CAG repeat-binding small molecule improves motor coordination impairment in a mouse model of Dentatorubral-pallidoluysian atrophy.
Dentatorubral-pallidoluysian atrophy (DRPLA) is a devastating genetic disease presenting myoclonus, epilepsy, ataxia, and dementia. DRPLA is caused by the expansion of a CAG repeat in the ATN1 gene. Aggregation of the polyglutamine-expanded ATN1 protein causes neuro-degeneration of the dentatorubral and pallidoluysian systems. The expanded CAG repeats are unstable, and ongoing repeat expansions contribute to disease onset, progression, and severity. Inducing contractions of expanded repeats can be a means to treat DRPLA, for which no disease-modifying or curative therapies exist at present. Previously, we characterized a small molecule, naphthyridine-azaquinolone (NA), which binds to CAG slip-out structures and induces repeat contraction in Huntington's disease mice. Here, we demonstrate that long-term intracerebroventricular infusion of NA leads to repeat contraction, reductions in mutant ATN1 aggregation, and improved motor phenotype in a murine model of DRPLA. Furthermore, NA-induced contraction resulted in the modification of repeat-length-dependent dysregulation of gene expression profiles in DRPLA mice. Our study reveals the therapeutic potential of repeat contracting small molecules for repeat expansion disorders, such as DRPLA.


[Forty cases of neuromeningeal cryptococcosis diagnosed at the Mycology-Parasitology Department of the Ibn Sina hospital in Rabat, over a 21-year period].
Neuromeningeal cryptococcosis is a common and severe opportunistic fungal infection caused by the encapsulated yeast Cryptococcus neoformans. It commonly occurs in immunocompromised patients, in particular in subjects with advanced stage HIV while it is rare in immunocompetent patients. We report 40 cases of neuromeningeal cryptococcosis (NMC) diagnosed at the Mycology-Parasitology Department of the Ibn Sina hospital in Rabat, over a 21-year period (1993-2014). The diagnosis was based on nested-PCR-based assay for the detection of Cryptococcus neoformans after staining with China ink and culture on Sabouraud agar without actidione as well as on the identification of soluble cryptococcal antigens. Thirty-five patients had HIV infection, 2 patients were apparently immunocompetent and 3 were immunocompromised patients without HIV (30 men and 10 women). The average age of patients was 38 years; neuromeningeal cryptococcosis was indicative of HIV infection in 13 cases. In 22 cases it was a complication of AIDS. Twenty-seven patients of our series were treated with fluconazole monotherapy. Amphotericin B was used in 13 patients. Outcome was favorable in 13 patients (32.5%) while 3 patients had complications (7.5%). Eighteen patients died (45%) and 6 were lost to follow-up (15%). The tests to diagnose a Cryptococcus neoformans infection should be performed systematically in patients with neurological signs for early diagnosis.


Sulodexide increases mRNA expression of glutathione-related genes in human umbilical endothelial cells exposed to oxygen-glucose deprivation.
Sulodexide (SDX), a heparinoid used to treat vascular diseases, exerts anti-ischemic properties. However, the underlying molecular mechanisms remain unclear. Induction of glutathione (GSH)-dependent genes protects against ischemia. Here, we investigated the effect of SDX on GSH-associated gene expression in human umbilical endothelial cells (HUVECs) using an in vitro ischemia model. The transcriptional expression of GSH-related genes (GCLc, xCT, GS, GPx1 and GR) in HUVECs treated without/with SDX (0.5 LRU/ml) under oxygen-glucose deprivation (OGD) condition for 1-6 h was analyzed by real-time polymerase chain reaction. GCLc and xCT were strongly up-regulated by SDX in HUVECs in the first 2 h of OGD. GS and GPx1 mRNA expression levels were significantly increased during any time interval in ischemic HUVECs treated with SDX. Furthermore, incubation of HUVECs with SDX in OGD for 1-4 h resulted in enhanced expression of GR. Our studies provide the first evidence that SDX activates GSH-related genes in OGD-injured HUVECs.


Synthesis and molecular modeling of (4'R)- and (4'S)- 4'-substituted 2'-{[(E)-androst-5-en-17-ylidene]-methyl}oxazolines.
Synthesis of four novel (4'R)- and (4'S)- 2'-{[(E)-3β-hydroxyandrost-5-en-17-ylidene]-methyl} oxazolines, comprising 4'-hydroxymethyl (1 and 2) and 4'-methoxycarbonyl (3 and 4) substituents is presented. Reaction of 17α-bromo-21-iodo-3β-acetoxypregn-5-en-20-one with either (L)-serine methyl ester, or (D)-serine methyl ester resulted in methyl N-[3β-acetoxy-21-oxopregna-5,17(20)-dien-21-yl]-(L)-serinate and methyl N-[3β-acetoxy-21-oxopregna-5,17(20)-dien-21-yl]-(D)-serinate (as mixtures of related [17(20)E]- and [17(20)Z]-isomers). Cyclization of obtained amides led to methyl 2'-{[(E)-3β-acetoxyandrost-5-en-17-ylidene]methyl}-(4'S)-4',5'-dihydro-1',3'-oxazole-4'-carboxylate and methyl 2'-{[(E)-3β-acetoxyandrost-5-en-17-ylidene]methyl}-(4'R)-4',5'-dihydro-1',3'-oxazole-4'-carboxylate which were transformed to titled compounds 1-4. The molecular docking of compounds 1-4 to ligand binding site of nuclear receptor LXRβ revealed significant differences due to stereochemical configuration of 4' atom and structure of 4'-substituent.


Daytime nap controls toddlers' nighttime sleep.
Previous studies have demonstrated that afternoon naps can have a negative effect on subsequent nighttime sleep in children. These studies have mainly been based on sleep questionnaires completed by parents. To investigate the effect of napping on such aspects of sleep quality, we performed a study in which child activity and sleep levels were recorded using actigraphy. The parents were asked to attach actigraphy units to their child's waist by an adjustable elastic belt and complete a sleep diary for 7 consecutive days. 50 healthy young toddlers of approximately 1.5 years of age were recruited. There was a significant negative correlation between nap duration and both nighttime sleep duration and sleep onset time, suggesting that long nap sleep induces short nighttime sleep duration and late sleep onset time. We also found a significant negative correlation between nap timing and nighttime sleep duration and also a significant positive correlation between nap timing and sleep onset time, suggesting that naps in the late afternoon also lead to short nighttime sleep duration and late sleep onset. Our findings suggest that duration-controlled naps starting early in the afternoon can induce a longer nighttime sleep in full-term infants of approximately 1.5 years of age.


Discovery of an ʟ-amino acid ligase implicated in Staphylococcal sulfur amino acid metabolism.
Enzymes involved in Staphylococcus aureus amino acid metabolism have recently gained traction as promising targets for the development of new antibiotics, however, not all aspects of this process are understood. The ATP-grasp superfamily includes enzymes that predominantly catalyze the ATP-dependent ligation of various carboxylate and amine substrates. One subset, ʟ-amino acid ligases (LALs), primarily catalyze the formation of dipeptide products in Gram-positive bacteria, however, their involvement in S. aureus amino acid metabolism has not been investigated. Here, we present the characterization of the putative ATP-grasp enzyme (SAOUHSC_02373) from S. aureus NCTC 8325 and its identification as a novel LAL. First, we interrogated the activity of SAOUHSC_02373 against a panel of ʟ-amino acid substrates. As a result, we identified SAOUHSC_02373 as an LAL with high selectivity for ʟ-aspartate and ʟ-methionine substrates, specifically forming an ʟ-aspartyl-ʟ-methionine dipeptide. Thus, we propose that SAOUHSC_02373 be assigned as ʟ-aspartate-ʟ-methionine ligase (LdmS). To further understand this unique activity, we investigated the mechanism of LdmS by X-ray crystallography, molecular modeling, and site-directed mutagenesis. Our results suggest that LdmS shares a similar mechanism to other ATP-grasp enzymes but possesses a distinctive active site architecture that confers selectivity for the ʟ-Asp and ʟ-Met substrates. Phylogenetic analysis revealed LdmS homologs are highly conserved in Staphylococcus and closely related Gram-positive Firmicutes. Subsequent genetic analysis upstream of the ldmS operon revealed several trans-acting regulatory elements associated with control of Met and Cys metabolism. Together, these findings support a role for LdmS in Staphylococcal sulfur amino acid metabolism.


The effect of pH and temperature on the stability and enzymatic activity of prostatic acid phosphatase. Studies on the optimization of a continuous monitored determination of acid phosphatase, II.
The catalytic activity and the stability of prostatic acid phosphatase were studied with respect to pH and temperature: 1. Enzymatic activity in serum decreases with time, and the rate of decrease depends on pH and temperature. Half life times were estimated. 2. To preserve at least 90% of its original activity, serum must be cooled as soon as possible below room temperature and/or the pH must be lowered to 6. 3. Considering the effect of pH on side reactions and kinetic parameters, a pH of 5.2 is recommended for the assay. 4. Between 25 and 37 degrees C, the value for Km app, in the absence of alcohols, is constant within the limits of error. In the presence of alcohols there is a significant increase of Km app at lower temperatures, and higher substrate concentrations are needed to avoid nonsaturation of the enzyme. vmax increases with temperature. Inactivation is observed above 45 degrees C, especially in the presenc of alcohols. 5. The Arrhenius plot shows a strict linear regression between 20 degrees C and 40 degrees C, in the presence or absence of 1,4-butanediol, 1,5-pentanediol or 1,6-hexanediol. 6. Temperature conversion factors for catalytic activity were calculated to be: 1.33 (25 to 30 degrees C), 1.96 (25 to 37 degrees C) and 1.47 (30 to 37 degrees C).


A novel mouse model for the study of endogenous neural stem and progenitor cells after traumatic brain injury.
Traumatic brain injury (TBI) is a leading cause of death and disability in the US. Neural stem/progenitor cells (NSPCs) persist in the adult brain and represent a potential cell source for tissue regeneration and wound healing after injury. The Notch signaling pathway is critical for embryonic development and adult brain injury response. However, the specific role of Notch signaling in the injured brain is not well characterized. Our previous study has established a Notch1CR2-GFP reporter mouse line in which the Notch1CR2 enhancer directs GFP expression in NSPCs and their progeny. In this study, we performed closed head injury (CHI) in the Notch1CR2-GFP mice to study the response of injury-activated NSPCs. We show that CHI induces neuroinflammation, cell death, and the expression of typical TBI markers (e.g., ApoE, Il1b, and Tau), validating the animal model. In addition, CHI induces cell proliferation in GFP+ cells expressing NSPC markers, e.g., Notch1 and Nestin. A significant higher percentage of GFP+ astrocytes and GABAergic neurons was observed in the injured brain, with no significant change in oligodendrocyte lineage between the CHI and sham animal groups. Since injury is known to activate astrogliosis, our results suggest that injury-induced GFP+ NSPCs preferentially differentiate into GABAergic neurons. Our study establishes that Notch1CR2-GFP transgenic mouse is a useful tool for the study of NSPC behavior in vivo after TBI. Unveiling the potential of NSPCs response to TBI (e.g., proliferation and differentiation) will identify new therapeutic strategy for the treatment of brain trauma.


