Effect of previous vaccination with pneumococcal conjugate vaccine on pneumococcal polysaccharide vaccine antibody responses.
During the past 10 years, pneumococcal conjugate vaccine (PCV) has become part of the standard childhood vaccination programme. This may impact upon the diagnosis of polysaccharide antibody deficiency by measurement of anti-polysaccharide immunoglobulin (Ig)G after immunization with unconjugated pneumococcal polysaccharide vaccine (PPV). Indeed, contrary to PPV, PCV induces a T-dependent, more pronounced memory response. The antibody response to PPV was studied retrospectively in patients referred for suspected humoral immunodeficiency. The study population was divided into four subgroups based on age (2-5 years versus ≥ 10 years) and time tested (1998-2005 versus 2010-12). Only 2-5-year-old children tested in 2010-12 had been vaccinated with PCV prior to PPV. The PCV primed group showed higher antibody responses for PCV-PPV shared serotypes 4 and 18C than the unprimed groups. To a lesser extent, this was also found for non-PCV serotype 9N, but not for non-PCV serotypes 19A and 8. Furthermore, PCV-priming elicited a higher IgG2 response. In conclusion, previous PCV vaccination affects antibody response to PPV for shared serotypes, but can also influence antibody response to some non-PCV serotypes (9N). With increasing number of serotypes included in PCV, the diagnostic assessment for polysaccharide antibody deficiency requires careful selection of serotypes that are not influenced by prior PCV (e.g. serotype 8). Further research is needed to identify more serotypes that are not influenced.


The effects of stress and trauma on brain and memory: a view from developmental cognitive neuroscience.
Many aspects of brain development depend on experience. Because the major macro-morphological events of brain development occur over the first 2-3 years of postnatal life, this time period can be considered both a period of opportunity as well as a period of vulnerability. In this paper we describe how experience with stress early in life can have a negative impact on certain aspects of brain development, and specifically, those neural circuits that underlie memory. We also describe the effects of traumatic events on the development of the neural basis of memory. In support of our argument, we review the literature on brain, stress, and memory in the context of development. Based on this review, we suggest that the developing brain is particularly vulnerable to the harmful physiological effects of stress, which in turn has the potential to lead to impairments in memory. Unfortunately, there are few empirical data that directly address this hypothesis. In this context we offer a number of suggestions for future research.


Age- and Parkinson's disease-related evaluation of gait by General Tau Theory.
The degeneration of postural control in the elderly and patients with Parkinson's disease (PD) can be debilitating and may lead to increased fall risk. This study evaluated the changes in postural control during gait affected by PD and aging using a new method based on the General Tau Theory. Fifteen patients with PD, 11 healthy old adults (HOs), and 15 healthy young adults (HYs) were recruited. Foot trajectories of each participant were monitored during walking by a three-camera Optotrak Certus(®) motion capture system. The anteroposterior direction of foot movement during stepping was analyzed by tau-G and tau-J guidance strategies. Two linear regression analyses suggested that the tau of the step-gap was strongly coupled onto the tau-J guidance during walking. The regression slope K could estimate the coupling ratio in the tau-coupling equation which reflects the performance of postural control during gait. The mean K value for the PD group, which was highest among the three groups, was approximately 0.5. Therefore, participants in the PD group walked with the poorest postural control and exhibited a relatively hard contact with the endpoint during stepping when compared with those in the HO and HY groups. The HY and HO groups obtained mean K values significantly lower than 0.5, which indicated that the gait was well controlled and ended at low speed with low deceleration. However, the HO group showed a decreased tendency for postural control, in which the mean K value was significantly higher than that of the HY group. The K value was moderately positively correlated with the double support time and negatively correlated with the stride length and walking speed. The tau-J coupling ratio can provide additional insight into gait disturbances and may serve as a reliable, objective, and quantitative tool to evaluate dynamic postural control during walking.


Cardiac and Non-Cardiac Abnormalities in Heterotaxy Syndrome.
Thoraco-abdominal viscera have unique morphological asymmetry, unlike the body's external organs. Heterotaxy syndrome is a disorder in which there is a loss of normal left to right asymmetry of thoraco-abdominal viscera and their naturally proscribed spatial relationship. It has multiple anatomical alterations, culminating into physiological and hemodynamic consequences. It is divided into two groups on the basis of morphology of the two atrial appendages. These subgroups are - 1) Isomerism of right atrial appendage (asplenia syndrome); 2) Isomerism of left atrial appendage (polysplenia syndrome); Patients from group I, usually have severe cardiac malformations and present early. They may have duct dependent lesions and eventually may undergo Fontan surgery. However, extracardiac anomalies are more common in group II. All the patients must be evaluated in detail to rule out anomalies like gut-malrotation. Patients must be provided with special care for their susceptibility to infection due to absence of spleen or presence of splenic malfunction. Majority of these patients may have genetic link and may present in families. Hence, genetic evaluation is necessary before assuming long term outcome.


