among injection drug users, women, and youth, as well as to develop effective strategies for implementation of antiretroviral treatment. Further strategies also need to consider the changing cultural, social, and economic characteristics of the Thai populations.


Monoclonal antibodies to barley alpha-amylase I: production, characterization, and application to a specific immunoassay.
Monoclonal antibodies (MAbs) to barley alpha-amylase I have been produced, purified and characterized. Six are specific for the alpha-amylase I isoform, while one also reacts with alpha-amylase II. All but one recognize the antigen in solution. Topology of the MAbs was investigated by additivity in ELISA, which led us to subdivide them into four groups. An immunoassay was developed using one of these MAbs, to measure alpha-amylase I activity in an extract containing both isoforms.


Current aspects of renal dysfunction after liver transplantation.
The development of chronic kidney disease (CKD) after liver transplantation (LT) exerts a severe effect on the survival of patients. The widespread adoption of the model for end-stage liver disease score strongly impacted CKD incidence after the procedure, as several patients are transplanted with previously deteriorated renal function. Due to its multifactorial nature, encompassing pre-transplantation conditions, perioperative events, and nephrotoxic immunosuppressor therapies, the accurate identification of patients under risk of renal disease, and the implementation of preventive approaches, are extremely important. Methods for the evaluation of renal function in this setting range from formulas that estimate the glomerular filtration rate, to non-invasive markers, although no option has yet proved efficient in early detection of kidney injury. Considering the nephrotoxicity of calcineurin inhibitors (CNI) as a factor of utmost importance after LT, early nephroprotective strategies are highly recommended. They are based mainly on delaying the application of CNI during the immediate postoperative-period, reducing their dosage, and associating them with other less nephrotoxic drugs, such as mycophenolate mofetil and everolimus. This review provides a critical assessment of the causes of renal dysfunction after LT, the methods of its evaluation, and the interventions aimed at preserving renal function early and belatedly after LT.


Sex-related illness perception and self-management of a Thai type 2 diabetes population: a cross-sectional descriptive design.
Increased knowledge concerning the differences in the illness perception and self-management among sexes is needed for planning proper support programs for patients with diabetes. The aim of this study was to investigate the illness perception and self-management among Thai women and Thai men with type 2 diabetes and to investigate the psychometric properties of the translated instruments used. In a suburban province of Thailand, 220 women and men with type 2 diabetes participated in a cross-sectional descriptive study. The participants were selected using a multistage sampling method. Data were collected through structured interviews and were analyzed using group comparisons, and psychometric properties were tested. Women and men with type 2 diabetes demonstrated very similar experiences regarding their illness perception and no differences in self-management. Women perceived more negative consequences of the disease and more fluctuation in the symptoms than men, whereas men felt more confident about the treatment effectiveness than women. Furthermore, the translated instruments used in this study showed acceptable validity and reliability. The Thai sociocultural context may influence people's perceptions and affect the self-care activities of Thai individuals, both women and men, with type 2 diabetes, causing differences from those found in the Western environment. Intervention programs that aim to improve the effectiveness of the self-management of Thai people with diabetes might consider a holistic and sex-related approach as well as incorporating Buddhist beliefs.


Mechanism-based inhibitors of serine proteinases based on the Gabriel-Colman rearrangement.
Neutrophil-derived mediators such as, for example, the serine proteinase elastase, cathepsin G and proteinase 3, play a critical role in inflammatory lung disease. This report describes the design, synthesis and in vitro inhibitory activity of some novel mechanism-based inhibitors of human leukocyte elastase and cathepsin G. The design of the inhibitors is based on the Gabriel-Colman rearrangement. The behavior of the synthesized compounds toward elastase and cathepsin G with respect to inhibitory prowess, mode of interaction, specificity, etc., has been found to be dependent on the recognition and reactivity elements present in each inhibitor.


R2TP/Prefoldin-like component RUVBL1/RUVBL2 directly interacts with ZNHIT2 to regulate assembly of U5 small nuclear ribonucleoprotein.
The R2TP/Prefoldin-like (R2TP/PFDL) complex has emerged as a cochaperone complex involved in the assembly of a number of critical protein complexes including snoRNPs, nuclear RNA polymerases and PIKK-containing complexes. Here we report on the use of multiple target affinity purification coupled to mass spectrometry to identify two additional complexes that interact with R2TP/PFDL: the TSC1-TSC2 complex and the U5 small nuclear ribonucleoprotein (snRNP). The interaction between R2TP/PFDL and the U5 snRNP is mostly mediated by the previously uncharacterized factor ZNHIT2. A more general function for the zinc-finger HIT domain in binding RUVBL2 is exposed. Disruption of ZNHIT2 and RUVBL2 expression impacts the protein composition of the U5 snRNP suggesting a function for these proteins in promoting the assembly of the ribonucleoprotein. A possible implication of R2TP/PFDL as a major effector of stress-, energy- and nutrient-sensing pathways that regulate anabolic processes through the regulation of its chaperoning activity is discussed.


A practical and scalable manufacturing process for an anti-fungal agent, Nikkomycin Z.
A scalable and reliable manufacturing process for Nikkomycin Z HCl on a 170 g scale has been developed and optimized. The process is characterized by a 2.3 g/L fermentation yield, 79% purification yield, and >98% relative purity of the final product. This method is suitable for further scale up and cGMP production. The Streptomyces tendae ΔNikQ strain developed during the course of this study is superior to any previously reported strain in terms of higher yield and purity of Nikkomycin Z.


The effectiveness of an antimicrobial stewardship program in an Australian rural hospital.
The aim of this study was to investigate the type, indication and duration of restricted antibiotics prescribed to inpatients who had undergone antimicrobial stewardship (AMS) review by the infectious diseases specialist and to assess the effectiveness of the AMS program in a rural hospital. This was an observational retrospective study. The study was conducted at a rural referral hospital in NSW. Inpatients from the medical, surgical and intensive care units were included. The main outcome measure was the type, indication and average duration of restricted antibiotics that were reviewed in the AMS rounds. The rate of adherence to AMS advice and the rate of step-down of antibiotics after AMS advice were other outcome measures. Data on participant characteristics were also collected. The most commonly prescribed restricted antibiotic in medicine and surgery was amoxicillin-clavulanic acid (28%), followed by ceftriaxone (15%) and piperacillin-tazobactam (10%), with the most common indication being intra-abdominal infection (37%). In intensive care, ceftriaxone (16.7%) and piperacillin-tazobactam (16.7%) were most prescribed, and the most common indication was community-acquired pneumonia (24.5%). The adherence rate to AMS advice was 86% in medicine and surgery and 83% in intensive care. AMS rounds managed to cease or step down antibiotics 60% of the time. The AMS program in a rural hospital was effective with an overall AMS advice adherence rate of 84.5% which measures well against tertiary-level centres. Continued AMS and advocacy of such programs in rural regions are fundamental to optimising patient outcomes in the rural community.


A novel mutation in the SURF1 gene in a child with Leigh disease, peripheral neuropathy, and cytochrome-c oxidase deficiency.
We report a 16-month-old boy with psychomotor regression, muscle hypotonia, peripheral neuropathy, and lactic acidosis. Brain magnetic resonance imaging showed a bilateral abnormal signal in the substantia nigra and in the subthalamic nucleus, suggestive of Leigh disease. Histochemical analysis of skeletal muscle showed decreased cytochrome-c oxidase activity. Biochemical analysis of respiratory chain enzymes in muscle homogenate and in cultured fibroblasts showed isolated cytochrome-c oxidase deficiency. Western blot analysis in fibroblasts showed the absence of Surf1 protein. Genetic analysis of the SURF1 gene revealed that the patient was compound heterozygous for a previously reported mutation at the splice-junction site of intron 3 (240 + 1G > T), and for a novel 4-bp deletion in exon 6 (531_534delAAAT). Our data further enlarge the spectrum of mutations in SURF1 gene in patients with Leigh disease and cytochrome-c oxidase deficiency, contributing to better characterization of the clinical and neuroradiologic features of this group of patients for genotype-phenotype correlations.