Toxic effect prediction of cefatirizine amidine sodium and its impurities by structure-toxicity relationship of cephalosporins.
The three-dimensional (3D) structure-toxicity relationship of cephalosporins was explored by computing the most stable conformations of 33 kinds of cephalosporins in aqueous solution and using the teratogenicity and lethality of these compounds obtained in zebrafish embryo toxicity testing to evaluate their toxic effects. The toxic effect of cefatirizine amidine sodium, a novel cephalosporin which has finished preclinical study, was investigated. It is thought that the teratogenic effect of the triazine ring at the C-3 position is the main toxic effect of cefatirizine amidine. In addition, cefatirizine amidine is no more toxic than cefathiamidine and ceftriaxone. The results of the zebrafish embryo toxicity test combined with gene expression microarray technology were consistent with the prediction. The toxic effects of some potential process-related impurities of cefatirizine amidine were also predicted.


Evolution of microstructures in materials induced by electropulsing.
Nanostructures were formed in several conventional materials under single electropulsing, that is nanophases of alpha-Cu(Zn) and beta'-(CuZn) in a cold-worked alpha-Cu(Zn) alloy, nanosized gamma-Fe in a low-carbon steel, nanosized alpha-Al in a superduralumin, and orientated nanosized TiC in a TiC/NiCr cermet. The mechanisms responsible for the above nanostructured transitions can be attributed to the competition of many factors induced by electropulsing, including high-rate heating, thermal stress, reduced thermodynamic energy barrier and high-rate electron impacting. Also, many low-energy dislocation configurations, twins and stacking faults were formed in the copper alloy and cermet under the electropulsing. Such evolution of defects was associated with the electrical, thermal and stress energies induced by the electropulsing.


[Effect of streptomycin sulfate on the process of higher nervous activity recovery in dogs in the postanesthesia period].
The effect of streptomycin on recovery of the higher nervous activity during the postanesthesia period was studied on 3 dogs with the method of the conditioned reflexes. It was found that streptomycin sulphate administered in a dose of 25 mg per 1 kg body weight induced no changes in the conditioned reflexes of the non-anesthetized animals. After ether anesthesia disorders in the conditioned and unconditioned reflexes, as well as differentiation was observed during the postanesthesia period. On an average they normalized in 7, 6 and 2 days respectively from the moment of anesthesia. When streptomycin sulphate was used during the post anesthesia period, both the strength and the character of the disorders in the conditioned reflexes changed. In this case recovery of the conditioned and unconditioned reflexes was registered in 2 days, while that of the differential inhibition was registered in 3--7 days from the moment of anesthesia.


Absence of complete internasal-interocular transfer of habituation of exploratory behavior in rats.
Normal, blind, anosmic, and unilaterally blind and contralaterally anosmic albino rats were submitted to unilateral peripheral sensory (olfactory and/or visual) occlusion and observed in an initially unfamiliar arena. Next day, either the same sensory periphery (control subjects) or the contralateral one (experimental subjects) was occluded and a new observation in the arena was made. The duration of the exploratory behavior of control and experimental subjects, on each occasion, was compared. There was not a complete internasal-interocular transfer of long-term habituation of exploratory behavior, either when olfaction and vision were suppressed on opposite sides or when they were suppressed on the same side, but there was a complete internasal transfer of this habituation in blind animals and a complete interocular transfer of this habituation in anosmic animals. These results suggest that long-term habituation of the exploratory behavior elicited by one olfactory and one visual periphery activation and that of the exploratory behavior elicited by the other olfactory and the other visual periphery activation depend upon different representations of the stimulatory situation in the central nervous system. These representations would, however, have only a small number of elements which are not shared.


Variations in hepatic progesterone 21-hydroxylase activity reflect differences in the microsomal concentration of rabbit cytochrome P-450 1.
A monoclonal antibody specific for cytochrome P-450 1 that extensively (greater than 95%) inhibits the hepatic 21-hydroxylation of progesterone was used in a two-site immunoradiometric assay to estimate the concentration of cytochrome P-450 1 in microsomes prepared from 24 individual, untreated New Zealand White rabbits. The progesterone 21-hydroxylase activities of these microsomes ranged from 0.2 to 5.8 nmol min-1 mg microsomal protein-1. Scatchard analysis revealed similar slopes and thus apparent affinities between the antibody and microsome samples that varied greater than 10-fold in 21-hydroxylase activity. The maximal extent of binding of the antibody to different microsomal preparations was greater for microsomes exhibiting high as compared to low 21-hydroxylase activity, suggesting that the level of binding reflects the microsomal content of P-450 1. Quantitation was based on the extent of binding of the 125I-labeled monoclonal antibody to P-450 1 sequestered from a sample by a heterologous monoclonal antibody adsorbed to the wells of a microtiter plate. These results indicate that the microsomal content of P-450 1 varies from less than 0.05 to 0.5 nmol/mg microsomal protein. The microsomal content of this antigen as determined in the two-site immunoradiometric assay was highly correlated (r = 0.97) with progesterone 21-hydroxylase activity. Linear regression analysis was used to estimate the turnover number for progesterone in situ, yielding a value of 11 nmol deoxycorticosterone formed min-1 nmol microsomal P-450 1(-1). This is similar to the value of 14 nmol deoxycorticosterone formed min-1 nmol-1 obtained for the reconstituted, purified P-450 1 used as a standard in the immunoquantitation assay.


Direct Cardiac Compression Devices to Augment Heart Biomechanics and Function.
The treatment of end-stage heart failure has evolved substantially with advances in medical treatment, cardiac transplantation, and mechanical circulatory support (MCS) devices such as left ventricular assist devices and total artificial hearts. However, current MCS devices are inherently blood contacting and can lead to potential complications including pump thrombosis, hemorrhage, stroke, and hemolysis. Attempts to address these issues and avoid blood contact led to the concept of compressing the failing heart from the epicardial surface and the design of direct cardiac compression (DCC) devices. We review the fundamental concepts related to DCC, present the foundational devices and recent devices in the research and commercialization stages, and discuss the milestones required for clinical translation and adoption of this technology.


Interictal spikes on intracranial recording: behavior, physiology, and implications.
The physiological, pathological, and clinical meaning of interictal spikes (IISs) remains controversial. We systematically analyzed the frequency, occurrence, and distribution of IISs recorded from multiple intracranial electrodes in 34 refractory epileptic patients with respect to seizures and antiepileptic drug (AED) changes. Continuous spike counts from all recorded contacts of all implanted electrodes, and also separately for the subset of contacts involved at seizure onset, were tabulated for every hour of every day of recording, and expressed as spikes per hour in six preselected, 24-h intervals (defined to exclude seizures): (1) on medications; (2) prepreseizure; (3) preseizure; (4) postseizure; (5) off meds; and (6) resumed meds. Mean spike rates were analyzed for differences between designated 24-h intervals. Spike rate in all recorded contacts consistently and significantly decreased after AED withdrawal, despite variability in initial spike rate, diurnal occurrence, seizure character/number/localization of onset, and type(s) of AED continued or withdrawn (p < 0.0001). A significant increase in spike rate was noted in the 24 h after seizures of medial temporal origin, in the medial temporal lobe contacts; neocortical onset seizures did not show any increase. These observations confirm and extend previous reports, suggesting a general effect of AED withdrawal, and a more specific effect of medial temporal lobe seizures, on IIS rate. AED mechanisms and efficacy might be demonstrated by quantifying IIS with changes in AEDs. Furthermore, variability in IIS rate after seizures distinguishes localization of seizure onset in medial temporal versus neocortical locations.


Rescue of a patient out of a grain container: the quicksand effect of grain.
Grain storage containers not only present inherent dangers to the operators, but also to the rescuers if someone falls in. Here we report the rescue of a patient from a grain container using a novel technique involving a cylinder placed around the patient. This allowed the grain to be sucked out from around the patient and enabled his rescue uninjured. The rescue action was complicated by acute chest pain in the patient while he was submerged in the grain, and a severe asthma attack in the emergency physician. The rescue and the dilemmas encountered are described together with a review of the relevant literature.


Poly-L-asparagine nanocapsules as anticancer drug delivery vehicles.
This work presents for the first time the development of novel poly-L-asparagine (PASN) nanocapsules and the in vitro evaluation of their potential as anticancer drug delivery systems. The design of PASN nanocapsules was inspired by the well-known avidity of cancer cells for the amino acid L-asparagine together with the expected ability of this hydrophilic polymer to escape to the mononuclear phagocytic system. Besides, these nanocapsules have an oily reservoir, which enables the efficient encapsulation of lipophilic drugs. PASN nanocapsules were obtained by an emulsification-polymer layer deposition process, which involves using a cationic surfactant as a bridge for the interaction of PASN with the lipid core. PASN nanocapsules showed sizes of around 170-200 nm and negative zeta potential values (around -20 mV to -40 mV). The model anticancer drug docetaxel was efficiently encapsulated (around 75%) and retained within the nanocapsule's structure upon dilution in a simulated physiological medium. Moreover, these nanocapsules exhibited the ability to interact with the NCI-H460 human cancer cells and to enhance the cellular toxicity of the anticancer drug. All these features together with their adequate stability profile render these nanocapsules a new attractive platform for anticancer intracellular drug delivery.


Understanding nonresponders of cardiac resynchronization therapy--current and future perspectives.
Cardiac resynchronization therapy (CRT) is now an established nonpharmacologic therapy for advanced heart failure with electromechanical delay. Despite compelling evidence of the benefits of CRT, one troubling issue is the lack of a favorable response in about one-third of patients. Currently, there is no unifying definition of responders, and published data were based on acute hemodynamic changes, chronic left ventricular reverse remodeling, as well as the intermediate or long-term clinical response. The lack of improvement with CRT can be due to many factors including the placement of the left ventricular pacing lead in an inappropriate location, the absence of electrical conduction delay or mechanical dyssynchrony despite wide QRS complexes, and possibly failure to optimize the CRT settings after device implantation. In acute hemodynamic studies, placing the left ventricular leads at the free wall region has been suggested to generate the best pulse pressure and positive dp/dt. The degree of mechanical dyssynchrony has recently been assessed noninvasively in CRT patients by echocardiography and in particular by tissue Doppler imaging. These studies suggested that responders of left ventricular reverse remodeling or systolic function had more severe systolic dyssynchrony. However, further studies are needed to examine the clinical utility of these parameters when applied to the standardized anatomic or functional endpoints. Optimization of atrioventricular and interventricular pacing intervals may also reduce the number of nonresponders, though newer methods, especially interventricular pacing intervals, are still under clinical investigation. With the adjunctive use of imaging technology, physicians are able to characterize the response to CRT objectively, and cardiac imaging is an important clinical tool for determining more precisely the presence and degree of mechanical dyssynchrony.