Mammary gland physiology and farm management of dairy mares and jennies.
Equid milk is arousing increasing interest in consumers and researchers because of its similarity in composition to human milk. The low and different protein content makes equid milk it suitable for children with cow milk protein allergy. Both horse and milk production, in many farms, still follow a characteristic and traditional method of separating the foal from the mother to allow milking procedures. This separation lasts at least 2 to 3 h before milking, a time in which the foal remains fasting. This operation is repeated several times a day, as the equid udder has little collection capacity, and milking frequency is one of the most important parameters to increase milk production; it must be emptied often. New partial artificially suckling techniques have been developed that allow the foal to be separated from its mother for many hours without starving. Furthermore, mechanical milking has been introduced in equid milk production, although in-depth knowledge is lacking on milking parameters and how these aspects affect milk production and udder health. Moreover, in some farms, new milking parlors for Equidae have been developed, ensuring that stress is minimized and production and animal welfare are ensured. It is important to develop and apply technologies for equid milk production, evaluating potential effects on welfare, health, and milk production. This represents the broadest perspective and the greatest challenge because of the need to understand management best practices, thinking to the possibility to introduce as soon as possible automatic milking systems that could ensure a good milking frequency.


The response of bacterial communities to V and Cr and novel reducing bacteria near a vanadium‑titanium magnetite refinery.
Soil contamination with multiple heavy metals has always been a pressing issue, but little attention has been given to V and Cr and their chemical fractions' impacts on microorganisms because Cr2O3 usually occurs as an associated mineral in vanadium mines. To investigate this issue, samples (N1-N6) less affected by anthropogenic activities were selected for microbial analysis. The area near the refinery was heavily contaminated according to the PLI (pollution load index). Actinobacteriota, Proteobacteria, and Chloroflexi were the dominant phyla in the soil. The diversity of bacteria was positively influenced by V and Cr and negatively influenced by pH, while the abundance was positively correlated with soil nutrients. Interestingly, the influence of heavy metals in the residual fraction on the microbial community structure and functional metabolism was higher than that in the oxidizable fraction, which may be due to the relatively low heavy metal valence of the oxidizable fraction, suggesting that low valence binding forms of multivalence elements have little effect on microorganisms in the soil. Ultimately, two strains with great efficiency in reducing V and Cr were screened, and co-occurrence network characteristics with significant positive interactions suggested that Bacillus can coordinate community structure in the same niche. This research will help to explore the bioavailability of heavy metals and further achieve the bioremediation of heavy metal contamination in soil.


Differing perspectives on parent access to their child's electronic medical record during neonatal intensive care hospitalization: a pilot study.
To improve informed medical decision-making, principles for family-centered neonatal care recommend that parents have access to their child's medical record on an ongoing basis during neonatal intensive unit care (NICU) hospitalization. Currently, many NICUs do not allow independent parent access to their child's electronic medical record (EMR) during hospitalization. We undertook a cross-sectional survey pilot study of medical professionals and parents to explore opinions regarding this practice. Inclusion criteria: 18-years old, English-literate, legal guardian of patients admitted to the NICU for 14 days. NICU medical professionals included physicians, nurse practitioners, nurses, and respiratory therapists. Medical professionals believed parent access would make their work more difficult, increase time documenting and updating families, making them more liable to litigation and hesitant to chart sensitive information. However, parents felt that they lacked control over their child's care and desired direct access to the EMR. Parents believed this would improve accuracy of their child's medical chart, and increase advocacy and understanding of their child's illness. NICU parents and medical professionals have differing perspectives on independent parental access to their child's EMR. More research is needed to explore the potential of independent parental EMR access to further improve family-centered neonatal care.


Inhibitory effect of eugenol on Cu2+-catalyzed lipid peroxidation in human erythrocyte membranes.
1. The effects of eugenol on lipid peroxidation catalyzed by hydrogen peroxide (H2O2) or benzoyl peroxide (BPO) in the presence of copper ions were studied in human erythrocyte membranes. 2. The production of hydroxyl radicals was suggested in the peroxidation system catalyzed by H2O2/Cu2+. 3. H2O2/Cu2+-dependent peroxidation was inhibited by eugenol in a concentration-dependent manner; peroxidation was inhibited 62% by 200 microM eugenol. 4. In the presence of eugenol, the peroxidation catalyzed by BPO/Cu2+ was inhibited in a concentration-dependent manner, and more than 100 microM eugenol completely inhibited peroxidation. 5. The inhibitory effect of eugenol was non-competitive against Cu2+ in H2O2/Cu2+- and BPO/Cu2+-dependent peroxidation. 6. It is suggested that eugenol inhibits formation of hydroxyl radicals.


Role of glutamate ionotropic and benzodiazepine receptors in the ventromedial hypothalamic nucleus on anxiety.
The dorsomedial part of the ventromedial hypothalamic nuclei (VMHdm) has been related to the modulation of defensive behavior in mammals. The objective of the present study was to test the hypothesis that administration into the VMHdm of midazolam, a benzodiazepine receptor full agonist, or AP7, a glutamate NMDA receptor antagonist, would produce anxiolytic effects in the elevated plus-maze (EPM) or the Vogel's punished licking tests. Male Wistar rats with unilateral cannulae aimed at the VMHdm received intra-cerebral injections of midazolam (15-60 nmol/0.25 microL), AP7 (0.2-2 nmol/0.3 microL) or saline and were submitted to the behavioral tests. Midazolam (30 nmol) increased the percentage of time spent in open arms of the EPM. AP7, on the other hand, decreased open and enclosed arm exploration. In the Vogel test, however, both midazolam (30-60 nmol) and AP7 increased the number of punished licks. Histological control experiments found no significant effects when the drugs were injected into the nearby lateral hypothalamic area. These results suggest that facilitation of gabaergic or antagonism of glutamatergic neurotransmission in the VMHdm can produce anxiolytic-like effects.