Mitochondria are linked to calcium stores in striated muscle by developmentally regulated tethering structures.
Bi-directional calcium (Ca(2+)) signaling between mitochondria and intracellular stores (endoplasmic/sarcoplasmic reticulum) underlies important cellular functions, including oxidative ATP production. In striated muscle, this coupling is achieved by mitochondria being located adjacent to Ca(2+) stores (sarcoplasmic reticulum [SR]) and in proximity of release sites (Ca(2+) release units [CRUs]). However, limited information is available with regard to the mechanisms of mitochondrial-SR coupling. Using electron microscopy and electron tomography, we identified small bridges, or tethers, that link the outer mitochondrial membrane to the intracellular Ca(2+) stores of muscle. This association is sufficiently strong that treatment with hypotonic solution results in stretching of the SR membrane in correspondence of tethers. We also show that the association of mitochondria to the SR is 1) developmentally regulated, 2) involves a progressive shift from a longitudinal clustering at birth to a specific CRU-coupled transversal orientation in adult, and 3) results in a change in the mitochondrial polarization state, as shown by confocal imaging after JC1 staining. Our results suggest that tethers 1) establish and maintain SR-mitochondrial association during postnatal maturation and in adult muscle and 2) likely provide a structural framework for bi-directional signaling between the two organelles in striated muscle.


Management of hydrocephalus associated with autoimmune diseases: a series of 19 cases.
To analyze the diagnosis and treatment of hydrocephalus associated with autoimmune diseases and to explore the possible mechanism of hydrocephalus in these patients. A retrospective case series study was conducted at Peking Union Medical College Hospital, Beijing, China. Files were retrieved from the hospital archives by screening records from Jan 1990 to Jan 2016. Medical records were screened for data regarding (1) the number of patients diagnosed with hydrocephalus associated with autoimmune diseases, (2) the clinical manifestation of hydrocephalus associated with autoimmune disease, and (3) the outcomes of these patients treated with medication or ventriculoperitoneal shunt (VPS). A total of 19 of 19,643 hospitalized autoimmune diseases patients were found to have hydrocephalus. Seven of the 19 patients had systemic lupus erythematosus (SLE), 3 patients had Sjögren's syndrome, 2 patients had rheumatoid arthritis (RA), 1 patient had connective tissue disease, 1 patient had juvenile idiopathic arthritis (JIA), 1 patient had Guillain-Barre syndrome (GBS), 1 patient had systemic sclerosis, 1 patient had Crohn's disease, 1 patient had relapsing polychondritis (RPC), and 1 patient had autoinflammatory disease (AID). Of the 19 patients, 13 received medication treatment, and the most commonly used drugs were corticosteroids and mannitol. A total of 6 patients received both medication therapy and VPS treatment with a programable valve. After average follow-up lengths of 11 months for patients who received VPS and 8.2 for patients who received medical treatment, the clinical symptoms of patients treated by VPS or medication were improved (83% (5/6) vs. 15.4% (2/13), respectively), patients were in stable condition (17% (1/6) vs. 30.8% (4/13), respectively), and mortality decreased (0% vs. 53.8% (7/13), respectively). VPS along with corticosteroids and immunosuppressants represents an effective treatment approach for patients who suffer from hydrocephalus associated with autoimmune diseases.


The expression and mechanism of Sirt1 and AMPK in nonsmall cell lung cancer.
To investigate the expression of sirtuin type 1 (Sirt1) and adenosine 5'-monophosphate (AMP)-activated protein kinase (AMPK) in non-small cell lung cancer (NSCLC), and to explore the mechanism of their functions in NSCLC. Cancer tissues (NSCLC group) and the adjacent normal healthy tissues (control group) of 50 patients with NSCLC were selected, and H&E staining was performed to identify the histopathological differences. Reverse transcription polymerase chain reaction (RT-PCR), immunofluorescence staining and Western blot were performed to detect the expression of Sirt1 and AMPK in tissues of NSCLC group and control group. SPSS17.0 statistical software was used to analyze the differences in the expression of Sirt1 and AMPK between control group and NSCLC group. Significant differences in histopathological structure were found between NSCLC and control group by H&E staining. Compared with control group, cell structure in NSCLC group was destroyed and condensed nuclei were observed, indicating the lung injury. Results of RT-PCR, immunofluorescence staining and Western blot showed that the expression levels of Sirt1 and AMPK were significantly lower in the NSCLC group than in the control group at both mRNA and protein levels. Results of variance analysis showed significant differences in the expression levels of Sirt1 and AMPK between control group and NSCLC group (p<0.01). The abnormal expression of Sirt1 and AMPK was closely related to the occurrence and development of NSCLC.


[Modern differentiation possibilities of angiocardiography in childhood].
1. Angiocardiography plays an irreplaceable method of investigation in the diagnosis of cardiac diseases in infancy and childhood. In many cases it is the "crown" of the diagnosis. 2. Cine-angiocardiography is indispensable in paediatric cardiology. In infancy, in rapid heart rates and in complicated malformations of the heart, only a movie film (35 mm) can register completely all the anatomic and haemodynamic details. 3. In certain cases the serial angiocardiography is also necessary in childhood. Today two methods of radiography can be made use of: the direct recording by means of rapid film changers on full size X-ray films and the indirect method on 70- or 100-mm size films. 4. According to our experience, the serial angiocardiography recordings on 70-mm size films have more advantages than the usual full size films (35 x 35 cm). In the interpretation of the 70-mm-size films there is no loss of information, and the radiators dose is 1/10 lower than in AOT-size.


Measurement and correction of lateral distortion in a Fizeau interferometer based on the self-calibration technique.
The lateral distortion of a surface measuring Fizeau interferometer may cause distorted image features in the lateral direction, as well as the surface form error in the axial direction (which is a source of the retrace error). Traditional method for lateral distortion measurement requires a high-accuracy calibration plate featuring a grid pattern. Such a calibration plate is not always available, especially when the required accuracy of the grid pattern comes to the order of sub-micrometer or even nanometer level. To remove the dependence on the plate accuracy, we propose a self-calibration method for the measurement and correction of lateral distortion in Fizeau interferometer. The self-calibration technique may separate the lateral distortion and the geometric error of the calibration plate. This method is verified using a 108-mm-aperture Fizeau interferometer. The experiments show that the form measurement error of a surface tilted at approximately 5° and 16° can be reduced from 92 nm to 43 nm and from 251 nm to 144 nm (peak-to-valley value), respectively, after the distortion correction.


Using taphonomy to infer differences in soft tissues between taxa: an example using basal and derived forms of Solnhofen pterosaurs.
In fossilised vertebrates, the presence of soft tissues is the most obvious way to determine aspects of anatomy and functional morphology; however, occurrences are rare and other lines of evidence must be sought to indicate its extent and strength. For example, pterosaurs possessed a large wing membrane that enabled powered flight but other tissues are not widely preserved. A semi-quantitative analysis comparing skeletal articulation and completeness of the pterodactyloid Pterodactylus and non-pterodactyloid pterosaur Rhamphorhynchus from Solnhofen-type deposits implies there were anatomical differences between soft-tissue structure and attachments articulating skeletal joints of each. Typically, skeletons of Pterodactylus disarticulate to a greater extent than those of Rhamphorhynchus, which in turn suggests decay progressed to more advanced states in the former. However, this generalisation masks a mosaic of differences between different body parts, for example Rhamphorhynchus tends to lose the wings as complete units but retains a complete and still articulated tail in a greater number of specimens than Pterodactylus.