Occupational stress and RANs.
This paper explores nurses' self-reported stress during a time of policy changes in the Northern Territory Health Department. It is argued that current research tends to associate nurses' stress with their personality or type of work, offering a psychological or occupational explanation. Little consideration is given to the complex structural subordination and ambivalence remote area nurses experience on Aboriginal settlements vis a vis their immediate superiors and clients. It is proposed that the nurses' self-reported stress can be partly accounted for by their marginal position between these two groups. The sociological concept of marginality can explain this.


Diabetes mellitus, revascularization and outcomes in elderly patients with myocardial infarction-related cardiogenic shock.
The prognostic role of diabetes mellitus (DM) in elderly patients with myocardial infarction-related cardiogenic shock (MI-CS) remains controversial. Little information exists about the impact of intensive cardiac care unit (ICCU) and revascularization on outcomes of elderly patients with MI-CS. We aimed to assess the prognostic impact of DM according to age in patients with MI-CS, and to analyze the impact ICCU management and revascularization on in-hospital mortality in MI-CS patients at older ages. Discharge episodes with diagnosis of CS associated with MI were selected from the Spanish National Health System's Basic Data Set. Centers were classified according to their availability of ICCU. Main outcome measured was in-hospital mortality. A total of 23, 590 episodes of MI-CS were identified, of whom 12, 447 (52.8%) were in patients aged ≥ 75 years. The impact of DM on in-hospital mortality was different among age subgroups. While in younger patients, DM was associated to a higher mortality risk (0.52 vs. 0.47, OR = 1.12, 95% CI: 1.06-1.18, χ 2 < 0.001), this association became non-significant in older patients (0.76 vs. 0.81, χ 2 = 0.09). Adjusted mortality rate of MI-CS aged ≥ 75 years was lower in patients admitted to hospitals with ICCU (adjusted mortality rate: 74.2% vs. 77.7%, P < 0.001) and in patients undergoing revascularization (74.9% vs. 77.3%, P < 0.001). Prognostic impact of DM in patients with MI-CS was different according to age, with a significantly lower impact at older ages. The availability of ICCU and revascularization were associated with better outcomes in these complex patients.


Electrogalvanic stimulation in the treatment of levator syndrome.
The records of 102 patients with levator syndrome were reviewed. All had failed trials of conservative management prior to treatments with electrogalvanic stimulation. The symptoms of 12 patients were subsequently found not to be due to levator syndrome. Of 90 patients with correct diagnoses, 77 percent were relieved or improved after courses of electrogalvanic stimulation, a valuable adjunct to the management of this frustrating condition.


[Animal study of the bone substitute material Ostim within osseous defects in Göttinger minipigs].
The aim of this study was to examine Ostim, a nanocrystalline hydroxyapatite suspension, with regard to its bio- and osteocompatibility, rate of resorption and remodeling dynamics within osseous defects. Ostim was implanted in a randomised fashion into the proximal metaphysis of either the right or the left tibia of 18 Göttinger minipigs. Based on microradiographs and histological examinations Ostim showed biocompatibility, bioactivity and osteoconductivity. This substitute material exhibited osseous integration. The degradation process stopped after six weeks. With regard to osseous regeneration within the defects, there were no significant differences between the time intervals of follow-up. Ostim could still be detected in significant amounts after one year with no complete resorption. A restitutio ad integrum could not be observed in spite of the histological evidence of the above-described reactions within the implantation site. A thorough osseous incorporation seemed to impede the degradation of the bone substitute material. The paramount goal is to improve the biological behaviour in favour of a higher rate of degradation.


Boosted charge transfer in ReS2/Nb2O5 heterostructure by dual-electric field: Toward superior electrochemical reversibility for lithium-ion storage.
Heterostructures with the electric field effect can excite the charge transfer kinetics of materials due to the driving force of the electric field. Herein, we report a new ReS2/Nb2O5 heterostructure of rhenium disulfide coupled to niobium oxide with a mutually compatible band structure and enriched oxygen vacancies. The unique heterostructure can facilitate the redistribution of charges to induce built-in electric fields and microlocalized electric fields. As expected, the ReS2/Nb2O5 heterostructure shows a superior lithium-ion reversible capacity of 805 mAh g-1 after 2400 h at 0.10 A g-1, and 414 mAh g-1 at 2.00 A g-1. In addition, in situ X-ray diffraction and ex situ X-ray photoelectron spectroscopy analysis reveal the phase transition process of the ReS2/Nb2O5 heterostructure during the electrochemical reaction. This provides deeper insights into the construction of high-performance lithium-ion storage materials based on heterostructures with dual-electric field-driven charge transfer.


A systematic review of the effects of cold exposure on pathological cardiac remodeling in mice.
Exposure to cold promotes cardiac remodeling, characterized by deleterious effects on structure and function, contributing to increased mortality from cardiovascular diseases. The mechanisms associated with these changes are poorly understood. This review gathers the literature data on the main alterations and mechanisms associated with the adverse cardiac structural and functional remodeling induced by cold exposure in mice. Original studies were identified by searching PubMed, Scopus, and Embase databases from January 1990 to June 2022. This systematic review was conducted in accordance with the criteria established by PRISMA and registered in PROSPERO (CRD42022350637). The risk of bias was evaluated by the SYRCLE. Eligible studies included original papers published in English that evaluated cardiac outcomes in mice submitted to short- or long-time cold exposure and had a control group at room temperature. Seventeen original articles were included in this review. Cold exposure induces pathological cardiac remodeling, characterized by detrimental structural and functional parameters, changes in metabolism and autophagy process, and increases in oxidative stress, inflammation, and apoptosis. In addition, Nppa, AT1A, Fbp3, BECN, ETA, and MT, appear to play fundamental roles in regulating cardiac remodeling. We suggest that strategies that seek to minimize the CVD risk and adverse effects of cold exposure should target these agents.


The relationship of genetic risk score with cardiometabolic risk factors: a cross-sectional study.
For more than eight decades, cardiovascular disease (CVD) has remained the leading cause of death in the world. CVD risk factors are multifaceted, with genetics and lifestyle both playing a role. The aim of this study was to investigate the association between a genetic profile risk score for obesity GRS and cardio-metabolic risk factors in overweight and obese women. The current cross-sectional study was conducted on 391 overweight and obese women. The genetic risk score was created by combining three single nucleotide polymorphisms [MC4R (rs17782313), CAV-1 (rs3807992), and Cry-1 (rs2287161)]. Anthropometric measurements, blood pressure, and some blood parameters were measured by standard protocols. A significant association between the GRS and some of cardiometabolic risk factors variables such as body mass index (β = 0. 49, 95%CI = 0.22 to 0.76, p < 0.001), waist circumference (β = 0. 86, 95%CI = 0.18 to 1.54, p = 0.01), body fat mass (β = 0. 82, 95%CI = 0.25 to 1.39, p = 0.005), %body fat (β = 0. 44, 95%CI = 0.06 to 0.82, p = 0.02), and hs-CRP (β = 0.46, 95% CI = 0.14 to 0.78, p = 0.005) was observed in crude model. After adjustment for confounding factors (age, BMI, and physical activity), a significant positive association was observed between BMI (p = 0.004), WC (p = 0.02), body fat mass (p = 0.01), %BF (p = 0.01), hs-CRP (p = 0.009), and GRS. In addition, we discovered a significant negative association between the GRS and BMC (= -0.02, 95%CI = -0.05 to -0.001, p = 0.04). But other variables did not show any significant association with GRS among obese and overweight women. We found a significant positive association between GRS, including MC4R (rs17782313), CAV-1 (rs3807992), and Cry-1 (rs2287161) and cardiometabolic risk factors among overweight and obese Iranian women.


Laboratory techniques of veterinary clinical immunology: a review.
Laboratory tests currently used or easily applicable in veterinary clinical immunology were reviewed in the following three categories: (1) tests detecting disorders in humoral immune response: serum protein screening tests, gammaglobulin estimation and complement testing; (2) tests detecting disorders in cellular immune response: phagocyte function tests and lymphocyte function tests; (3) tests detecting autoimmune disorders: detection of antinuclear antibodies, rheumatoid factor, autoimmune hemolytic diseases, and autoimmune organ and tissue disorders. The principles of the tests and the interpretations of the results are presented with the appropriate references.


Hypoxic depression of circadian oscillations in sino-aortic denervated rats.
We hypothesized that hypoxia depresses the circadian oscillations of body temperature (T(b)) and oxygen consumption (V(O(2))) even in the absence of inputs from the peripheral chemoreceptors. Adult rats were sino-aortic denervated bilaterally (SAX, N=17) or sham-operated (Sham, N=17). Ten rats of each group were instrumented for measurements of T(b) and activity by telemetry. Animals were exposed to normoxia (21% O(2)), hypoxia (10.5% O(2)), and again normoxia, each for a 5-day duration, in constant light ('free-running') conditions. Hypoxia almost eliminated the T(b) circadian oscillations, mostly by abolishing the daily rise in T(b). Upon return to normoxia T(b) rapidly increased and the normal oscillation was reestablished at the expected phase of the cycle. The hypoxic effects did not differ between Sham and SAX. During hypoxia the amplitude of the circadian oscillation of activity was reduced by approximately 25%, and that of V(O(2)), measured by an open flow method in the remaining Sham and SAX rats (N=7 each), was reduced by almost 50%. In all cases there was no difference between the two groups. We conclude that activation of the peripheral chemoreceptors is not required for the manifestation of the hypoxic depression of the metabolic and temperature circadian oscillations. The results are compatible with the view that hypoxia depresses thermogenesis acting on the thermoregulatory centers of the hypothalamus.


Individual variations in ankle brachial index measurement among Turkish adults.
Variability of ankle brachial index (ABI) measured by the same observer in the same individual on three different occasions was examined. A single morning ABI was initially determined (measurement 1) with handheld Doppler device. One to four weeks apart, another morning (measurement 2) and afternoon (measurement 3) ABI was measured on the same day. A total of 161 adults were enrolled. Mean ABI was similar among the three measurements. ABI differed more than ≥0.15 in 15 individuals between measurement 1 and 3, in 10 subjects between measurement 1 and 2, and in 12 individuals between measurement 2 and 3. Intra-group correlation coefficients of reproducibility of ABI were 0.808 for single measurements (coefficient of the values lacking association with each other), and 0.927 for average measurements (coefficient of the values that were associated with each other). Although reproducibility of ABI values was found satisfactory, up to 12% of participants displayed more than 0.15 alternations between measurements, either on the same day or more than a week apart.