[Medical Care for People Without Regular Residence Status in the French Health Care System].
According to the Index for Integration Policy in Europe (MIPEX), France is one of the countries with the most favorable health rights for migrants. The main reason for this is the historically developed social assistance benefit Aide médicale de l'État (AME), the concept and implementation of which is described based on a literature review. The AME is exemplary for addressing the question of what might be an appropriate use of national social benefits for the inclusion of people without regular residence status in health care. Even though the assistance tends to be increasingly restricted, compared to the situation in Germany, it represents a nationally established option for the provision of health care to people without regular residence status.


Antioedematogenic effect of marrubiin obtained from Marrubium vulgare.
This paper describes the antioedematogenic profile of marrubiin (1), the main constituent of Marrubium vulgare, a medicinal plant used in folk medicine of several countries to treat different pathologies. Compound (1) was analyzed in a model of microvascular leakage in mice ears. The results show that it exhibits significant and dose-related antioedematogenic effects. The results obtained for ID50 values (mg/kg, i.p.) and maximal inhibition (%) for the different phlogistic agents used were as follows: histamine (HIS, 13.84 mg/kg and 73.7%); (BK, 18.82 mg/kg and 70.0%); carrageenan (CAR, 13.61 mg/kg and 63.0%). The other phlogistic agonists, such as prostaglandin E2 (PGE2), caused inhibition of less than 50%. In addition, (1) (100 mg/kg) significantly inhibited the OVO-induced allergic edema in actively sensitized animals (maximal inhibition 67.6+/-4%). Our results demonstrate that the systemic administration of marrubiin exerts a non-specific inhibitory effect on pro-inflammatory agent-induced microvascular extravasation of Evans blue in mouse ear.


Comparative sensitivity of different methods to detect and quantify circulating fibrinogen/fibrin split products.
This study compared the sensitivity of three methods: staphyloccocal clumping test, SCT (Sigma and Calbiochem-Behring, CBC, reagents); Thrombo-Wellcotest (TWT); and Dade fibrinogen degradation products detection set, to quantify fibrinogen/fibrin split products (FSP) in blood samples from 696 patients and 124 normal donors using fibrinogen as the reference value. The Dade method gave quantitative results closely approaching the stated amount of fibrinogen. The SCT using Sigma reagents gave higher "fibrinogen" values, while the CBC reagents gave markedly lower "fibrinogen" values. The TWT detected only 25% of the fibrinogen standard. Detection of FSP following plasmin digestion of fibrinogen varied considerably for each test. The TWT, insensitive to most of the native fibrinogen, detected most of the FSP following only 15 minutes of plasmin digestion. In contrast, both assays relying on the SCT were completely negative after 24 hours of plasmin digestion. All four methods yielded FSP titers of less than 10 micrograms/mL in 97 (78.2%) of 124 blood samples from normal donors. The SCT Sigma reagents consistently gave results of less than 10 micrograms/mL in all normal donors. No instance of an FSP value greater than 40 micrograms/mL was noted for the 124 normal donors. Of the 696 patient blood samples tested, the Dade assay gave the highest or equally highest (with respect to another FSP method) value in 604 (87%) cases; the Sigma SCT did so in 360 (52%); the TWT in 316 (45%); and the CBC assay in 184 (26%) cases. The Dade test classified the largest number of blood samples, 328 (47.1%), in the greater than 10 less than 40 micrograms/mL titer category; however, the proportion of cases (32.2%) in which this test yielded values greater than 40 micrograms/mL was about the same as those produced by the Sigma SCT (29.9%) and TWT products (25.8%). Thus, with the exception of the normal (less than 10 micrograms/mL) and the suspicious (10-40 micrograms/mL) range, all three methods (Dade, Sigma, and TWT) are comparable in their abilities to detect abnormal levels of FSP. In the normal range, the Dade method will yield results that are frequently in the suspicious range. The CBC was noticeably inferior in detecting both suspicious and frankly abnormal values of FSP. Eight patients with acute leukemia were monitored sequentially with FSP and fibrinopeptide A (FpA) assays during their first course of chemotherapy. In all instances, elevated FpA levels correlated with elevated FSP values, as determined by the Dade, Sigma, or TWT assays.(ABSTRACT TRUNCATED AT 400 WORDS)


Learning spinal manipulation: the effect of expertise on transfer capability.
Transfer capability represents the changes in performance in one task that result from practice or experience in other related tasks. Increased transfer capability has been associated with expertise in several motor tasks. The purpose of this study was to investigate if expertise in spinal manipulation therapy, assessed in groups of trainees and experienced chiropractors, is associated with increased transfer capabilities. Forty-nine chiropractic students (fifth- and sixth-year students) and experienced chiropractors were asked to perform blocks of 10 thoracic spine manipulations in 3 different conditions: preferred position and table setting, increased table height, and unstable support surface. Spinal manipulations were performed on a computer-connected device developed to emulate a prone thoracic spine manipulation. Thrust duration, thrust force rate of force application, and preload force were obtained for each trial and compared across groups and conditions. Results indicated that both expertise and performance conditions modulated the biomechanical parameters of spinal manipulation. Decreased thrust duration and increased rate of force application were observed in experienced clinicians, whereas thrust force and thrust rate of force application were significantly decreased when task difficulty was increased. Increasing task difficulty also led to significant increases in performance variability. Overall, this study suggests that when instructed to perform spinal manipulation in a challenging context, trainees and experts choose to modulate force to optimize thrust duration, a characteristic feature of high-velocity, low-amplitude spinal manipulation. Given its known association with motor proficiency, transfer capability assessments should be considered in spinal manipulative therapy training.