Exercise Capacity Is Improved by Levosimendan in Heart Failure and Sarcopenia via Alleviation of Apoptosis of Skeletal Muscle.
Patients suffering from chronic heart failure (CHF) show an increased prevalence of sarcopenia. Levosimendan is an effective drug for the treatment of heart failure, but its effect on sarcopenia is still unclear. We aimed to explore whether levosimendan could enhance skeletal muscle contractibility, improve skeletal muscle atrophy, and thus improve exercise tolerance of individuals with heart failure. C57BL6/J mice were used to establish the heart failure with sarcopenia model and injected of levosimendan. Mice were separated into control group, sham operation group, HF group, HF + solvent group, HF + levosimendan group, HF + sarcopenia group, HF + sarcopenia + solvent group, HF + sarcopenia + levosimendan group (n = 5-12). After the treatment, exercise capacity and cardiac function were evaluated. Muscle morphology, inflammation level and apoptosis levels were detected, in which mitochondrial function and oxidative stress level were also assessed. Levosimendan could increase forelimb grip strength/body weight, hanging impulse, maximum running distance and time in mice with HF and sarcopenia (P < 0.0001 for all), and these improvements were independent of EF (P = 0.0019 for hanging impulse, P < 0.001 for forelimb grip strength/body weight and maximum running distance). Levosimendan directly increased the CSA of gastrocnemius in mice with HF and sarcopenia (P < 0.0001). After levosimendan injection, the proportion of slow muscle fibers increased (P < 0.0001), but this improvement of muscle fiber typing might be attributed to improved cardiac function (P > 0.05). Levosimendan also maintained mitochondrial membrane potential, decreased cleaved caspase-3 (P = 0.034), cleaved caspase-9 (P < 0.0001), Bax expression (P < 0.0001), and increased Bcl2 expression (P = 0.0036). This effect is independent of improved cardiac function (P = 0.028 for bax, P < 0.001 for cleaved caspase-9 and Bcl2). IL-6, TNF-α expression (P < 0.0001 for both) decreased, and SOD activity (P = 0.0038), GSH/GSSG ratio (P = 0.002) significantly increased in skeletal muscle after injection of levosimendan. The improvement in oxidative stress level was attributed to improved cardiac function (P > 0.05). Levosimendan reduce the loss of skeletal muscle mitochondrial membrane potential, decrease the apoptosis, alleviate the inflammation and oxidative stress, and ultimately improve the exercise capacity of mice with heart failure and sarcopenia. Therefore, levosimendan may be a potential drug for the treatment of heart failure with sarcopenia.


Nitric oxide and blood pressure in mice lacking extracellular-superoxide dismutase.
Nitric oxide is a major vasorelaxant and regulator of the blood pressure. The blood vessels contain several active sources of the superoxide radical, which reacts avidly with nitric oxide to form noxious peroxynitrite. There are large amounts of extracellular-superoxide dismutase (EC-SOD) in the vascular wall. To evaluate the importance of EC-SOD for the physiology of nitric oxide, here we studied the blood pressure in mice lacking the enzyme. In chronically instrumented non-anaesthetized mice there was no difference in mean arterial blood pressure between wild-type controls and EC-SOD mutants. Extensive inhibition of nitric oxide synthases with N-monomethyl-L-arginine however resulted in a larger increase in blood pressure, and infusion of the nitric oxide donor nitrosoglutathione caused less reduction in blood pressure in the EC-SOD null mice. We interpret the alterations to be caused by a moderately increased consumption of nitric oxide by the superoxide radical in the EC-SOD null mice. One role of EC-SOD may be to preserve nitric oxide, a function that should be particularly important in vascular pathologies, in which large increases in superoxide formation have been documented.


Randomized Clinical Trial to Evaluate MTA Indirect Pulp Capping in Deep Caries Lesions After 24-Months.
This clinical study aimed to assess the efficacies of mineral trioxide aggregate (MTA) and calcium hydroxide [Ca(OH)2] in the treatment of deep carious lesions by the direct complete caries removal technique. A total of 100 permanent molar/premolar teeth were capped with either Ca(OH)2 (n=49) or MTA (n=51) and restored with composite resin in 73 patients. Periapical radiographs were acquired prior to the treatment as well as at six, 12, and 24 months posttreatment. Two calibrated examiners performed the clinical and radiographic assessment of the periapical pathology and pulpal symptoms. Intergroup comparisons of the observed values were performed using the Fisher exact test. Significance was predetermined at α = 0.05. The recall rates were 100% at six and 12 months posttreatment and 98.6% at 24 months posttreatment. Four teeth capped with Ca(OH)2 (two each at six and 12 months posttreatment) and two capped with MTA (one each at 12 and 24 months posttreatment) received endodontic emergency treatment because of symptoms of irreversible pulpitis, which were clinically and/or radiographically established. There were no significant differences in pulp vitality between the two pulp-capping agents at six, 12, or 24 months posttreatment (p=0.238, p=0.606, and p=0.427, respectively). Both pulp-capping materials were found to be clinically acceptable at 24 months posttreatment.


Synthesis and Determination of Anticancer Activity of Dicobalt Hexacarbonyl 2'-Deoxy-5-alkynylfuropyrimidines.
Dicobalt hexacarbonyl 5-alkynyl furopyrimidine nucleoside analogs, with 4-methylphenyl (p-tolyl) and 4-pentylphenyl substituents attached at the C-6 base position, designed in the form of ribose acetyl esters, were synthesized (42-96%). Attached at the C-5 position were propargyl alcohol, its methyl ether and acetate derivatives, butynol, and the 4-methylphenyl- (p-tolyl) and 4-pentylphenyl-substituted alkynyl groups, which were coordinated to a dicobalt hexacarbonyl unit. The structure of 5-(3-acetoxyprop-1-yn-1-yl)-6-p-tolyl-2'-deoxyribofuranosyl-furo[2,3-d]pyrimidin-2-one was determined by X-ray crystallography. Density functional theory calculations performed on the corresponding derivative yielded geometric parameters for the dicobalt hexacarbonyl adduct of this ligand. The cytotoxic activity of each of dicobalt modified nucleosides on cancer cells of different phenotypes was determined in vitro. The investigated compounds showed antiproliferative effects with median inhibitory concentration (IC50) values in the ranges of 14-90 and 9-50 μM for HeLa and K562 cells, respectively. The formation of reactive oxygen species in the presence of modified nucleosides was determined in K562 cells. The results indicate that the mechanism of action for the studied compounds may be related to the induction of oxidative stress.


In search of the glass ceiling: gender and recruitment to management in Norway's state bureaucracy.
There are still fewer female than male managers in Norway's state bureaucracy. This article asks if there are organizational barriers which prevent women from entering these positions. Is there really a glass ceiling, or must one look outside the organizational environment to find an explanation? Is it rather the case that the scarcity of female managers is caused by women's own preferences or their life situations outside work? Or do both contribute to the situation? The study shows that female managers are treated just as well as male managers in central parts of the state bureaucracy. Employers give equal shares of respect and attention to both genders. Female managers are encouraged to apply for the same number of jobs as men and are offered an equal number of jobs as men when they apply; in fact, women are offered more jobs than men, when one controls for the number of job applications. This indicates that organizational barriers are not the problem. The study also shows that there are no differences in work orientation between male and female managers. Female managers are just as ambitious as male managers. Nor do female managers find it more difficult than male managers to combine work and family life. So, how can one explain the low number of female managers? The study shows that one reason can be that female managers apply for management jobs less often than their male colleagues. The cause of this seems to be anticipated discrimination rather than lack of ambition or self-confidence. However, this slows down women's movement into higher management positions in the state bureaucracy.