Hypericin in cancer treatment: more light on the way.
Photodynamic therapy (PDT) has been described as a promising new modality for the treatment of cancer. PDT involves the combination of a photosensitizing agent (photosensitizer), which is preferentially taken up and retained by tumor cells, and visible light of a wavelength matching the absorption spectrum of the drug. Each of these factors is harmless by itself, but when combined they ultimately produce, in the presence of oxygen, cytotoxic products that cause irreversible cellular damage and tumor destruction. Hypericin, a powerful naturally occurring photosensitizer, is found in Hypericum perforatum plants, commonly known as St. John's wort. In recent years increased interest in hypericin as a potential clinical anticancer agent has arisen since several studies established its powerful in vivo and in vitro antineoplastic activity upon irradiation. Investigations of the molecular mechanisms underlying hypericin photocytotoxicity in cancer cells have revealed that this photosensitizer can induce both apoptosis and necrosis in a concentration and light dose-dependent fashion. Moreover, PDT with hypericin results in the activation of multiple pathways that can either promote or counteract the cell death program. This review focuses on the more recent advances in the use of hypericin as a photodynamic agent and discusses the current knowledge on the signaling pathways underlying its photocytotoxic action.


Disseminated intravascular coagulation in carcinoma of prostate: role of estrogen therapy.
Advanced carcinoma of the prostate may present as disseminated intravascular coagulation and its sequelae. It is postulated that the slow release of thromboplastic material from tumor cells eventually overcomes normal homeostatic mechanisms. High-dose intravenous diethylstilbestrol diphosphate successfully reversed this coagulopathy in 2 cases of metastatic carcinoma of the prostate.


Preservation and Processing of Intestinal Tissue for the Assessment of Histopathology.
The intestine is often examined histologically in connection with allergies and in search for pathological changes. To be able to examine the intestine histologically with a microscope, it must be sampled and processed correctly. For microscopic analysis, the samples have to be cut into thin sections, stained, and mounted on slides. Since it is not possible to cut fresh samples without damaging them, they must first be fixed. The most common method, which is described herein, is the fixation in formalin with subsequent embedding in paraffin and staining of the slides with hematoxylin and eosin (H&E). Hematoxylin solutions (in this case Mayer's hemalum solution) stain the acidic components of the cell, i.e., cell nuclei, blue. The staining with eosin gives a pink staining of cytoplasm. This chapter describes the method of processing intestinal tissue for paraffin-embedding, sectioning, and staining with H&E. Tissue processing can be done in tissue processing machines or manually. We describe the manual processing that is often used for smaller batches of samples.


A standardized nursing mathematics competency program.
Mathematics competency in nursing is an ongoing problem. The author discusses a standardized mathematics competency program based on current practices reported in nursing literature. Dimensional analysis is the method that students learn to find solutions to nursing problems that require mathematics and is important to the success of the program.


A new method to evaluate the stability of the covalent compound: by the charges on the common atom or group.
A new method of comparing and analyzing the electrostatic potential (ESP) charges of the common atom or group to evaluate and compare the stabilities of covalent compounds was introduced. That is, covalent compounds will become more stable when the electron acceptors accept adequate electrons and possess adequate negative charges, and the electron donors donate adequate electrons and possess adequate positive charges accordingly. All calculations were performed by density functional theory (DFT) and the general gradient approximation (GGA) method with the Beck-LYP hybrid functional and the DNP basis set in Acceryls' code Dmol3. Calculation results verified the method considering the molecular structure is well applied in the covalent molecule systems of hydrides, oxides, alkyl radicals, and nitro compounds. Furthermore, the method has good operability, for the charges can be easily obtained by simple calculation.


Association of whole blood metals/metalloids with severity in sepsis patients: A prospective, single-center, pilot study.
Trace metals/metalloids were important for the biological functions of both the eukaryotic host and the microorganism. Their concentrations and variations may associate with the critical illness in sepsis, which still needs to be investigated. We performed a prospective cohort study on the patients with sepsis admitted to Tongji hospital (Wuhan, China) from Jul 01 to Dec 31, 2021. Sepsis was diagnosed in accordance with the third international consensus definitions for sepsis and septic shock (Sepsis-3). The concentrations of metals/metalloids including magnesium (Mg), calcium (Ca), chromium (Cr), manganese (Mn), iron (Fe), copper (Cu), zinc (Zn), arsenic (As), cadmium (Cd), mercury (Hg), thallium (Tl) and lead (Pb) in whole blood were analyzed by ICP-MS based methods. Compared to the healthy controls, patients with sepsis showed higher levels of Ca, Cr and Cu, and lower levels of Mg, Mn, Fe, Zn, As, Hg and Pb. Further analysis between the critical illness and noncritical illness, revealed the Mn, Fe were significantly lower in the critically-ill sepsis. The longitudinal profile of the two metals show the differences appeared to exist almost throughout the clinical course. By performing the binary regression logistic analysis, we determined the Fe, Mn as independently risk factors for critical illness in sepsis, with effect sizes (β) of 17.14 (95%CI: 1.79-163.81) and 10.83 (1.96-59.83), respectively, which collectively discriminated 83.3% of all cases between critical-illness and non-critically illness. The variations of whole blood metals/metalloids were associated with the critically-ill sepsis.


High-performance hydroxyapatite chromatography of integral membrane proteins and water-soluble proteins in complex with sodium dodecyl sulphate.
Integral membrane proteins from human erythrocytes were fractionated in the presence of sodium dodecyl sulphate (SDS) on four types of high-performance hydroxyapatite columns. A column of 2-microns sintered hydroxyapatite beads from Asahi Optical (Tokyo, Japan) gave the best resolution. With this column, glycophorin was eluted early in a gradient of increasing sodium phosphate buffer concentration, the glucose transporter was eluted later in two zones, one of which contained this protein alone, and the anion transporter was eluted last. Water-soluble proteins applied in complex with SDS also separated reasonably well upon elution. The water-soluble proteins and the membrane proteins were all eluted mainly in the order of increasing polypeptide length, but with considerable individual variation. SDS-polypeptide complexes are probably adsorbed onto hydroxyapatite by the interaction of positively charged amino acid side groups with phosphate ions (at P-sites) and of negatively charged amino acid side groups and polypeptide-bound dodecyl sulphate anions with calcium ions (at C-sites). As a rule, the number of charged side groups and dodecyl sulphate anions, and thus the number of binding sites, increases with the polypeptide chain length, which explains the general order of release of the polypeptides.


Inhibitory effects of terpenoids from the fermented broth of the ascomycete Stilbohypoxylon elaeicola YMJ173 on nitric oxide production in RAW264.7 macrophages.
A series of six isopimarane-type diterpene glycosides, along with an eremophilane-type sesquiterpene, i.e., elaeicolasides A-C (1-3, resp.), 16-(α-D-mannopyranosyloxy)isopimar-7-en-19-oic acid (4), hymatoxin K (5), hymatoxin L (6), and elaeicolalactone (7), were isolated from the AcOEt extract of the fermented broth of Stilbohypoxylon elaeicola YMJ173. Among these, 1-3 and 7 are new compounds based on their spectroscopic data and sugar composition analysis. The effects of 1-7 on the inhibition of nitric oxide (NO) production in lipopolysaccharide (LPS)-activated murine macrophage RAW264.7 cells were evaluated. All these compounds inhibited NO production, detected as nitrite in the culture medium, in activated macrophages without any cytotoxicity at a concentration of 100 μM. Among these compounds, 2 showed a significant activity with the average maximum inhibition (E(max)) and median inhibitory concentration (IC(50)) values of 93.3±0.5% and 79.3±0.4 μM, respectively.


Bone marrow-derived and resident liver macrophages display unique transcriptomic signatures but similar biological functions.
Kupffer cells (KCs), the resident tissue macrophages of the liver, play a crucial role in the clearance of pathogens and other particulate materials that reach the systemic circulation. Recent studies have identified KCs as a yolk sac-derived resident macrophage population that is replenished independently of monocytes in the steady state. Although it is now established that following local tissue injury, bone marrow derived monocytes may infiltrate the tissue and differentiate into macrophages, the extent to which newly differentiated macrophages functionally resemble the KCs they have replaced has not been extensively studied. We studied the two populations of KCs using intravital microscopy, morphometric analysis and gene expression profiling. An ion homeostasis gene signature, including genes associated with scavenger receptor function and extracellular matrix deposition, allowed discrimination between these two KC sub-types. Bone marrow derived "KCs" accumulating as a result of genotoxic injury, resemble but are not identical to their yolk sac counterparts. Reflecting the differential expression of scavenger receptors, yolk sac-derived KCs were more effective at accumulating acetylated low density lipoprotein, whereas surprisingly, they were poorer than bone marrow-derived KCs when assessed for uptake of a range of bacterial pathogens. The two KC populations were almost indistinguishable in regard to i) response to lipopolysaccharide challenge, ii) phagocytosis of effete red blood cells and iii) their ability to contain infection and direct granuloma formation against Leishmania donovani, a KC-tropic intracellular parasite. Bone marrow-derived KCs differentiate locally to resemble yolk sac-derived KC in most but not all respects, with implications for models of infectious diseases, liver injury and bone marrow transplantation. In addition, the gene signature we describe adds to the tools available for distinguishing KC subpopulations based on their ontology. Liver macrophages play a major role in the control of infections in the liver and in the pathology associated with chronic liver diseases. It was recently shown that liver macrophages can have two different origins, however, the extent to which these populations are functionally distinct remains to be fully addressed. Our study demonstrates that whilst liver macrophages share many features in common, regardless of their origin, some subtle differences in function exist. Gene expression data are available from the European Bioinformatics Institute ArrayExpress data repository (accession number E-MTAB-4954).


(4aR,9R,9aR)-7-Bromo-9-nitro-methyl-2,3,4,4a,9,9a-hexa-hydro-1H-xanthen-1-one.
The title compound, C14H14BrNO4, contains a tricyclic ring system including three contiguous stereocenters all of which exhibit an R configuration. The cyclo-hexa-none ring adopts a chair conformation. The central oxane ring assumes a strained envelope conformation, with five of the ring atoms being nearly coplanar with the bromo-phenyl group and with the C atom adjacent to the O atom and fused with the cyclo-hexa-none ring as the flap. In the crystal, mol-ecules are linked into a three-dimensional network by C-H⋯O inter-actions.