Transformation of bone mineral morphology: From discrete marquise-shaped motifs to a continuous interwoven mesh.
Continual bone apposition at the cranial sutures provides the unique opportunity to understand how bone is built. Bone harvested from 16-week-old Sprague Dawley rat calvaria was either (i) deproteinised to isolate the inorganic phase (i.e., bone mineral) for secondary electron scanning electron microscopy or (ii) resin embedded for X-ray micro-computed tomography, backscattered electron scanning electron microscopy, and micro-Raman spectroscopy. Interdigitated finger-like projections form the interface between frontal and parietal bones. Viewed from the surface, bone mineral at the mineralisation front is comprised of nanoscale mineral platelets arranged into discrete, ~0.6-3.5 μm high and ~0.2-1.5 μm wide, marquise-shaped motifs that gradually evolve into a continuous interwoven mesh of mineralised bundles. Marquise-shaped motifs also contribute to the burial of osteoblastic-osteocytes by contributing to the roof over the lacunae. In cross-section, apices of the finger-like projections resemble islands of mineralised tissue, where new bone apposition at the surface is evident as low mineral density areas, while the marquise-shaped motifs appear as near-equiaxed assemblies of mineral platelets. Carbonated apatite content is higher towards the internal surface of the cranial vault. Up to 4 μm from the bone surface, strong Amide III, Pro, Hyp, and Phe signals, distinct PO4 3- bands, but negligible CO3 2- signal indicate recent bone formation and/or delayed maturation of the mineral. We show, for the first time, that the extracellular matrix of bone is assembled into micrometre-sized units, revealing a superstructure above the mineralised collagen fibril level, which has significant implications for function and mechanical competence of bone.


Acute modulation of the extent of apoB mRNA editing and the relative rates of syntheses of apoB48 and apoB100 in cultured rat hepatocytes by osmotic and other stress stimuli.
The mRNA for apolipoprotein B (apoB) is edited by the enzyme APOBEC-1, which acts as part of a multiprotein complex or editosome. In cultured rat hepatocytes obtained from fed animals this results in the presence of edited and unedited apoB mRNA in a ratio of approximately 3:2 in the basal state. In this study we show that hyper-osmotic media, which induce cell shrinkage, resulted in an acute increase in the degree of editing of apoB mRNA (hypo-osmotic conditions had no effect). This increase was accompanied by a parallel and highly positively correlated change in the ratio of the rate of synthesis of apoB48 relative to that of apoB100. These changes occurred in the absence of any changes in the overall APOBEC-1 mRNA levels, indicating that the activation of editing occurred at a post-transcriptional level. Levels of total apoB mRNA were also unaffected by hyper-osmotic exposure of the cells indicating that changes in the relative rates of synthesis of apoB48 and apoB100 were due to post/translational events. Exposure of cells to anisomycin at concentrations (50 micrograms/ml) that inhibit protein synthesis or to the transcriptional inhibitor actinomycin D produced changes in the degree of apoB mRNA editing that were similar to those given by hyper-osmotic shock indicating that editing is able to respond acutely to transcriptional or translational inhibition. Anisomycin, at concentrations (50 ng/ml) that activate SAPK/JNK but do not inhibit protein synthesis, gave only a fraction of the effect of hyper-osmotic shock. SB203580, an inhibitor of p38 kinase, did not attenuate the effects of hyper-osmotic conditions on APOBEC-1 editing. These observations suggest that these MAPkinase pathways play a relatively minor part in the transduction of the osmotic stimulus to the editing mechanism. The hyper-osmotically-induced increase in apoB mRNA editing was also insensitive to PD98059 and wortmannin (inhibitors of MEK and PI3 kinase, respectively). These data provide evidence that apoB mRNA editing is capable of acute modulation independently of transcriptional or translational mechanisms and suggest that one or more components of the editosome may undergo post-translational activation.


Future alternatives to heparin: low-molecular-weight heparin and hirudin.
The antithrombotic effects of standard heparin were compared with those of low-molecular-weight heparin (LMWH) and hirudin by use of an in vitro perfusion system. Fresh blood collected from human volunteers was treated with varying doses of these three agents and perfused in a recirculating system over everted porcine vein segments. A low shear rate (100/sec) was selected to simulate conditions in large arteries and veins. Platelet and fibrinogen deposition were evaluated with indium 111 and iodine 125 radiolabels, respectively. Anticoagulant activity was assessed by measuring the activated clotting time (ACT). Anti-Xa activity was assayed to determine the degree to which these agents used antithrombin III pathways. Low-molecular-weight heparin was the weakest anticoagulant, requiring 32 micrograms/ml blood to double the ACT. By contrast, the ACT doubled with only 0.75 and 1.10 micrograms/ml blood of heparin and hirudin, respectively. Heparin and hirudin inhibited platelet and fibrin deposition at equivalent doses. Low-molecular-weight heparin was a less potent inhibitor of fibrin than heparin or hirudin. Hirudin, a direct thrombin inhibitor, exhibited minimal anti-Xa activity, contrasted with 0.14 anti-Xa units/micrograms for LMWH and 0.13 anti-Xa units/mg for heparin. These data suggest that heparin and hirudin are more potent anticoagulants and antiplatelet agents than LMWH.