Extracellular Vesicle-Encapsulated MicroRNA-375 from Bone Marrow-Derived Mesenchymal Stem Cells Inhibits Hepatocellular Carcinoma Progression through Regulating HOXB3-Mediated Wnt/β-Catenin Pathway.
Nowadays, microRNA-375 (miR-375) has been implicated in many types of cancers, including hepatocellular carcinoma (HCC), and the functions of miRNAs encapsulated by extracellular vesicles (EV) in HCC progression have also been extensively investigated. In this research, we aimed to probe into the mechanism of EV-encapsulated miR-375 from bone marrow-derived mesenchymal stem cells (BM-MSCs) in HCC progression. At first, miR-375 expression in HCC tissues and cells was detected using RT-qPCR, and miR-375 was overexpressed to specify the effects of miR-375 on the malignant phenotype of HCC cells. miR-375 was downregulated in HCC, and overexpression of miR-375 suppressed HCC cell growth. Then, BM-MSCs and EV were isolated and identified, and, EV were cocultured with HCC cells for further functional assays. It was found that miR-375 encapsulated by EV could restrict the malignant phenotypes of HCC cells. Furthermore, the downstream genes and signaling cascades involved in HCC growth were investigated. HOXB3 was determined to be a downstream target of miR-375, and upregulation of miR-375 decreased Wnt1 and β-catenin protein expression. Furthermore, HOXB3 blocked the repressive effects of miR-375 on HCC cells and Wnt1 and β-catenin expression. This study highlights that miR-375 encapsulated by EV inhibits HCC development via modulating the HOXB3/Wnt/β-catenin axis.


Glucose metabolism in a patient with hyperthyroidism and an insulinoma.
A 67-year-old woman was admitted in hypoglycemic coma, with fever and signs of hyperthyroidism. Diagnosis was made of both an insulinoma and subacute ("De Quervain") thyroiditis. This rare coincidence of two diseases with opposite effects on serum glucose levels, offered a rare opportunity to study glucose metabolism in this peculiar physiopathological situation. During the day abnormally high postprandial blood glucose levels were seen, pointing to the glucose intolerance usually seen in the hyperthyroid state. During the night and after prolonged fasting, however, hypoglycemia predominated, consistent with the clinical picture typical of an insulinoma. After resection of the insulinoma and spontaneous healing of hyperthyroidism, glucose metabolism reverted to normal. As shown in this case, concurrent hyperthyroidism and an insulinoma may lead to consecutive episodes of glucose intolerance and hypoglycemia within the same 24-hour period.


Overview of systematic reviews of therapeutic ranges: methodologies and recommendations for practice.
Many medicines are dosed to achieve a particular therapeutic range, and monitored using therapeutic drug monitoring (TDM). The evidence base for a therapeutic range can be evaluated using systematic reviews, to ensure it continues to reflect current indications, doses, routes and formulations, as well as updated adverse effect data. There is no consensus on the optimal methodology for systematic reviews of therapeutic ranges. An overview of systematic reviews of therapeutic ranges was undertaken. The following databases were used: Cochrane Database of Systematic Reviews (CDSR), Database of Abstracts and Reviews of Effects (DARE) and MEDLINE. The published methodologies used when systematically reviewing the therapeutic range of a drug were analyzed. Step by step recommendations to optimize such systematic reviews are proposed. Ten systematic reviews that investigated the correlation between serum concentrations and clinical outcomes encompassing a variety of medicines and indications were assessed. There were significant variations in the methodologies used (including the search terms used, data extraction methods, assessment of bias, and statistical analyses undertaken). Therapeutic ranges should be population and indication specific and based on clinically relevant outcomes. Recommendations for future systematic reviews based on these findings have been developed. Evidence based therapeutic ranges have the potential to improve TDM practice. Current systematic reviews investigating therapeutic ranges have highly variable methodologies and there is no consensus of best practice when undertaking systematic reviews in this field. These recommendations meet a need not addressed by standard protocols.


Idiopathic orbital inflammation syndrome with retro-orbital involvement: a retrospective study of eight patients.
The aim of this retrospective study was to document the clinical findings and radiological features of idiopathic orbital inflammation syndrome with retro-orbital involvement. We searched for ophthalmological patients who received orbital imaging at Zhejiang Provincial People's Hospital between October 2003 and April 2010. Seventy-three patients were diagnosed with idiopathic orbital inflammation syndrome based on clinicoradiological features, with pathological confirmation of nonspecific inflammatory conditions in 47 patients. Eight patients (11%) had MRI or CT evidence of retro-orbital involvement. All 8 patients were diagnosed with idiopathic orbital inflammation syndrome after biopsy of the orbital lesion. MR images were obtained for all 8 patients; 3 patients also had a contrast-enhanced CT scan. Seven out of 8 patients with retro-orbital involvement also had orbital apex lesions. Of the 65 patients without retro-orbital involvement, 19 had orbital apex lesions. The difference in the number of patients with orbital apex lesions between the two populations was significant (Fisher exact test P = .002). In all 8 patients with retro-orbital involvement, the inflammation spread through the superior orbital fissure. The retro-orbital lesions were isointense to grey matter on T1-weighted images, hypointense on T2-weighted images, and displayed uniform contrast enhancement; on contrast-enhanced CT scans, they were hyperdense relative to the contralateral mirror area and had radiological contours that were similar to those seen on MR images. The diffuse inflammation with marked sclerosis and hyalinization that we observed in the patients with retro-orbital involvement is consistent with the diagnosis of the sclerosing subtype of idiopathic orbital inflammation syndrome. All 8 patients also complained of mild to moderate periorbital pain (headache). In patients with idiopathic orbital inflammation syndrome, it is important to perform MRI and CT scans to identify possible retro-orbital involvement. Retro-orbital involvement is more frequent when the lesion is present in the orbital apex.


Structural features that stabilize halophilic malate dehydrogenase from an archaebacterium.
The high-resolution structure of halophilic malate dehydrogenase (hMDH) from the archaebacterium Haloarcula marismortui was determined by x-ray crystallography. Comparison of the three-dimensional structures of hMDH and its nonhalophilic congeners reveals structural features that may promote the stability of hMDH at high salt concentrations. These features include an excess of acidic over basic residues distributed on the enzyme surface and more salt bridges present in hMDH compared with its nonhalophilic counterparts. Other features that contribute to the stabilization of thermophilic lactate dehydrogenase and thermophilic MDH-the incorporation of alanine into alpha helices and the introduction of negatively charged amino acids near their amino termini, both of which stabilize the alpha helix as a result of interaction with the positive part of the alpha-helix dipole-also were observed in hMDH.