C7-Prenylation of Tryptophan-Containing Cyclic Dipeptides by 7-Dimethylallyl Tryptophan Synthase Significantly Increases the Anticancer and Antimicrobial Activities.
Prenylated natural products have interesting pharmacological properties and prenylation reactions play crucial roles in controlling the activities of biomolecules. They are difficult to synthesize chemically, but enzymatic synthesis production is a desirable pathway. Cyclic dipeptide prenyltransferase catalyzes the regioselective Friedel-Crafts alkylation of tryptophan-containing cyclic dipeptides. This class of enzymes, which belongs to the dimethylallyl tryptophan synthase superfamily, is known to be flexible to aromatic prenyl receptors, while mostly retaining its typical regioselectivity. In this study, seven tryptophan-containing cyclic dipeptides 1a-7a were converted to their C7-regularly prenylated derivatives 1b-7b in the presence of dimethylallyl diphosphate (DMAPP) by using the purified 7-dimethylallyl tryptophan synthase (7-DMATS) as catalyst. The HPLC analysis of the incubation mixture and the NMR analysis of the separated products showed that the stereochemical structure of the substrate had a great influence on their acceptance by 7-DMATS. Determination of the kinetic parameters proved that cyclo-l-Trp-Gly (1a) consisting of a tryptophanyl and glycine was accepted as the best substrate with a KM value of 169.7 μM and a turnover number of 0.1307 s-1. Furthermore, docking studies simulated the prenyl transfer reaction of 7-DMATS and it could be concluded that the highest affinity between 7-DMATS and 1a. Preliminary results have been clearly shown that prenylation at C7 led to a significant increase of the anticancer and antimicrobial activities of the prenylated derivatives 1b-7b in all the activity test experiment, especially the prenylated product 4b.


Primary structure of the rat kidney band 3 anion exchange protein deduced from a cDNA.
A rat kidney cDNA library was screened using an oligonucleotide hybridization probe derived from an amino acid sequence of the mouse erythrocyte Band 3 Cl-/HCO3- exchanger. Ten cDNAs representing a single class of mRNA and encoding the kidney Band 3 anion exchanger were isolated. Analysis of the deduced amino acid sequence revealed that kidney Band 3 is a truncated version of erythrocyte Band 3. The 848-amino acid rat kidney protein is virtually identical to mouse erythrocyte Band 3 except that it lacks the first 79 amino acids of the N-terminal cytoplasmic domain. Exons 1, 2, and 3 of the Band 3 gene, which are included in erythrocyte Band 3 mRNA, are not present in the kidney cDNA. The 5'-untranslated regions of kidney Band 3 transcripts contain sequences from the third intron and exons 4 and 5 of the Band 3 gene. The sequences from exons 4 and 5 that serve as untranslated sequences in the rat kidney mRNA have the potential to encode amino acids 46-79 of erythrocyte Band 3 but are not part of an open reading frame; the apparent translation initiation site corresponds to codon 80 of mouse erythrocyte Band 3 mRNA. Northern blot hybridization studies indicate that two additional Band 3 mRNAs, which differ in size from the major 4.5-kilobase pair transcript in kidney, are expressed at low levels in kidney and brain.


Studies on the thromboxane synthesizing system in human platelet microsomes.
The thromboxane synthesizing system from human platelets has been characterized by using arachidonic acid and prostaglandin endoperoxide as indirect and direct substrates. The synthesis of thromboxanes from either substrates catalyzed by the microsomal fraction was monitored by measuring the formation of thromboxane B2 immunoreactivity. Both hemoglobin and phenolic compounds were required for the maximal synthesis of thromboxane B2 from arachidonic acid but not from prostaglandin endoperoxide. Studies on the kinetics of the formation of thromboxane B2 from either substrates indicated that the synthesis of prostaglandin endoperoxide intermediate is the rate-limiting step in the overall production of thromboxanes from arachidonic acid. Effect of the microsomal protein concentrations on the rate of formation of thromboxane B2 showed concave upward relationship suggesting the possible involvement of endogenous stimulator(s) in thromboxane synthetase catalyzed reaction. A variety of compounds including sulfhydryl inhibitors, prostaglandin endoperoxide analog, prostaglandin antagonist, N-0164, and N-substituted imidazoles could directly inhibit the thromboxane synthetase, while nonsteroidal antiinflammatory drugs apparently affected the prostaglandin endoperoxide synthetase which catalyzes the synthesis of the immediate precursor of thromboxanes.


Allostructions revisited.
An important recent innovation in Construction Grammar (CxG) has been to assume the existence of a general underspecified construction underlying two or more alternating constructions, which themselves are considered to be formally and functionally related allostructions of the general construction. Despite this novel proposal, the meaning side of the general construction has either been neglected or couched in a single-layered view of meaning that does not adequately distinguish semantics from pragmatics. Building on state-of-the-art developments at the semantics-pragmatics interface, this article proposes an account whereby the distinction between the meaning of the general construction and the meaning of the allostructions aligns with the distinction between encoded (semantic) and inferred (pragmatic) meaning. We argue in favor of an allostructional account for two grammatical alternations which have previously been treated as an epiphenomenon of two underlying independent constructions: the German ditransitive alternation and the English genitive alternation. While demonstrating the fruitfulness of an allostructional analysis for these two new cases, we also provide critical observations about the wider applicability of allostructional analyses. In particular, we argue that an allostructional analysis proves to be trivial for Lambrechtian 'allosentences'.


Molecular recognition of a membrane-anchored HIV-1 pan-neutralizing epitope.
Antibodies against the carboxy-terminal section of the membrane-proximal external region (C-MPER) of the HIV-1 envelope glycoprotein (Env) are considered as nearly pan-neutralizing. Development of vaccines capable of producing analogous broadly neutralizing antibodies requires deep understanding of the mechanism that underlies C-MPER recognition in membranes. Here, we use the archetypic 10E8 antibody and a variety of biophysical techniques including single-molecule approaches to study the molecular recognition of C-MPER in membrane mimetics. In contrast to the assumption that an interfacial MPER helix embodies the entire C-MPER epitope recognized by 10E8, our data indicate that transmembrane domain (TMD) residues contribute to binding affinity and specificity. Moreover, anchoring to membrane the helical C-MPER epitope through the TMD augments antibody binding affinity and relieves the effects exerted by the interfacial MPER helix on the mechanical stability of the lipid bilayer. These observations support that addition of TMD residues may result in more efficient and stable anti-MPER vaccines.


Is Parkinson's disease of early onset a separate disease entity?
Two groups of patients suffering from Parkinson's disease were studied. The first group consisted of 23 patients with an onset age before 40 years; in the second group of 21 patients the onset was after age 50. The clinical findings and the course of the disease were very similar in each group. In spite of a longer disease duration in the patients with early onset of the disease there was no difference in motor impairment; the younger patients did better in mental testing and they were taking less dopaminergic medication. These differences are thought to be due to the age difference rather than to the existence of different disease entities. In the early onset group more familial cases (mostly affecting siblings) were found than in the older ones. The points in favour of there being a hereditary subgroup of early onset Parkinson's disease or of environmental factors causing the disease are reviewed.


Leadership and crisis management and their link to improvement of hotel performance: A study of the Jordanian hotel sector.
The current environment of volatility, uncertainty, complexity and ambiguity has created a prolonged state of uncertainty for the Jordanian hotel industry. Crisis management leadership is one of the most important attributes for a hotel. The main aim of this study is to evaluate the mediating role of crisis management, the moderating role of a leader's experience, their relationship to styles of leadership (transformational and transactional) and the resultant performance of Jordanian hotels. Research was based on a self-distributed questionnaire survey of 119 respondents currently holding managerial positions in Jordanian 3 to 5 star hotels. Partial Least Square Structural Equation Modelling was then employed. The findings suggest a transformational leadership style and crisis management experience are the most important attributes for a leader to sustain hotel performance during a crisis. Leaders with a transactional leadership style need crisis management skills to sustain hotel performance rather than experience which is not as important in their case. This paper proves that different leadership styles have a different influence on a hotel's survivability during a crisis. Therefore, a hotel's management group must ensure that a leader with an appropriate leadership style takes control during these situations. By combining leadership attributes, experience, and crisis management in a comprehensive framework to ensure sustainable hotel performance in the face of a crisis, this study adds to the body of knowledge on leadership and crisis management practices.


A practical approach to evidence-based dentistry: VII: How to use patient management recommendations from clinical practice guidelines.
Clinical practice guidelines represent highly processed evidence with associated recommendations to inform clinical practice and optimize patient care. Appropriately developed, evidence-based recommendations will integrate the best evidence regarding benefits and harms, the certainty of the evidence, patients' values and preferences, and resource utilization. The authors provide a structure for clinicians to critically appraise clinical practice guidelines to determine whether the guidelines offer trustworthy recommendations.


Efficacy of '8-drugs-in-one-day' combination in treatment of recurrent GBM patients.
Thirty-five adult recurrent GBM patients, divided randomly in two groups of 19 and 16 cases, had been treated with two regimens of chemotherapy: a) 'eight-drugs-in-one-day'; b) procarbazine + CCNU + vincristine (PCV) respectively. Chemotherapy was planned at the tumour relapse and delivered as long as tolerated without irreversible sequelae or until the CT scan showed tumor progression. Multiple agents are used simultaneously in the therapeutic approach using 'eight-in-one' to kill as many heterogeneous cells of malignant glial tumor as possible and minimize the emergence of cellular resistance to chemotherapy. Rate response to chemotherapy and the median adjunctive survival time (6.5 and 6 months, respectively) are not significantly different in the two arms of this study. Our experience with such an aggressive multi-drugs combination 'eight-in-one-day' was disappointing if compared with less toxic, better tolerated and easy delivered (PCV) regimen.


Biodiversity of Trichoderma from grassland and forest ecosystems in Northern Xinjiang, China.
Trichoderma spp., a cosmopolitan fungal genus, has remarkable economic value in industry and agriculture. The resources of Trichoderma spp. in the grassland and forest ecosystems of northern Xinjiang were explored in this study. A total of 634 soil samples was collected, and 312 strains assigned to 23 species of Trichoderma spp. were identified. T. harzianum was the dominant species with 28.2% from all isolates. The principal components analysis indicated that ecosystem was the most dominant impact factor among longitude, latitude, altitude and ecosystems for the species diversities of Trichoderma spp. with the decreasing trend from the north to the south of northern Xinjiang (e.g., from Altay, followed by Yili, Changji, Bayingolin and finally Urumqi). Overall, Trichoderma spp. were more frequently encountered in forest ecosystems (coniferous forest and coniferous and broadleaf mixed forest) than in grassland ecosystems (desert steppe and temperate steppe). Frequency of Trichoderma spp. was significantly decreased along with increased altitude and only a few strains were isolated from altitudes above 3000 m. The results provided essential information on Trichoderma occurrence and distribution, which should benefit the application of Trichoderma in agriculture.