Assessment of contact location in subthalamic stimulation for Parkinson's disease by co-registration of computed tomography images.
To study the validity of a co-registration method for postimplantation computed tomography (CT) images for localizing the location of an intracranial deep brain stimulator. Three-dimensional reconstruction images of postimplantation CTs were co-registered with preoperative CTs by stereotactic planning software and used to localize 18 leads in the subthalamic nuclei of 10 patients with Parkinson's disease. Our conventional method using superimposition of sagittal postimplantation magnetic resonance (MR) images were employed as a comparison. The co-registered CT images separately visualized four individual contacts; on the other hand, the MR superimposition method demonstrated the leads as a group of no MR signal areas. Although laterality of the distal contact did not differ between two methods, the distal contact was located more anteriorly and inferiorly by the MR superimposition method than by the CT co-registration method. The CT co-registration method is superior to MR in visualizing deep brain stimulation contacts and resolves problems of MR safety in patients treated with a neurostimulator.


Cellular and molecular outcomes of glutamine supplementation in the brain of succinic semialdehyde dehydrogenase-deficient mice.
Succinic semialdehyde dehydrogenase deficiency (SSADHD) manifests with low levels of glutamine in the brain, suggesting that central glutamine deficiency contributes to pathogenesis. Recently, we attempted to rescue the disease phenotype of aldh5a1 -/- mice, a murine model of SSADHD with dietary glutamine supplementation. No clinical rescue and no central glutamine improvement were observed. Here, we report the results of follow-up studies of the cellular and molecular basis of the resistance of the brain to glutamine supplementation. We first determined if the expression of genes involved in glutamine metabolism was impacted by glutamine feeding. We then searched for changes of brain histology in response to glutamine supplementation, with a focus on astrocytes, known regulators of glutamine synthesis in the brain. Glutamine supplementation significantly modified the expression of glutaminase (gls) (0.6-fold down), glutamine synthetase (glul) (1.5-fold up), and glutamine transporters (solute carrier family 7, member 5 [slc7a5], 2.5-fold up; slc38a2, 0.6-fold down). The number of GLUL-labeled cells was greater in the glutamine-supplemented group than in controls (P < .05). Reactive astrogliosis, a hallmark of brain inflammation in SSADHD, was confirmed. We observed a 2-fold stronger astrocyte staining in mutants than in wild-type controls (optical density/cell were 1.8 ± 0.08 in aldh5a1 -/- and 0.99 ± 0.06 in aldh5a1 +/+ ; P < .0001), and a 3-fold higher expression of gfap and vimentin. However, glutamine supplementation did not improve the histological and molecular signature of astrogliosis. Thus, glutamine supplementation impacts genes implicated in central glutamine homeostasis without improving reactive astrogliosis. The mechanisms underlying glutamine deficiency and its contribution to SSADHD pathogenesis remain unknown and should be the focus of future investigations.


Mapping of extreme resistance to PVY (Ry (sto)) on chromosome XII using anther-culture-derived primary dihaploid potato lines.
The inheritance of extreme resistance to PVY (Ry (sto)) by a single dominant locus was confirmed by obtaining a 1:1 segregation ratio in a virus inoculation test with 28 resistant (Ryry) to 29 susceptible (ryry) anther culture-derived dihaploid lines (2n=2x=24) from cv. "Assia" (2n=4x=48) having extreme resistance derived from Solanum stoloniferum in simplex constitution (Ryryryry). Twelve Ry (sto) markers selected in AFLP assays using bulked segregant analysis were applied to 106 tested potato cultivars from Germany, The Netherlands and Poland and 19 potato cultivars were identified by these markers as extremely resistant to PVY in alignment with phenotypic data. The locus for extreme resistance (Ry (sto)) to PVY was mapped on chromosome XII co-segregating with the SSR marker STM 0003. The utility of anther-culture derived dihaploid potatoes for genetic marker development was demonstrated. Marker transferability from diploids to tetraploids provides an optimistic potential for marker-assisted selection in potato breeding programs.


Changes of AVT levels in plasma, neurohypophysis and hypothalamus in relation to oviposition in the laying hen.
Arginine vasotocin (AVT) is a neurohypophysial hormone involved in the reproductive function in avian species. We measured AVT concentrations in the neurohypophysis and plasma in relation to indomethacin blocked oviposition and to prostaglandin (PG) E2-induced premature oviposition in the hen. In addition, AVT concentration in the hypothalamus was measured in relation to spontaneous oviposition. In the control group the concentration of AVT decreased in the neurohypophysis and increased in plasma at oviposition. In hens that were administrated indomethacin, oviposition was delayed for several hours and no changes in the levels of AVT in neurohypophysis and plasma were observed at the predicted time of oviposition. Premature oviposition was induced within 5 min after the administration of PGE2. The levels of AVT decreased in the neurohypophysis and increased in plasma at the PGE2-injected premature oviposition. The increases of AVT levels in paraventricular and supraoptic nuclei were observed 2 and 5 h after spontaneous oviposition. The results indicate that oviposition causes an increase in the release of AVT from neurohypophysis and suggest that the synthesis of hypothalamic AVT may be stimulated by oviposition.