Family study of the inheritance of pectus excavatum.
The most common congenital deformity of the chest wall is pectus excavatum, a malformation that is present in between 1 in 400 and 1 in 1000 live births and causes the body of the sternum to be displaced, producing a depression. There are many different shapes of the pectus, and multiple factors probably contribute to the final form. The etiology of pectus excavatum is uncertain, but a familial tendency has been found in clinical experience, where it may be seen in more than one sibling. Pectus excavatum is commonly associated with connective tissue disorders such as Marfan and Ehlers Danlos syndromes. Extensive literature review failed to identify articles documenting families with multiple affected members. The purpose of this study was to collect evidence that pectus excavatum is familial and may be an inherited disorder. Using the Children's Surgical Specialty Group database at Children's Hospital of The King's Daughters, families with more than one affected individual were selected. With Institutional Review Board-approved informed consent, 34 families agreed to participate. Family histories were obtained, and a 4-generation pedigree was constructed for each family. Forty questions were asked about each individual's medical history, and comprehensive systems review included features of connective tissue-related problems. Inheritance patterns for each family were determined by pedigree analysis. A total of 14 families suggested autosomal dominant inheritance, 4 families suggested autosomal recessive inheritance, and 6 families suggested X-linked recessive inheritance. Ten families had complex inheritance patterns. Pectus excavatum occurred more frequently in males than in females (1.8:1). Long arms, legs, and fingers; high-arched palate; mitral valve prolapse; heart arrhythmia; scoliosis; double jointedness; flexibility; flat feet; childhood myopia; poor healing; and easy bruising were commonly associated with pectus excavatum. Pedigree analysis of 34 families provides evidence that pectus excavatum is an inherited disorder, possibly of connective tissue. Although some families demonstrate apparent Mendelian inheritance, most appear to be multifactorial.


Primary systemic amyloidosis presenting as idiopathic inflammatory colitis.
A 75-year old-female was referred with chest pain. She was fully investigated and it was felt that her symptoms were non-cardiac. Four months later, she was seen in gastroenterology outpatients with bloody diarrhoea and abdominal pain. Colonoscopy demonstrated inflammation up to the splenic flexure and histology confirmed inflammatory colitis. Later, she developed dyspepsia and weight loss. An oesophagogastroduodenoscopy (OGD) showed Helicobacter pylori negative erosive gastritis with a benign duodenal ulcer. Whole body CT scan was normal. Ten months later, she was admitted with dyspnoea due to severe heart failure. The admission ECG had significantly changed, now showing low voltage complexes and repeat echocardiography showed restrictive cardiomyopathy. Specific congo red staining on the biopsy specimens from the previous OGD and colonoscopy confirmed amyloid deposits. Further investigations detected an underlying light chain myeloma causing systemic (AL) amyloidosis. Unfortunately, her condition deteriorated rapidly and she died shortly afterwards.


Insomnia. Safe and effective therapy for sleep problems in the older patient.
Insomnia is a problem in all stages of life but is particularly common after age 65. A number of factors--including advanced age, psychosocial influences, medical illness, and the use of medications and alcohol--may disturb sleep architecture. Evaluation of insomnia in the older patient requires a careful history and physical examination, supplemented by a sleep diary. Treatment of underlying conditions and nonpharmacologic improvements in sleep hygiene are first-line therapy, but pharmacologic agents such as benzodiazepines, nonbenzodiazepine hypnotics, or antidepressants may be needed. Nonbenzodiazepines with rapid elimination may offer a lower side-effect profile than other hypnotic agents when used for insomnia in the older population.


Regulation of interferon gamma signaling by suppressors of cytokine signaling and regulatory T cells.
Regulatory T cells (Tregs) play an indispensable role in the prevention of autoimmune disease, as interferon gamma (IFNγ) mediated, lethal auto-immunity occurs (in both mice and humans) in their absence. In addition, Tregs have been implicated in preventing the onset of autoimmune and auto-inflammatory conditions associated with aberrant IFNγ signaling such as type 1 diabetes, lupus, and lipopolysaccharide (LPS) mediated endotoxemia. Notably, suppressor of cytokine signaling-1 deficient (SOCS1(-/-)) mice also succumb to a lethal auto-inflammatory disease, dominated by excessive IFNγ signaling and bearing similar disease course kinetics to Treg deficient mice. Moreover SOCS1 deficiency has been implicated in lupus progression, and increased susceptibility to LPS mediated endotoxemia. Although it has been established that Tregs and SOCS1 play a critical role in the regulation of IFNγ signaling, and the prevention of lethal auto-inflammatory disease, the role of Treg/SOCS1 cross-talk in the regulation of IFNγ signaling has been essentially unexplored. This is especially pertinent as recent publications have implicated a role of SOCS1 in the stability of peripheral Tregs. This review will examine the emerging research findings implicating a critical role of the intersection of the SOCS1 and Treg regulatory pathways in the control of IFN gamma signaling and immune system function.


A Regio- and Enantioselective CuH-Catalyzed Ketone Allylation with Terminal Allenes.
We report a method for the highly enantioselective CuH-catalyzed allylation of ketones that employs terminal allenes as allylmetal surrogates. Ketones and allenes bearing diverse and sensitive functional groups are efficiently coupled with high stereoselectivity and exclusive branched regioselectivity. In stoichiometric experiments, each elementary step of the proposed hydrocupration-addition-metathesis mechanism can be followed by NMR spectroscopy.


Leaching of Mn, Co, and Ni from manganese nodules using an anaerobic bioleaching method.
An anaerobic bioleaching of a manganese nodule by anaerobic Mn-reducing bacteria was evaluated for the leaching of metals, Mn, Co, and Ni. Insoluble Mn4+ in the nodule could be reduced to soluble Mn2+ by dissimilatory Mn-reducing bacteria that use a carbon source and Mn4+ as an electron donor and acceptor, respectively. As a result of the Mn reduction, Co and Ni could be leached from the loosed Mn matrix. Leaching experiments were carried out to optimize various process parameters, such as inoculation, pH, temperature, mineral salts, and particle size of the nodule used. The leaching efficiencies of Mn, Co, and Ni increased from 18, 7, and 10% to 77, 70, and 75%, respectively by the inoculation of the Mn-reducing enrichment culture broth. Metals could be efficiently recovered from the nodule in the ranges of pH from 5.0 to 6.5 and temperature from 30 to 45 degrees C by anaerobic bioleaching. External addition of mineral salts was not necessary for Mn, Co, and Ni leaching from the nodule. The optimum ratio of nodule to glucose was 0.1 (w/w). To obtain a leaching efficiency above 70%, the particle size of the nodules must be less than 0.6 mm.


Alpha-Amylase Inhibition and Antioxidative Capacity of Some Antidiabetic Plants Used by the Traditional Healers in Southeastern Nigeria.
Oxidative stress plays a significant role in the pathogenesis of metabolic syndrome including diabetes mellitus (DM). The inhibition of alpha-amylase is an important therapeutic target in the regulation of postprandial increase of blood glucose in diabetic patients. The present study investigated the alpha-amylase inhibitory and antioxidant potential of selected herbal drugs used in the treatment of DM by the traditional healers in Isiala Mbano and Ikwuano regions of southeastern Nigeria. Antioxidant activity was evaluated in terms of free radical scavenging, reducing power, and total phenolic (TPC) and flavonoid content (TFC) in consonance with the TLC profiling. The results showed that methanol crude extracts from Anacardium occidentale (AO) and Ceiba pentandra (CP) recorded higher TPC and TFC, potent free radical scavenging, and efficient reducing power (RP) as compared with other plant samples. All the plant extracts exhibited a relative alpha-amylase inhibition apart from Strophanthus hispidus (SH) extract with a negative effect. We discovered a mild to weak correlation between alpha-amylase inhibition or antioxidative capacity and the total phenol or flavonoid content. At least in part, the results obtained in this work support the traditional use of certain plant species in the treatment of patients with DM.