In Vitro Assessment of Histology Verified Intracranial Atherosclerotic Disease by 1.5T Magnetic Resonance Imaging: Concentric or Eccentric?
Clinical trial studies show that plaque eccentricity (symmetry) is among the plaque features that have been associated with more frequent cerebrovascular events. Plaque eccentricity of intracranial atherosclerotic disease is unclear because of lacking of cerebral artery specimens. 1.5T magnetic resonance imaging was performed in the postmortem brains to scan the cross sections of middle cerebral artery. Plaque eccentricity of histology-verified middle cerebral artery atherosclerosis was calculated on T1-weighted fat-suppressed sequence. Validated by histology, concentric atherosclerotic plaques were identified in 46 middle cerebral arteries (63.9%) on magnetic resonance imaging and eccentric plaques in 26 arteries (26.1%). Eccentric plaques showed higher maximum wall thickness and lower minimum wall thickness than concentric plaques (both P<0.001). Plaque burden and brain infarctions were similar between concentric and eccentric plaques. Intracranial atherosclerosis presents as eccentric or concentric in geometry, which may be not linked to intracranial plaque risk. Further in vivo imaging studies are needed to identify morphological features of intracranial plaques and to verify its association with brain infarctions.


A novel method of isolation and some characteristic properties of human pancreatic elastases.
One component of elastases of human pancreatic juice and pancreatic extract was obtained in a highly purified state by chromatography on a column of sawdust. The elastase obtained after repeated adsorption chromatography with NaCl-containing buffers was almost homogeneous by gel filtration and polyacrylamide gel electrophoresis. This elastase showed relatively high elastolytic activity, but relatively low hydrolytic activity towards succinyl trialanine p-nitroanilide, as compared with another component of pancreatic juice elastase (which was not absorbed onto sawdust). Both elastases isolated were alkaline earth metal-dependent enzymes.


The role of the blood-brain barrier in hypertension.
What is the topic of this review? This review highlights the importance of the blood-brain barrier in the context of diseases involving autonomic dysfunction, such as hypertension and heart failure. What advances does it highlight? It highlights the potential role of pro-inflammatory cytokines, leucocytes and angiotensin II in disrupting the blood-brain barrier in cardiovascular diseases. Advances are highlighted in our understanding of neurovascular unit cells, astrocytes and microglia, with a specific emphasis on their pathogenic roles within the brain. The blood-brain barrier (BBB) is a crucial barrier that provides both metabolic and physical protection to an immune-privileged CNS. The BBB has been shown to be disrupted in hypertension. This review addresses the importance of the BBB in maintaining homeostasis in the context of diseases related to autonomic dysfunction, such as hypertension. We highlight the potentially important roles of the immune system and neurovascular unit in the maintenance of the BBB, whereby dysregulation may lead to autonomic dysfunction in diseases such as heart failure and hypertension. Circulating leucocytes and factors such as angiotensin II and pro-inflammatory cytokines are thought ultimately to downregulate endothelial tight junction proteins that are a crucial component of the BBB. The specific mechanisms underlying BBB disruption and their role in contributing to autonomic dysfunction are not yet fully understood but are a growing area of interest. A greater understanding of these systems and advances in our knowledge of the molecular mechanisms causing BBB disruption will allow for the development of future therapeutic interventions in the treatment of autonomic imbalance associated with diseases such as heart failure and hypertension.


Mucinous syringometaplasia--a case report and review of the literature.
A case of a long-standing lesion on the hand of a 64-year-old man is reported. Histology of the excision specimen showed characteristic features of mucinous syringometaplasia. The histopathological findings are described in detail including the first immunohistochemical study of this entity. Previous cases in the literature are reviewed. Mucinous syringometaplasia is a benign, presumably reactive verrucous lesion most commonly occurring on acral sites. Complete excision is curative.


Zinc oxide nanoparticles modulate the gene expression of ZnT1 and ZIP8 to manipulate zinc homeostasis and stress-induced cytotoxicity in human neuroblastoma SH-SY5Y cells.
Zinc ions (Zn2+) are important messenger molecules involved in various physiological functions. To maintain the homeostasis of cytosolic Zn2+ concentration ([Zn2+]c), Zrt/Irt-related proteins (ZIPs) and Zn2+ transporters (ZnTs) are the two families of proteins responsible for decreasing and increasing the [Zn2+]c, respectively, by fluxing Zn2+ across the membranes of the cell and intracellular compartments in opposite directions. Most studies focus on the cytotoxicity incurred by a high concentration of [Zn2+]c and less investigate the [Zn2+]c at physiological levels. Zinc oxide-nanoparticle (ZnO-NP) is blood brain barrier-permeable and elevates the [Zn2+]c to different levels according to the concentrations of ZnO-NP applied. In this study, we mildly elevated the [Zn2+]c by ZnO-NP at concentrations below 1 μg/ml, which had little cytotoxicity, in cultured human neuroblastoma SH-SY5Y cells and characterized the importance of Zn2+ transporters in 6-hydroxy dopamine (6-OHDA)-induced cell death. The results show that ZnO-NP at low concentrations elevated the [Zn2+]c transiently in 6 hr, then declined gradually to a basal level in 24 hr. Knocking down the expression levels of ZnT1 (located mostly at the plasma membrane) and ZIP8 (present in endosomes and lysosomes) increased and decreased the ZnO-NP-induced elevation of [Zn2+]c, respectively. ZnO-NP treatment reduced the basal levels of reactive oxygen species and Bax/Bcl-2 mRNA ratios; in addition, ZnO-NP decreased the 6-OHDA-induced ROS production, p53 expression, and cell death. These results show that ZnO-NP-induced mild elevation in [Zn2+]c activates beneficial effects in reducing the 6-OHDA-induced cytotoxic effects. Therefore, brain-delivery of ZnO-NP can be regarded as a potential therapy for neurodegenerative diseases.


Photosynthetic response of Ulva rotundata to light and temperature during emersion on an intertidal sand flat.
We have investigated the diurnal response of photosynthesis and variable photosystem II (PSII) chlorophyll fluorescence at 77 K for thalli of the chlorophyte macroalga, Ulva rotundata, grown in outdoor culture and transplanted to an intertidal sand flat in different seasons. The physiological response in summer indicated synergistic effects of high PFD and aerial exposure, the latter probably attributable to temperature, which usually increased by 8 to 10° C during midday emersion. Except at extreme emersed temperatures in summer (38° C), the light-saturated photosynthesis rate (Pm) did not decline at midday. In contrast, light-limited quantum yield of photosynthetic O2 exchange (τ) and the ratio of variable to maximum fluorescence yield (Fv/Fm) reversibly declined during midday low tides in all seasons. Shade-grown thalli exhibited a fluorescence response suggestive of greater photodamage to PSII, whereas sun-grown thalli had greater photoprotective capacity. The fluorescence decline was smaller when high tide occurred at midday, and was delayed during morning cloudiness. These results suggest that the diurnal response to PFD in this shallow water species is modified by tidal and meteorological factors. U. rotundata has a great capacity for photoprotection which allows it to tolerate and even thrive in the harsh intertidal environment.


In vitro phosphorylation in isolated horizontal cells of the fish retina: effects of the state of light adaptation.
Horizontal cells, which are second-order neurons of the vertebrate retina, exhibit synaptic plasticity governed by light and dark adaptation. We have investigated the alterations in the protein phosphorylation patterns of isolated carp (Cyprinus carpio) horizontal cells in relation to their state of light adaptation by using an in vitro phosphorylation assay and compared the resulting data with protein synthesis patterns of the whole retina. Phosphoproteins and [35S]methionine-labelled proteins were analysed by one- and two-dimensional gel electrophoresis followed by autoradiography. The state of light adaptation significantly affected the in vitro phosphorylation of horizontal cell proteins with molecular weights of 68, 56/58, 47, 28 and 15 kDa, but had no effect on the protein synthesis of retinal proteins. In the light the most prominent increase of 32P incorporation was observed in the 47 kDa protein. The biochemical properties of this protein closely resembled those of the growth-associated GAP-48, found in the fish retina. In addition, the phosphorylation of horizontal cell homogenates in the presence of protein kinase activators such as cyclic AMP, calcium, calmodulin and phospholipids revealed that horizontal cells of the fish retina contain cyclic AMP-, calcium/calmodulin- and calcium/phospholipid-dependent protein kinase activity resulting in the phosphorylation of several horizontal cell proteins, including the phosphoproteins which were affected by the state of light adaptation.


The influence of bladder fullness on upper urinary tract dimensions and renal excretory function.
Nearly full bladders (375 ml.) produced significantly greater dimensions of the renal calices, pelves and ureters on excretory urograms compared to nearly empty bladders. These dimensions were frequently to the point of being considered pathological dilatations. On planimetry the urographic areas of the pelviocaliceal systems decreased by 43 per cent on the right side and 38 per cent on the left side when the nearly full bladder was compared to the nearly empty bladder in 10 patients. Renal excretory function also was affected by nearly full bladders. Urea clearances after 1 hour were 24 per cent lower and creatinine clearances were 9 per cent lower when starting with a nearly full bladder as compared to starting with an empty bladder. The implications of these findings are of potential significance with respect to 1) interpretation of excretory urograms and 2) chronic urine holding in patients with recurrent urinary tract infections, impaired renal function and/or urolithiasis.


Incidental finding of metastatic prostatic adenocarcinoma of frontotemporal bone presenting as subdual hematoma: A case report and review of literature.
and important: Prostatic cancer is often prone to metastasis and bone invasion. Skull metastasis in prostate cancer is uncommon, accounting for less than 2% of all metastases. However, frontotemporal bone metastasis without dural or brain metastasis is rare. Herein, we report the case of a 91-year-old male patient who presented with a sudden-onset dizziness, a fall to the ground, and gradual loss of consciousness. Computed tomography (CT) of the brain revealed an aggressive bony lesion secondary to locally advanced metastatic malignancy and subdural hematoma. Subsequently, he underwent decompressive craniectomy. Histopathological and immunohistochemical (IHC) examinations demonstrated metastatic prostatic adenocarcinoma (PCa). Although after treatment by a multidisciplinary team, unfortunately, the patient expired two months after the surgery and could no longer be traced. In the majority of reported cases, CT scans of the brain are often mistaken for subdural hematoma or meningioma. The present case suggests is a preliminary incidental case of a single frontotemporal bony lesion. This is the first case described in the literature of incidental finding of metastatic PCa presenting with asymptomatic characteristics. Awareness of the possibility of metastatic PCa involving the skull bones, as well as histopathological and IHC examinations, are important to arrive at a correct initial diagnosis.