Biosynthetic incorporation for visualizing bacterial glycans.
Cell-surface glycans are central to many biological processes, yet methods for their site-selective modification are limited. Strategies for interrogating the structure and function of proteins have been enabled by chemoselective reactions of sidechain functionality for covalent modification, capture, or imaging. However, unlike protein sidechains, glycan building blocks lack distinguishing reactivity. Moreover, glycans are not primary gene products, so encoding glycan variants through genetic manipulation is challenging. Reactive functional groups can be introduced into glycans through metabolic engineering, which involves the generation of modified nucleotide-sugar building blocks. Lipid-linked building blocks, which are also used in glycan biosynthesis, have the advantage that they can be delivered directly to glycosyltransferases to function as surrogate substrates. This process, termed "biosynthetic incorporation," takes advantage of the properties of bacterial glycosyltransferase: they are selective for the products they generate yet promiscuous in their donor preferences. We describe how this strategy can be implemented to label arabinofuranose-containing glycans on the surface of mycobacterial cells. We anticipate that this platform can be expanded to develop chemoselective labeling agents for other important bacterial monosaccharides.


Spine Anatomy Imaging: An Update.
Spinal MR imaging is excellent for identifying details of spinal anatomy, including intraspinal contents, neural foramina, joints, ligaments, intervertebral discs, and bone marrow. Cortical bony structures of the spine are better imaged using CT. Conventional and CT myelography is an alternative to MR imaging in those with contraindications to MR imaging or in evaluation of spinal cerebrospinal fluid leaks. Motion- and flow-related artifacts may occur during imaging and should not be mistaken for lesions. With advancements in MR imaging hardware and software, spinal MR imaging can expand its role in the delineation of normal and abnormal spinal anatomy.


A novel mouse model demonstrates that oncogenic melanocyte stem cells engender melanoma resembling human disease.
Melanoma, the deadliest skin cancer, remains largely incurable at advanced stages. Currently, there is a lack of animal models that resemble human melanoma initiation and progression. Recent studies using a Tyr-CreER driven mouse model have drawn contradictory conclusions about the potential of melanocyte stem cells (McSCs) to form melanoma. Here, we employ a c-Kit-CreER-driven model that specifically targets McSCs to show that oncogenic McSCs are a bona fide source of melanoma that expand in the niche, and then establish epidermal melanomas that invade into the underlying dermis. Further, normal Wnt and Endothelin niche signals during hair anagen onset are hijacked to promote McSC malignant transformation during melanoma induction. Finally, molecular profiling reveals strong resemblance of murine McSC-derived melanoma to human melanoma in heterogeneity and gene signatures. These findings provide experimental validation of the human melanoma progression model and key insights into the transformation and heterogeneity of McSC-derived melanoma.


Synthesis and expression of functional angiotensin II receptors in Xenopus oocytes injected with rat brain mRNA.
Xenopus laevis oocytes were injected with poly(A)+ mRNA isolated from rat brain and superfused in a medium containing either serotonin, angiotensin II or bradykinin. Applications of serotonin or angiotensin II to injected oocytes elicited, in a dose-dependent manner, changes in membrane potential. The angiotensin II receptor was desensitized fairly rapidly in the continued presence of the agonist. No response was obtained with bradykinin. The selectivity of the angiotensin II-induced response was demonstrated by the finding that the angiotensin II antagonist [( Sar1,Ala8]angiotensin II, saralasin) blocked the angiotensin II-induced response. It is concluded that an appropriate fraction of brain mRNA is capable of directing the synthesis and correct insertion of functional angiotensin II receptors in the Xenopus oocyte membrane.


Mode of action of the staphylococcin-like peptide Pep 5 and culture conditions effecting its activity.
Pep 5, a staphylococcin-like peptide produced by Staphylococcus epidermidis 5 was bactericidal for staphylococci and micrococci (Fig. 1). A stable L-phase variant of Staphylococcus aureus, but not of Streptococcus faecalis, was susceptible, too, indicating that the selectivity of Pep 5 is not due to the presence of a cell wall receptor. Addition of Pep 5 to cultures of the indicator strain caused immediate inhibition of DNA, RNA, protein, and polysaccharide synthesis (Fig. 5). The action of Pep 5 could be inhibited by increasing the cation content of the medium (e.g., to 100 mM Mg2+ or 600 mM K+) (Fig. 3), indicating a primary binding to anionic sites on the cell wall. Sublethally injured cells could be rescued by the addition of trypsin or 1 M KCl (Fig. 4).


Switch circular DNA formed in cytokine-treated mouse splenocytes: evidence for intramolecular DNA deletion in immunoglobulin class switching.
We have characterized circular DNA in mouse splenocytes treated with the mitogen lipopolysaccharide (LPS) and various cytokines, including transforming growth factor beta (TGF-beta) and interleukin 4 (IL-4). Using probes of immunoglobulin heavy chain constant genes (CH), excision products of class switch recombination were identified. The majority of the clones contained the 3' portion of the switch mu (S mu) region and the 5' portion of other switch regions. Some clones contained 3'-S gamma sequences instead of 3'-S mu. This indicates that isotype switching may occur not only from C mu, but also from one of the C gamma genes to other CH genes further down-stream. In the presence of LPS, the cytokine TGF-beta enhanced the detection of 5'-S alpha-positive clones, while the lymphokine IL-4 enhanced 5'-S gamma 1 positives. The data support the notion that TGF-beta and IL-4 can direct isotype-specific class switching.