Evidence-based medicine and myocardial protection--where is the evidence?
Myocardial protection with cardioplegia is an integral component of most cardiac surgical procedures, providing protection of the heart by limiting metabolic activity and increasing the myocardium's capacity to withstand ischemia for prolonged periods of time. Cardioplegia has greatly affected the landscape of cardiothoracic surgery since its introduction in the 1960s, but, to this day, there continues to be a debate over what the ideal cardioplegic solution should be. The goal of this analysis is to describe current practices in cardioplegia and to point out the lack of quality human research and subsequent publications that prevent best practices from being utilized. This study is a systematic review of journal publications pertaining to the composition of commonly used cardioplegic solutions. Four main types of cardioplegia were assessed to give a narrower field of examination; specifically, microplegia, del Nido, Custodiol HTK, and 4:1 blood cardioplegia. Other combinations of cardioplegia, including St. Thomas's Solution and the University of Wisconsin (UW) Solution, were considered when applicable according to the context of the publication being reviewed. Factors being assessed consisted of scientific validity, nature of the test subject (isolated organ vs. animal vs. human studies), experimental setup (retrospective trials vs. randomized clinical trials) and patient outcomes. There are very few randomized clinical trials with human subjects comparing commonly used cardioplegic solutions. Numerous retrospective studies exist, but often show similar intraoperative and postoperative outcomes between the solutions. Some solutions, del Nido cardioplegia in particular, were found to have few or no significant human trials to back the rigor required in such a highly specialized field as cardiovascular surgery. A wide variation in the types of surgeries and primary outcomes were included in the publications, so it is difficult to perform an accurate systematic review of the topic. Uniform variables among different studies would be preferable for analysis of this topic; thus, it is the researchers' recommendation that the collection of multicenter data be undertaken in order to more fully answer this research question.Comparative effectiveness studies to associate commonly used solutions are needed. Without this research, surgeon preference remains the primary determining factor for deciding which cardioplegic solution to use. Cardioplegia selection should rely more on higher scientific research, using evidenced-based medicine and ranking of clinical studies.


Double sterility barrier between Saccharomyces species and its breakdown in allopolyploid hybrids by chromosome loss.
The analysis of 57 synthetic interspecies hybrids revealed that Saccharomyces cerevisiae and Saccharomyces uvarum ( Saccharomyces bayanus var. uvarum) are isolated by a double sterility barrier: by hybrid sterility (hybrid cells cannot produce viable spores) operating in allodiploids and by F1 sterility (F1 cells cannot produce viable spores) operating in allopolyploids. F1-sterility is caused by mating-type heterozygosity. It can be overcome by eliminating chromosome 2 of the S. uvarum subgenome that carries a MAT locus. The loss of this MAT gene abolishes the repression of mating activity. In cultures of the resulting fertile alloaneuploid F1 segregants, the cells can conjugate with each other like haploids and form zygotes capable of performing meiotic divisions producing viable and fertile F2 spores. To the best of our knowledge, this is the first report on breaking down interspecies hybrid sterility by chromosome loss in eukaryotic organisms. The filial generations are genetically unstable and can undergo additional changes mainly in the S. uvarum subgenome (directional changes). It is proposed that regaining fertility and subsequent preferential reduction in one of the subgenomes may account for the formation of chimerical ('natural hybrid') genomes found among wine and brewery strains and may also play roles in speciation of hybrid taxa in the Saccharomyces genus.


Arch-first technique used with commercial T-graft to treat subacute type-A aortic dissection in patient with Marfan syndrome.
Staged repair of extensive thoracic aortic aneurysms puts certain patients at risk of rupture. We report the case of a patient with Marfan syndrome who presented with subacute type-A aortic dissection and a large descending aortic aneurysm. We used the arch-first technique with a commercially available Dacron T-graft. A clamshell incision was used for exposure. A button of arch vessels was anastomosed to the T-graft. Antegrade cerebral perfusion was established through the side branch. The distal end of the graft was anastomosed to the descending aorta and the proximal end to a composite graft. The duration of cerebral ischemia was 30 minutes; antegrade cerebral perfusion lasted 52 minutes. The patient experienced no neurologic dysfunction and was discharged with no major deficit. This technique shortens brain-ischemia time and is a good option if the risk of rupture of the descending component of an extensive thoracic aortic aneurysm is high. To the best of our knowledge, this is the 1st reported case in which the arch-first technique has been used with a commercially available T-graft to treat subacute type-A aortic dissection in a patient with Marfan syndrome.


Auditory brainstem responses: masking related changes in wave VI.
Auditory brainstem responses (ABRs) were recorded in a group of nine normally-hearing subjects. Wide-band clicks were delivered at 70, 80 and 90 dB SL, both with and without 50 dB SL of contralateral masking. The amplitude of wave VI was significantly reduced in the presence of masking for the 90 dB SL stimulus but there was no effect at the lower stimulus levels. A possible explanation for this is that the observed response, to a 90 dB SL stimulus without masking, is a summation of the ipsilateral wave VI and a wave V elicited from the contralateral ear. Supporting evidence is provided and the implications of this result are discussed.


Oscillations and bistability in the stochastic model of p53 regulation.
The p53 regulatory pathway controls cell responses, which include cell cycle arrest, DNA repair, apoptosis and cellular senescence. We propose a stochastic model of p53 regulation, which is based on two feedback loops: the negative, coupling p53 with its immediate downregulator Mdm2, and the positive, which involves PTEN, PIP3 and Akt. Existence of the negative feedback assures homeostasis of healthy cells and oscillatory responses of DNA-damaged cells, which are persistent when DNA repair is inefficient and the positive feedback loop is broken. The positive feedback destroys the negative coupling between Mdm2 and p53 by sequestering most of Mdm2 in cytoplasm, so it may no longer prime the nuclear p53 for degradation. It works as a clock, giving the cell some time for DNA repair. However, when DNA repair is inefficient, the active p53 rises to a high level and triggers transcription of proapoptotic genes. As a result, small DNA damage may be repaired and the cell may return to its initial "healthy" state, while the extended damage results in apoptosis. The stochasticity of p53 regulation, introduced at the levels of gene expression, DNA damage and repair, leads to high heterogeneity of cell responses and causes cell population split after irradiation into subpopulations of apoptotic and surviving cells, with fraction of apoptotic cells growing with the irradiation dose.


Strategies to preserve or regenerate spiral ganglion neurons.
Degeneration of spiral ganglion neurons following hair cell loss carries critical implications for efforts to rehabilitate severe cases of hearing loss with cochlear implants or hair cell regeneration. This review considers recently identified neurotrophic factors and therapeutic strategies which promote spiral ganglion neuron survival and neurite growth. Replacement of these factors may help preserve or regenerate the auditory nerve in patients with extensive hair cell loss. Spiral ganglion neurons depend on neurotrophic factors supplied by hair cells and other targets for their development and continued survival. Loss of this trophic support leads to spiral ganglion neuron death via apoptosis. Hair cells support spiral ganglion neuron survival by producing several peptide neurotrophic factors such as neurotrophin-3 and glial derived neurotrophic factor. In addition, neurotransmitter release from the hair cells drives membrane electrical activity in spiral ganglion neurons which also supports their survival. In animal models, replacement of peptide neurotrophic factors or electrical stimulation with an implanted electrode attenuates spiral ganglion neuron degeneration following deafferentation. Cell death inhibitors can also preserve spiral ganglion neuron populations. Preliminary studies show that transfer of stem cells or neurons from other ganglia are two potential strategies to replace lost spiral ganglion neurons. Inducing the regrowth of spiral ganglion neuron peripheral processes to approximate or contact cochlear implant electrodes may help optimize signaling from a diminished population of neurons. Recent studies of spiral ganglion neuron development and survival have identified several trophic and neuritogenic factors which protect these specialized cells from degeneration following hair cell loss. While still preliminary, such strategies show promise for future clinical applications.