Factors Relating to Managerial Stereotypes: The Role of Gender of the Employee and the Manager and Management Gender Ratio.
PURPOSE: Several studies have shown that the traditional stereotype of a "good" manager being masculine and male still exists. The recent changes in the proportion of women and female managers in organizations could affect these two managerial stereotypes, leading to a stronger preference for feminine characteristics and female leaders. This study examines if the gender of an employee, the gender of the manager, and the management gender ratio in an organization are related to employees' managerial stereotypes. DESIGN/METHODOLOGY/APPROACH: 3229 respondents working in various organizations completed an electronic questionnaire. FINDINGS: The results confirm our hypotheses that, although the general stereotype of a manager is masculine and although most prefer a man as a manager, female employees, employees with a female manager, and employees working in an organization with a high percentage of female managers, have a stronger preference for feminine characteristics of managers and for female managers. Moreover, we find that proximal variables are much stronger predictors of these preferences than more distal variables. IMPLICATIONS: Our study suggests that managerial stereotypes could change as a result of personal experiences and changes in the organizational context. The results imply that increasing the proportion of female managers is an effective way to overcome managerial stereotyping. ORIGINALITY/VALUE: This study examines the influence on managerial stereotypes of various proximal and distal factors derived from theory among a large group of employees (in contrast to students).


Safety and tolerability of virucidal hand rubs: a randomized, double-blind, cross-over trial with healthy volunteers.
The hands of the medical staff play an important role in transmission of pathogens in the health care environment. Hand hygiene is efficient, easy to perform and cost-effective. Safety, tolerability and acceptance of hand hygiene preparations play a major role in hand hygiene compliance, and apply, in particular, to formulations with high anti-viral activity. Clinical trial to evaluate the safety and tolerability of different virucidal hand rubs. In a randomized, double-blind, four-period cross-over trial, healthy volunteers received three different virucidal hand rubs (P1-P3) and a reference product (R) in randomized sequence over a period of 4 days each with a washout period. The primary endpoint was skin barrier function measured by transepidermal water loss (TEWL) after application. Twenty-two subjects (seven male, 15 female; median age 25, range 21-54) were randomized and started at least one period. TEWL was 22.5; 95 %-confidence interval (CI): 19.6-25.4 after P1, 16.3; 13.5-19.1 after P2, 16.4; 13.4-19.3 after P3, and 24.0; 21.1-27.0 after R; p < 0.0001. The percentage of subjects experiencing at least one adverse event (AE) was 86 % with P1, 25 % with P2, 89 % with P3 and 56 % with R. The majority of AEs were skin reactions classified as of mild severity. No serious AEs were observed. Results were inconsistent. The number of AEs was higher than expected for all products. In summary, there is room for improvement both for hand rub development and the scientific approaches taken to practically and reproducibly evaluate hand rub safety and tolerability.


Orexin receptors regulate hippocampal sharp wave-ripple complexes in ex vivo slices.
Orexin is a neuromodulatory peptide produced by lateral hypothalamic orexin neurons and binds to G-protein-coupled orexin-1 receptor and orexin-2 receptors. Whether orexin modulates learning and memory is not fully understood. Orexin has biphasic effects on learning and memory: promoting learning and memory at homeostatic levels and inhibiting at supra- and sub-homeostatic levels. Hippocampal sharp wave-ripples encode memory information and are essential for memory consolidation and retrieval. The role of orexin on sharp wave-ripples in hippocampal CA1 remains unknown. Here, we used multi-electrode array recordings in acute ex vivo hippocampal slices to determine the effects of orexin receptor antagonists on sharp wave-ripples. Bath-application of either the orexin-1 receptor antagonist N-(2-Methyl-6-benzoxazolyl)-N'-1,5-naphthyridin-4-yl urea (SB-334867) or the orexin-2 receptor antagonist N-Ethyl-2-[(6-methoxy-3-pyridinyl)[(2-methylphenyl)sulfonyl]amino]-N-(3-pyridinylmethyl)-acetamide (EMPA) reduced sharp wave and ripple incidence, sharp wave amplitude, and sharp wave duration. SB-334867 and EMPA effects on sharp wave amplitude and duration were equivalent, whereas EMPA exhibited a greater reduction of sharp wave and ripple incidence. EMPA also increased ripple duration, whereas SB-334867 had no effect. Inhibition of both orexin receptors with a dual orexin receptor antagonist N-[1,1'-Biphenyl]-2-yl-1-[2-[(1-methyl-1H-benzimidazol-2-yl)thio]acetyl-2-pyrrolidinedicarboxamide (TCS-1102) had effects similar to EMPA, however, sharp wave amplitude and duration were unaffected. Region-specific expression of orexin receptors suggests orexin may regulate sharp wave generation in CA3, dentate gyrus-mediated sharp wave modification, sharp wave propagation to CA1, and local ripple emergence in CA1. Our study indicates an orexin contribution to hippocampal sharp wave-ripple complexes and suggests a mechanism by which sub-homeostatic concentrations of orexin may inhibit learning and memory function.


Detection of species specific chromosomes in somatic cell hybrids.
We describe an in situ hybridization technique which allows rapid identification of species-specific chromosomes in somatic cell hybrid lines. Chromosome preparations from rodent-human hybrid lines are hybridized to biotinylated total human DNA which is subsequently detected by a series of immunocytochemical reactions which culminate in a peroxidase reaction visible by light microscopy. This technique not only allows identification of intact human chromosomes but also fragmented and rearranged human chromosomal segments. We have detected as little as 1 X 10(7) bp of human DNA inserted into a mouse chromosome using this procedure and estimate that the sensitivity of the technique would allow detection of sequences 5- to 10-fold smaller. The usefulness of the technique for screening hybrid cell gene mapping panels is discussed.


Development of auditory brainstem responses (ABRs) in Tshr mutant mice derived from euthyroid and hypothyroid dams.
Developmental changes in auditory brainstem responses (ABRs) to clicks and tone bursts were studied in genetically hypothyroid Tshr mutant mice that were homozygous for the hypothyroid trait (hyt/hyt), as well as in euthyroid individuals that were heterozygous for the trait (+/hyt). The developmental role of maternal thyroid hormones was determined by comparing homozygotes that were offspring of euthyroid (hyt/hyt(c)) or hypothyroid (hyt/hyt(h)) dams; all heterozygotes were born to euthyroid dams (+/hyt(e)). Clear responses to high-level stimuli were recorded from heterozygotes on postnatal day 12 (P12) for most stimulus conditions, and thresholds, response amplitudes, interpeak intervals, and latencies developed normally, achieving nearly adult properties by P21. Most hyt/hyt(h) animals were unresponsive to acoustic stimulation throughout the period of study. Grossly immature responses to high-level stimuli were observed in many hyt/hyt(e) pups on P15; however, clear, low-amplitude responses were not routinely observed until P21. Thresholds improved with age in +/hyt(e) and hyt/hyt(e) individuals, and latency-level curves were relatively steep in young animals and developed normally in +/hyt(e) mice with the most significant changes occurring between P15 and P21. In general, hyt/hyt(e) mice exhibited prolonged latencies, interpeak intervals, and central conduction times throughout the age range studied, and slopes of latency-level curves remained abnormally steep through P28. Response amplitudes were generally larger in heterozygotes than in hyt/hyt(e) mice, regardless of level. Replacement of thyroxin during the first 10 postnatal days in hyt/hyt(h) pups had little to no effect on the development of auditory function, although more animals from this group were responsive at very high stimulation levels. We conclude that auditory function is impaired in hypothyroid Tshr animals throughout development and that impairment is profound when individuals are not exposed to maternal thyroid hormone, i.e., a clear thyroxin-dependent critical prenatal period exists in the Tshr mutant mouse.


Characterization of canine intestinal microRNA expression in inflammatory bowel disease and T-cell lymphoma.
Differentiating between canine inflammatory bowel disease (IBD) and intestinal T-cell lymphoma by histopathological examination of endoscopically-derived intestinal biopsies can be challenging and involves an invasive procedure requiring specialized equipment and training. A rapid, non-invasive method of diagnosis, such as blood or faecal analysis for a conserved and stable biomarker, would be a useful adjunct or replacement. Studies on dogs and humans with various types of lymphoma have shown altered microRNA (miRNA) expression patterns in blood, faeces and tissues indicating their potential use as biomarkers of disease. The present study used residual archived endoscopically-derived, formalin-fixed, paraffin-embedded (FFPE) duodenal tissue taken from pet dogs undergoing routine investigation of gastrointestinal disease. The dogs had previously been diagnosed with either normal/minimal intestinal inflammation, severe IBD or intestinal T-cell lymphoma. Next generation sequencing with qPCR validation was used to elucidate differentially expressed miRNAs between groups. Our results show that miRNA can be extracted from archived endoscopically-derived FFPE tissues from the canine duodenum and used to differentiate normal/minimally inflamed canine duodenal tissue from severe lymphoplasmacytic IBD and T-cell lymphoma.


Iron responses in hepatic, intestinal and macrophage/monocyte cell lines under different culture conditions.
Iron homeostasis is mainly controlled by the liver-produced hepcidin peptide, which induces the degradation of the ferroportin iron exporter and thus regulates serum iron level. Hepcidin transcription is clearly up-regulated by the pro-inflammatory cytokine IL-6 and down-regulated, in the case of iron depletion, at least via HIF transcription factors. In addition, in vivo iron overload up-regulates hepcidin, but this cannot be reproduced in cell culture or isolated hepatocytes. Here, we investigated the steady state mRNA levels of a series of genes involved in iron metabolism in hepatic HepG2, intestinal Caco-2, and monocyte/macrophage THP-1 cell lines under different iron and culture conditions. Our results showed that iron-saturated transferrin up-regulated hepcidin mRNA synthesis from HepG2 via cross-talk with macrophages or enterocyte cytokine-producing cells, whereas non-transferrin-bound iron down-regulated hepcidin, likely due to missing TfR-iron-transferrin uptake.


1,2-Alkyl migration as a key element in the invention of cascade reactions catalyzed by pi-acids.
This brief overview highlights recent progress in the field of cascade reactions that are initiated by the activation of a pi-system using platinum and gold catalysts and that are coupled with a 1,2-alkyl migration step. While the reactions discussed aim to rapidly evolve molecular complexity, they are experimentally straightforward and easy to perform. Primarily guided by the type of 1,2-alkyl migration, methods are categorized as shifts to metal carbenoid centers and pinacol-type rearrangements.