The development of (99m)Tc-analog of Cu-DTS as an agent for imaging hypoxia.
Works on dithiosemicarbazone (DTS) derivatives radiolabeled with divalent Cu (Cu-62, Cu-64) indicate its potentiality as an ischemic tissue detecting agent. Development of analogous derivatives labeled with the more accessible technetium-99m (Tc) is most desirable. Various synthesized DTS derivatives are radiolabeled with a novel approach, using a macromolecular Sn(II)-complex under an anaerobic condition at pH 3.4-4.5 and stabilization by ascorbate solution at pH 6.7-7.0. Characterization of Tc-DTS derivatives done by various analytical methods (TLC, HPLC, EP, PC) and by in vivo studies in normal mice and in rats myocardial LAD (left anterior descent coronary artery) occlusion model. Among tested DTS, only Tc-ATSE, Tc-ATSM and Tc-ATSM(2) showed distinctive characteristics, with the latter presenting high myocardium uptake in regions of ischemia in LAD rat myocardium model. Potentiality of the Cu-DTS mimetic agent, Tc-ATSM(2) as an ischemia-damaged myocardium agent is discussed.


[Binding of monoclonal antibodies to fragmented erythrocyte membranes in patients with arterial hypertension].
The data obtained by radioimmunoassay indicate that monoclonal antibodies (MA) to sarcoplasmic reticulum membranes can also bind to erythrocyte membranes. The binding of MA to fragmented erythrocyte membranes from patients with essential hypertension (n = 20) is 35% higher, as compared to normal subjects (n = 14) or patients with secondary (renal) hypertension (n = 9). Possible use of radioimmunoassays for MA is discussed with reference to differential diagnosis of arterial hypertensions.


Cross-protection to new drifted influenza A(H3) viruses and prevalence of protective antibodies to seasonal influenza, during 2014 in Portugal.
Immune profile for influenza viruses is highly changeable over time. Serological studies can assess the prevalence of influenza, estimate the risk of infection, highlight asymptomatic infection rate and can also provide data on vaccine coverage. The aims of the study were to evaluate pre-existing cross-protection against influenza A(H3) drift viruses and to assess influenza immunity in the Portuguese population. We developed a cross-sectional study based on a convenience sample of 626 sera collected during June 2014, covering all age groups, both gender and all administrative health regions of Portugal. Sera antibody titers for seasonal and new A(H3) drift influenza virus were evaluated by hemagglutination inhibition assay (HI). Seroprevalence to each seasonal influenza vaccine strain virus and to the new A(H3) drift circulating strain was estimated by age group, gender and region and compared with seasonal influenza-like illness (ILI) incidence rates before and after the study period. Our findings suggest that seroprevalences of influenza A(H3) (39.9%; 95% CI: 36.2-43.8) and A(H1)pdm09 (29.7%; 95% CI: 26.3-33.4) antibodies were higher than for influenza B, in line with high ILI incidence rates for A(H3) followed by A(H1)pdm09, during 2013/2014 season. Low pre-existing cross-protection against new A(H3) drift viruses were observed in A(H3) seropositive individuals (46%). Both against influenza A(H1)pdm09 and A(H3) seroprotection was highest in younger than 14-years old. Protective antibodies against influenza B were highest in those older than 65years old, especially for B/Yamagata lineage, 33.3% (95% CI: 25.7-41.9). Women showed a high seroprevalence to influenza, although without statistical significance, when compared to men. A significant decreasing trend in seroprotection from north to south regions of Portugal mainland was observed. Our results emphasize that low seroprotection increases the risk of influenza infection in the following winter season. Seroepidemiological studies can inform policy makers on the need for vaccination and additional preventive measures.


Dopamine receptors in rabbit and rat eye: characterization and localization of DA1 and DA2 binding sites.
In vitro autoradiography is used to characterize and localize DA1 and DA2 receptors in rabbit and rat eyes. The bindings of 125I-SCH 23982 (DA1 antagonist) and of 125I-Iodosulpride (DA2 antagonist) to slide mounted tissue sections take place with characteristics expected of substances that recognize DA1 and DA2 receptors respectively. They are saturable, have high affinity and exhibit an appropriate pharmacology. The regional distribution of these receptors indicates that they are mainly present in retina. Precise cellular localizations are visualized in retinal structures by means of histoautoradiography: DA1 receptors are found in inner plexiform layer, outer plexiform layer and inner nuclear layer and DA2 binding sites are present in the two plexiform layers.


Screening for family and intimate partner violence: recommendation statement.
This statement summarizes the U.S. Preventive Services Task Force (USPSTF) recommendations on screening for family and intimate partner violence, based on the USPSTF's examination of evidence specific to family and intimate partner violence, and updates the 1996 recommendations on this topic. In 1996, the USPSTF found insufficient evidence to recommend for or against the use of specific instruments to detect domestic violence (a grade C recommendation, according to 1996 grade definitions). The USPSTF now uses an explicit process in which the balance of benefits and harms is determined exclusively by the quality and magnitude of the evidence. As a result, current letter grades are based on different criteria from those in 1996. The complete information on which this statement is based, including evidence tables and references, is available in the accompanying article in this issue and in the summary of the evidence and systematic evidence review on the USPSTF Web site (http://www.preventiveservices.ahrq.gov) and through the National Guideline Clearinghouse (http://www.guideline.gov). The USPSTF recommendation, the accompanying summary article, and the complete systematic evidence review are available through the USPSTF Web site (http://www.preventiveservices.ahrq.gov). The summary article and the USPSTF recommendation statement are available in print through the Agency for Healthcare Research and Quality Publications Clearinghouse (telephone, 800-358-9295; e-mail, firstname.lastname@example.com).