High Temporal and Spatial Variability of Atmospheric-Methane Oxidation in Alpine Glacier Forefield Soils.
Glacier forefield soils can provide a substantial sink for atmospheric CH4, facilitated by aerobic methane-oxidizing bacteria (MOB). However, MOB activity, abundance, and community structure may be affected by soil age, MOB location in different forefield landforms, and temporal fluctuations in soil physical parameters. We assessed the spatial and temporal variability of atmospheric-CH4 oxidation in an Alpine glacier forefield during the snow-free season of 2013. We quantified CH4 flux in soils of increasing age and in different landforms (sandhill, terrace, and floodplain forms) by using soil gas profile and static flux chamber methods. To determine MOB abundance and community structure, we employed pmoA gene-based quantitative PCR and targeted amplicon sequencing. Uptake of CH4 increased in magnitude and decreased in variability with increasing soil age. Sandhill soils exhibited CH4 uptake rates ranging from -3.7 to -0.03 mg CH4 m-2 day-1 Floodplain and terrace soils exhibited lower uptake rates and even intermittent CH4 emissions. Linear mixed-effects models indicated that soil age and landform were the dominating factors shaping CH4 flux, followed by cumulative rainfall (weighted sum ≤4 days prior to sampling). Of 31 MOB operational taxonomic units retrieved, ∼30% were potentially novel, and ∼50% were affiliated with upland soil clusters gamma and alpha. The MOB community structures in floodplain and terrace soils were nearly identical but differed significantly from the highly variable sandhill soil communities. We concluded that soil age and landform modulate the soil CH4 sink strength in glacier forefields and that recent rainfall affects its short-term variability. This should be taken into account when including this environment in future CH4 inventories.IMPORTANCE Oxidation of methane (CH4) in well-drained, "upland" soils is an important mechanism for the removal of this potent greenhouse gas from the atmosphere. It is largely mediated by aerobic, methane-oxidizing bacteria (MOB). Whereas there is abundant information on atmospheric-CH4 oxidation in mature upland soils, little is known about this important function in young, developing soils, such as those found in glacier forefields, where new sediments are continuously exposed to the atmosphere as a result of glacial retreat. In this field-based study, we investigated the spatial and temporal variability of atmospheric-CH4 oxidation and associated MOB communities in Alpine glacier forefield soils, aiming at better understanding the factors that shape the sink for atmospheric CH4 in this young soil ecosystem. This study contributes to the knowledge on the dynamics of atmospheric-CH4 oxidation in developing upland soils and represents a further step toward the inclusion of Alpine glacier forefield soils in global CH4 inventories.


Machine Learning-Based and Experimentally Validated Optimal Adhesive Fibril Designs.
Setae, fibrils located on a gecko's feet, have been an inspiration of synthetic dry microfibrillar adhesives in the last two decades for a wide range of applications due to unique properties: residue-free, repeatable, tunable, controllable and silent adhesion; self-cleaning; and breathability. However, designing dry fibrillar adhesives is limited by a template-based-design-approach using a pre-determined bioinspired T- or wedge-shaped mushroom tip. Here, a machine learning-based computational approach to optimize designs of adhesive fibrils is shown, exploring a much broader design space. A combination of Bayesian optimization and finite element methods creates novel optimal designs of adhesive fibrils, which are fabricated by two-photon-polymerization-based 3D microprinting and double-molding-based replication out of polydimethylsiloxane. Such optimal elastomeric fibril designs outperform previously proposed designs by maximum 77% in the experiments of dry adhesion performance on smooth surfaces. Furthermore, finite-element-analyses reveal that the adhesion of the fibrils is sensitive to the 3D fibril stem shape, tensile deformation, and fibril microfabrication limits, which contrast with the previous assumptions that mostly neglect the deformation of the fibril tip and stem, and focus only on the fibril tip geometry. The proposed computational fibril design could help design future optimal fibrils with less help from human intuition.


Targeting SR proteins improves SMN expression in spinal muscular atrophy cells.
Spinal muscular atrophy (SMA) is one of the most common inherited causes of pediatric mortality. SMA is caused by deletions or mutations in the survival of motor neuron 1 (SMN1) gene, which results in SMN protein deficiency. Humans have a centromeric copy of the survival of motor neuron gene, SMN2, which is nearly identical to SMN1. However, SMN2 cannot compensate for the loss of SMN1 because SMN2 has a single-nucleotide difference in exon 7, which negatively affects splicing of the exon. As a result, most mRNA produced from SMN2 lacks exon 7. SMN2 mRNA lacking exon 7 encodes a truncated protein with reduced functionality. Improving SMN2 exon 7 inclusion is a goal of many SMA therapeutic strategies. The identification of regulators of exon 7 inclusion may provide additional therapeutic targets or improve the design of existing strategies. Although a number of regulators of exon 7 inclusion have been identified, the function of most splicing proteins in exon 7 inclusion is unknown. Here, we test the role of SR proteins and hnRNP proteins in SMN2 exon 7 inclusion. Knockdown and overexpression studies reveal that SRSF1, SRSF2, SRSF3, SRSF4, SRSF5, SRSF6, SRSF7, SRSF11, hnRNPA1/B1 and hnRNP U can inhibit exon 7 inclusion. Depletion of two of the most potent inhibitors of exon 7 inclusion, SRSF2 or SRSF3, in cell lines derived from SMA patients, increased SMN2 exon 7 inclusion and SMN protein. Our results identify novel regulators of SMN2 exon 7 inclusion, revealing potential targets for SMA therapeutics.


Homocysteine levels, MTHFR C677T genotype, and MRI Hyperintensities in late-onset major depressive disorder.
Epidemiological studies suggest that elevated plasma homocysteine is associated with an increased risk of depression and cerebrovascular disease. There are no published reports of homocysteine levels and methylenetetrahydrofolate reductase (MTHFR) C677T genotype in clinical samples of patients with late-onset major depressive disorder (MDD). The purpose of this study was to examine the association of homocysteine levels or MTHFR C677T genotype and late-onset MDD and assess whether this may be affected by brain magnetic resonance imaging (MRI) hyperintensities. Authors recruited 39 elderly patients with MDD with first episode occurring after age 50 and 20 comparison subjects and assessed total plasma homocysteine levels, MTHFR genotype, and brain MRIs. Plasma total homocysteine levels were higher in elderly patients with late-onset MDD versus comparison subjects. The association did not change after controlling for MRI hyperintensities, and the distribution of MTHFR C677T genotype was not different between the groups. In this exploratory study, elevated homocysteine levels were associated with late-onset MDD, and the association did not appear to be mediated by vascular pathology as identified by brain MRI hyperintensities.


Osteomyelitis in leukocyte adhesion deficiency type 1 syndrome.
Leukocyte adhesion deficiency type 1 (LAD-1) is a rare, inherited immunodeficiency that affects one per million people yearly and usually presents with recurrent, indolent bacterial infections of the skin, mouth, and respiratory tract and impaired pus formation and wound healing. A 13-year-old girl diagnosed LAD-I at the age of 7 years was brought to the Immunology, Asthma and Allergy Research Institute, Tehran University of Medical Sciences, because of a draining plaque on the left leg for 2.5 years. She had recurrent skin infections and had been treated with repeated courses of different antibiotic combinations, with temporary responses, since 5 years of age. Examination revealed a 7 x 8 cm minimally erythematous hyperpigmented plaque with multiple draining sinuses on the left leg. Tissue culture yielded Pseudomonas aeruginosa. Flow cytometry showed CD18 (18.79%), CD11a (51.59%), CD11b (18.61%) and CD11c(10.60%). A plain radiography of the left leg revealed osteomyelitis. It is highly suggested that patients diagnosed mild to moderate LAD-1 with recurrent skin infection and simultaneous weak response to conventional therapy undergo (BMT) marrow transplant to prohibit subsequent life-threatening complications.