Prevalence and associated positive psychological variables of depression and anxiety among Chinese cervical cancer patients: a cross-sectional study.
The prevalence of depression and anxiety and its associated factors in cervical cancer are not well evaluated in China. Meanwhile, with increasing attention given to positive psychological variables in oncology field, there is a need to conduct a study to explore the integrative effects of positive psychological variables on depression/anxiety so as to provide patients a more holistic cancer care. The aim of this study was to assess the prevalence of depression/anxiety as well as the integrative effects of hope, optimism and general self-efficacy on depression/anxiety among Chinese cervical cancer patients. A multi-centre, cross-sectional study was conducted of consecutive inpatients at the Liaoning Cancer Hospital & Institute and the Shengjing Hospital of China Medical University in Liaoning Province, northeast China. A total of 224 cervical cancer patients eligible for this study completed questionnaires on demographic and clinic variables, Hospital Anxiety and Depression Scale, Herth Hope Index, Life Orientation Scale-Revised, and General Self-Efficacy Scale during February and August 2013. The prevalence of depression and anxiety was 52.2% and 65.6% in cervical cancer patients. The anxiety score was significantly higher in patients at the period of 4-6 months after diagnose and at cancer stage II. Hierarchical regression analyses indicated that hope, optimism and general self-efficacy as a whole accounted for 31.3% variance of depression and 35.6% variance of anxiety. Under standardized estimate (β) sequence, hope, optimism and general self-efficacy significantly associated with depression, respectively; hope and optimism were also significant individual predictors of anxiety. The high prevalence of depression and anxiety among cervical cancer patients should receive more attention in Chinese medical settings. More importantly, efforts to develop the integrated psychosocial interventions are effective and necessary to alleviate depression/anxiety in cervical cancer patients by synthesizing and integrating the individual protective effects of hope, optimism and general self-efficacy.


Sympathetic nervous system "switch off" with severe hypothermia.
Hypothermia occurs frequently in the critically ill patient, yet little is known about the endogenous catecholamine response to this stress. To study this problem, we measured heart rate (HR), mean arterial blood pressure (MAP), and plasma levels of norepinephrine (NE) and epinephrine (Epi) in subhuman primates (baboons) during progressive hypothermia from 37 degrees to 29 degrees C and then during rewarming to 37 degrees C. As the core temperature decreased from 37 degrees to 33 degrees C, HR and MAP increased significantly (p less than 0.05), but as core temperature further decreased from 33 degrees to 29 degrees C, the HR and MAP fell to prehypothermic levels. Plasma concentrations of NE and Epi increased significantly (p less than 0.01) as core temperature fell from 37 degrees to 31 degrees C, but as core temperature dropped from 31 degrees to 29 degrees C, plasma NE and Epi levels decreased towards prehypothermic concentrations. These findings indicate that the sympathetic nervous system (SNS) responds quickly to hypothermia but may be "switched off" at a threshold temperature of about 29 degrees C. We speculate that hypotensive patients with temperatures less than or equal to 29 degrees C may benefit from infusions of exogenous catecholamines, especially if there have been only minimal benefits achieved with conventional therapy such as fluids, and an increase in ambient temperature.


Comparison of receptor models for source identification of organophosphate esters in major inflow rivers to the Bohai Sea, China.
A better understanding of the sources of organophosphate esters (OPEs) is a prerequisite for OPE control and the establishment of related environmental policies. Sources of OPEs in 35 major inflow rivers to the Bohai Sea of China were quantitatively analyzed using three effective receptor models (principal component analysis-multiple linear regression (PCA-MLR), positive matrix factorization (PMF), and Unmix) in this paper. The similarities and differences in results from PCA-MLR, PMF, and Unmix were discussed in depth. All three models well predicted the spatial variability of the total concentrations of nine OPEs (triethyl phosphate, tri-n-butyl phosphate, triisobutyl phosphate, tri (2-ethylhexyl) phosphate, tri (2-chloroethyl) phosphate, tris(1-chloro-2-propyl) phosphate, tris(1,3-dichloro-2-propyl) phosphate, triphenyl phosphate, and triphenylphosphine oxide) (∑9OPEs) (r2 = 0.90-0.96, p = 0.000) and explained 98.4%-101.2% of the observed ∑9OPEs. The predicted ∑9OPEs values from each pairwise model were significantly correlated (r2 = 0.88-0.91, p = 0.000). Three OPE sources were extracted by all three models: rigid and flexible polyurethane foam/coating, cellulosic/acrylic/vinyl polymer/unsaturated polyester, and polyvinyl chloride, contributing 49.9%, 29.7%, and 20.5% by PCA-MLR, 57.9%, 28.6%, and 13.5% by PMF, and 47.9%, 30.8%, and 22.4% by Unmix to the ∑9OPEs, respectively. PMF was recommended as the preferred receptor model for analyzing OPE sources in water during the monitoring period because of its optimal performance.


Recent Advances in Nanotechnology-Based Targeted Therapeutics for Breast Cancer Management.
Despite the great efforts that have been achieved in breast cancer treatment, it remains a significant cause of death in women and is a serious health problem. Treatment with chemotherapy drugs faces various challenges, such as toxicity and chemoresistance to chemotherapeutic drugs, which hinder their therapeutic success and clinical experiments. This review focuses on targeting nanocarrier approaches to target chemotherapy drugs to receptor targets that are overexpressed on the surface of breast cancer cells. In particular, the most commonly targeted nanocarriers for the chemotherapeutic agents examined by the different researcher groups, such as liposomes, dendrimers, polymeric micelles, lipid particulates, polymeric nanoparticles, and carbon nanotubes, have been reviewed. Moreover, we summarized the molecular receptors or targets that are the most commonly overexpressed in breast cancer cells and the natural and synthetic ligands studied for use as targeting moieties to functionalize chemotherapeutically loaded nanocarriers for potential specific breast cancer targeting.


Pattern reversal retinal potentials in ocular hypertensives at high and low risk of developing glaucoma.
The human pattern-reversal retinal potential (PRRP) is a bioelectrical response which reflects neural activity generated in the proximal retina. Visual diseases which affect the retinal ganglion cells and the optic nerve often produce significant reductions in the amplitude of the PRRP. PRRP amplitude reductions are frequently observed in patients with primary open-angle glaucoma. This investigation was designed to determine whether patients with ocular hypertension who are at risk of developing glaucoma also exhibit PRRP amplitude reductions. The results indicate that PRRP amplitude reductions do occur in some ocular hypertensives, but many other ocular hypertensives do not exhibit PRRP abnormalities.


Adverse neonatal and maternal outcome following vacuum-assisted vaginal delivery: does indication matter?
To estimate the impact of indication for vacuum-assisted vaginal delivery on neonatal and maternal adverse outcome. Retrospective analysis of women carrying singleton-term pregnancies undergoing vacuum-assisted vaginal delivery in a tertiary hospital (2007-2014). Cohort was stratified by indication: non-reassuring fetal heart rate or prolonged second stage. Primary outcome was adverse neonatal outcome and secondary outcome was maternal morbidity. Logistic regression analysis was utilized to adjust for potential confounders. Overall, 4931 women met inclusion criteria. Delivery indication was prolonged second stage in 3143 (64%) cases and non-reassuring fetal heart rate in 1788 (36%). In the non-reassuring fetal heart rate group, there were higher rates of cephalohematoma, low 5-min Apgar-score, and asphyxia. In the prolonged second-stage group, there were higher rates of sepsis and post-partum hemorrhage. Composite neonatal birth trauma and maternal morbidity were higher for vacuum-assisted vaginal delivery following prolonged second stage. Following adjustment for confounders cephalohematoma (aOR 1.21, 95% CI 1.04-1.41), low 5-min Apgar-score (aOR 2.91, 95% CI 1.26-4.67) and asphyxia (aOR 1.81 95% CI 1.35-2.44) remained significant in the non-reassuring fetal heart rate group and neonatal sepsis remained significant for the prolonged second-stage group (aOR 1.77, 95% CI 1.38-2.27), p < 0.05 for all. However, there was no longer difference in the composite birth trauma, other neonatal or maternal morbidity. The indication for vacuum-assisted vaginal delivery has an impact on neonatal outcome. While cephalohematoma, low 5' Apgar score, and asphyxia were more common in the non-reassuring fetal heart rate group, neonatal sepsis was more common in cases of prolonged second stage of labor.


Temozolomide in the management of dopamine agonist-resistant prolactinomas.
The majority of prolactinomas respond to dopamine agonist therapy, but a proportion are resistant, requiring other treatments including surgery and/or radiotherapy. Temozolomide is an oral chemotherapy agent, which has been used as a salvage therapy to treat aggressive pituitary adenomas and carcinomas, including prolactinomas, unresponsive to all conventional treatment. We report three patients where temozolomide was used in the treatment of refractory prolactinomas. Case 1 describes a patient with a highly invasive prolactinoma, resistant to all conventional therapy, which responded dramatically to temozolomide used as a salvage treatment. In case 2, temozolomide was used after incomplete surgical resection to relieve chiasmal compression and avoid chiasm exposure to radiotherapy. In case 3, temozolomide enabled radiotherapy to be deferred in a 16-year old with a resistant prolactinoma. In all three cases, the tumours were negative by immunostaining for methylguanine methyltransferase (MGMT). A review of the published literature reveals 51 reported cases of temozolomide treatment for pituitary tumours, including 20 prolactinomas. Fifteen of the 20 prolactinomas showed a good response to temozolomide. Our analysis demonstrates a strong association between MGMT-negative staining and a good response to temozolomide (OR 9.35, P = 0.0030). Current clinical practice is to use temozolomide as a salvage therapy after all conventional modalities of treatment have failed. We suggest that, in selected cases, consideration should be given to using temozolomide earlier in the treatment algorithm.


Self-adjuvanted mRNA vaccines induce local innate immune responses that lead to a potent and boostable adaptive immunity.
mRNA represents a new platform for the development of therapeutic and prophylactic vaccines with high flexibility with respect to production and application. We have previously shown that our two component self-adjuvanted mRNA-based vaccines (termed RNActive® vaccines) induce balanced immune responses comprising both humoral and cellular effector as well as memory responses. Here, we evaluated the early events upon intradermal application to gain more detailed insights into the underlying mode of action of our mRNA-based vaccine. We showed that the vaccine is taken up in the skin by both non-leukocytic and leukocytic cells, the latter being mostly represented by antigen presenting cells (APCs). mRNA was then transported to the draining lymph nodes (dLNs) by migratory dendritic cells. Moreover, the encoded protein was expressed and efficiently presented by APCs within the dLNs as shown by T cell proliferation and immune cell activation, followed by the induction of the adaptive immunity. Importantly, the immunostimulation was limited to the injection site and lymphoid organs as no proinflammatory cytokines were detected in the sera of the immunized mice indicating a favorable safety profile of the mRNA-based vaccines. Notably, a substantial boostability of the immune responses was observed, indicating that mRNA can be used effectively in repetitive immunization schedules. The evaluation of the immunostimulation following prime and boost vaccination revealed no signs of exhaustion as demonstrated by comparable levels of cytokine production at the injection site and immune cell activation within dLNs. In summary, our data provide mechanistic insight into the mode of action and a rational for the use of mRNA-based vaccines as a promising immunization platform.