The BTK Inhibitor Ibrutinib (PCI-32765) Overcomes Paclitaxel Resistance in ABCB1- and ABCC10-Overexpressing Cells and Tumors.
Paclitaxel is one of the most widely used antineoplastic drugs in the clinic. Unfortunately, the occurrence of cellular resistance has limited its efficacy and application. The ATP-binding cassette subfamily B member 1 (ABCB1/P-glycoprotein) and subfamily C member 10 (ABCC10/MRP7) are the major membrane protein transporters responsible for the efflux of paclitaxel, constituting one of the most important mechanisms of paclitaxel resistance. Here, we demonstrated that the Bruton tyrosine kinase inhibitor, ibrutinib, significantly enhanced the antitumor activity of paclitaxel by antagonizing the efflux function of ABCB1 and ABCC10 in cells overexpressing these transporters. Furthermore, we demonstrated that the ABCB1 or ABCC10 protein expression was not altered after treatment with ibrutinib for up to 72 hours using Western blot analysis. However, the ATPase activity of ABCB1 was significantly stimulated by treatment with ibrutinib. Molecular docking analysis suggested the binding conformation of ibrutinib within the large cavity of the transmembrane region of ABCB1. Importantly, ibrutinib could effectively enhance paclitaxel-induced inhibition on the growth of ABCB1- and ABCC10-overexpressing tumors in nude athymic mice. These results demonstrate that the combination of ibrutinib and paclitaxel can effectively antagonize ABCB1- or ABCC10-mediated paclitaxel resistance that could be of great clinical interest. Mol Cancer Ther; 16(6); 1021-30. ©2017 AACR.


A 3D pencil-beam-based superposition algorithm for photon dose calculation in heterogeneous media.
In this work, a novel three-dimensional superposition algorithm for photon dose calculation is presented. The dose calculation is performed as a superposition of pencil beams, which are modified based on tissue electron densities. The pencil beams have been derived from Monte Carlo simulations, and are separated into lateral and depth-directed components. The lateral component is modeled using exponential functions, which allows accurate modeling of lateral scatter in heterogeneous tissues. The depth-directed component represents the total energy deposited on each plane, which is spread out using the lateral scatter functions. Finally, convolution in the depth direction is applied to account for tissue interface effects. The method can be used with the previously introduced multiple-source model for clinical settings. The method was compared against Monte Carlo simulations in several phantoms including lung- and bone-type heterogeneities. Comparisons were made for several field sizes for 6 and 18 MV energies. The deviations were generally within (2%, 2 mm) of the field central axis d(max). Significantly larger deviations (up to 8%) were found only for the smallest field in the lung slab phantom for 18 MV. The presented method was found to be accurate in a wide range of conditions making it suitable for clinical planning purposes.


[Studies on the absorption, excretion and distribution of aclacinomycin A: absorption, excretion and distribution of 14C- or 3H-aclacinomycin A in mice, rats and rabbits (author's transl)].
A new anthracycline antitumor antibiotic, aclacinomycin A, was labeled with 3H uniformly or with 14C simultaneously at the anthracycline nucleus and L-rhodosamine. These labeled drugs were administered intravenously to normal dd mice, solid type Sarcoma 180 tumor-bearing ICR mice, normal or pregnant Wistar rats and normal rabbits, respectively. 14C-Aclacinomycin A given to rabbits (5 mg/kg) was rapidly cleared from the blood and transferred to tissues. But low level of radioactivity (equivalent to about 0.5 mcg/ml) was remained in the blood even 8 approximately 10 hours after administration. About 45% of the radioactivity were recovered from the urine and 20% from the feces by 72 hours after administration. Tissue levels of 3H-14C-aclacinomycin A given to normal and tumor-bearing mice were highest in the lungs and spleen. Higher distribution was observed also in the liver and kidneys 2 hours after administration. Bioassay revealed that the drug was present in the lungs and spleen in biologically active form and in the liver and kidneys in inactive form, respectively. In the tumor tissue the radioactivity was low but it persisted for 48 hours. Autoradiography with 14C-aclacinomycin A in rats demonstrated that radioactivity due to the drug distributed in the lungs, spleen, kidneys, thymus, intestine, lymph nodes, bone marrow, salivary gland, hypophysis and pineal body but it was rapidly cleared. About 0.2% of radioactivity given to a pregnant rat were transferred to a fetus when 14C-aclacinomycin A was administered intravenously on the 18 approximately 19th day of pregnancy.


Knot-So-Fast: a learning plan to minimize patient restraint in critical care.
In 2001, new legislation in Ontario, the Patient Restraint Minimization Act, mandated that all hospitals develop a policy to minimize the use of restraints. Since restraining patients was a common practice in our intensive care unit (ICU), a practice change was necessary. To do this, a learning plan was created to share key information pertaining to the Act that would support humane and dignified care for our critically ill patients. Change was accomplished through a survey of nursing staff to establish learning needs, the development of a learning plan titled "Knot-So-Fast", and the creation of a tool titled the "Restraint Decision Wheel" to support staff in making restraint decisions quickly and appropriately. To measure the effect of our Knot-So-Fast learning plan, the staff was resurveyed one year later. Results showed there was a statistically significant decrease in restraint use in our ICU. The learning plan and tools developed have been found to be adaptable to other hospital units and are provided. This article includes the educational content and methods used in our ICU to effect a change in restraint practice. Tools, such as a nursing survey and a decision wheel, developed to enhance learning are also included.


Feasibility and accuracy of 3DTEE versus CT for the evaluation of aortic valve annulus to left main ostium distance before transcatheter aortic valve implantation.
The aims of this study were to analyze in a large series of patients undergoing transcatheter aortic valve implantation (TAVI): 1) the accuracy of 3-dimensional transesophageal echocardiographic (3DTEE) measurement of left coronary cusp (LCC) length and of the distances from left main coronary ostium (LM) to the aortic annulus (AA) pre-operatively and to the aortic prosthesis post-operatively; and 2) the role of the 3DTEE measurements in predicting the prosthetic deployment and the association between prosthesis position and aortic regurgitation (AR) and/or prosthesis-patient mismatch (PPM). Coronary ostia occlusion is a possible complication in TAVI; therefore, the careful pre-operative evaluation of AA-LM and LCC length, and the post-operative analysis of the relationship between the prosthesis and LM, may influence the procedural outcomes. Even though multidetector computed tomography (MDCT) is the gold standard pre-operatively, sometimes it cannot be performed and it is rarely repeated post-operatively. In 122 patients undergoing TAVI, pre-operative AA-LM and LCC measurements obtained by 3DTEE and MDCT were compared. Post-operatively, the feasibility of 3DTEE evaluation of the prosthesis-LM distance was performed. The relationship between 3DTEE overlap of the prosthesis with the anterior mitral leaflet and AR/PPM was assessed. Pre-operatively, 3DTEE AA-LM (r = 0.83) and LCC (r = 0.69) significantly correlated with MDCT. Post-operatively, 3DTEE prosthesis-LM distance was 2.1 ± 1.9 mm. The prosthesis reached or exceeded LM in 6 and 10 cases, respectively. Prosthesis overlap with mitral leaflet was 4.7 ± 1.8 mm. Significant correlation between the 3DTEE computed and nominal length of the prosthesis was found (r = 0.61). No correlations were found between prosthesis-mitral leaflet overlap and aortic regurgitation or PPM. AA-LM distance and LCC length may be accurately estimated by 3DTEE, which may represent a valid alternative to MDCT. Pre- and post-3DTEE data concerning the aortic root, such as LM, aortic valve, and prosthetic morphology, give new insights into TAVI and its complications.