Usability issues in the operating room - Towards contextual design guidelines for medical device design.
Most usability assessments of medical devices describe the problems of individual devices in detail, but few account for the real context of use or provide designers with actionable guidelines for improvement. To fill this gap, this paper reports the results of a case study on the usability of operating room technologies and documents the creation of contextual design guidelines for operating room device design. We spent 64 h in a gynecological operating unit conducting interviews with staff and observing device use during surgery. With qualitative analysis methods and based on existing usability principles, we created 21 design guidelines for the operating room context. The new guidelines highlight interactions between multiple devices, staff members, as well as other contextual factors. While the guidelines require further validation, they can potentially support the creation of more safe, ergonomic, and intuitive medical devices.


Immunofluorescence protocol for localizing protein targets in brain tissue from diverse model and non-model mammals.
Previous immunostaining protocols are highly specific for model organisms and often not suitable for diverse specimens that are non-perfused and over-fixed (i.e., tissues sitting in fixatives for months/year). Here, we present an immunofluorescence protocol for localizing protein targets in brain tissue from 11 model and non-model mammals. We describe preparation of both fresh and fixed tissues including steps for deparaffinization, fixation, and cryoprotection. We then detail immunofluorescence procedures including antigen retrieval, reducing autofluorescence, nuclear staining, mounting, and image collection.


Long-Term Survival after Progressive Multifocal Leukoencephalopathy in a Patient with Primary Immune Deficiency and NFKB1 Mutation.
To describe the development of progressive multifocal leukoencephalopathy (PML) in a patient with primary immune deficiency (PID) due to a NFKB1 (nuclear factor kB subunit 1) mutation, who was treated successfully with a combination of mirtazapine and mefloquine. We've based the treatment of our patient on literature research and provide a review of PML in CVID patients. Only a few reports have been published on the occurrence of PML in PID. PML is mainly observed in patients with reduced cellular immunity, which was not the case in our patient. Successful treatment options in this population are limited. Though severely disabled, our patient still survives, more than 4 years after symptom onset and shows consistent improvement on MRI (magnetic resonance imaging) and CSF (cerebrospinal fluid) analysis. We conclude that some patients with PML might be treatable and can show long-term survival although neurological deficits remain. Involvement of humoral immunity in the pathogenesis of PML as well as the possible role of NFKB1 mutations in response to specific pathogens deserves further investigation.


Discrete-Particle Model to Optimize Operational Conditions of Proton-Exchange Membrane Fuel-Cell Gas Channels.
Operation of proton-exchange membrane fuel cells is highly deteriorated by mass transfer loss, which is a result of spatial and temporal interaction between airflow, water flow, channel geometry, and its wettability. Prediction of two-phase flow dynamics in gas channels is essential for the optimization of the design and operating of fuel cells. We propose a mechanistic discrete particle model (DPM) to delineate dynamic water distribution in fuel cell gas channels and optimize the operating conditions. Similar to the experimental observations, the model predicts seven types of flow regimes from isolated, side wall, corner, slug, film, and plug flow droplets for industrial temporal and spatial scales. Consequently, two-phase flow regime maps are proposed. The results suggest that an increase in water accumulation in the channel is related to the increase in the water cluster density emerging from the gas diffusion layer rather than the increased water flow rate through constant water pathways. From a modeling perspective, the DPM replicated well volume-of-fluid channel simulation results in terms of saturation, water coverage ratio, and interface locations with an estimated 5 orders of magnitude increase in calculation speed.


Prostacyclin is a specific effector of adipose cell differentiation. Its dual role as a cAMP- and Ca(2+)-elevating agent.
The mitogenic-adipogenic activity of carbaprostacyclin (cPGI2), a stable analogue of prostacyclin (PGI2), has been proposed to be related to its ability to elicit cAMP production and to activate the protein kinase A cascade (Négrel, R., Gaillard, D., and Ailhaud, G. (1989) Biochem. J. 257, 399-405). In the present study, cPGI2 has been compared with other activators of the cAMP pathway, namely isoproterenol, forskolin and 8-bromo-cAMP, with respect to adipose cell differentiation. Carbaprostacyclin behaved as a much more potent and efficient effector of mouse Ob1771 preadipocyte differentiation than the latter agents. Moreover, cPGI2 also exerted a specific amplifying mitogenic-adipogenic role, as compared with isoproterenol in rat as well as human adipose precursor cells in primary culture, suggesting that the prostanoid was able to generate an additional second messenger. The fact that ionomycin was able to potentiate and amplify the differentiation induced by 8-bromo-cAMP led us to give evidence, using preadipocytes preloaded with the fluorescent calcium chelator Indo-1, that cPGI2, besides its ability to activate adenyl cyclase, was also able to induce a transient increase in intracellular free calcium. This phenomenon was independent of cAMP production or inositol phospholipid breakdown and appeared to be mediated after binding to a single class of PGI2 receptor. The potential to generate simultaneously two synergistic intracellular signals allows us to ascribe to PGI2 a key and specific role in the differentiation of adipose precursor cells in vitro that would likely lead in vivo to the recruitment of "dormant" preadipocytes to become adipocytes.


11C-Choline-Pet Guided Stereotactic Body Radiation Therapy for Lymph Node Metastases in Oligometastatic Prostate Cancer.
aim is outcome of 11C-Choline-PET guided SBRT on lymph node metastases. patients with 1 - 4 lymph node metastases detected by 11C-choline-PET were treated with SBRT. Toxicity, treated metastases control and Progression Free Survival were computed. twenty-six patients, 38 lymph node metastases were irradiated. No grade ≥ 2 toxicity. Median PSA-nadir after RT was 1.02 ng/mL. Post-treatment 11C-Choline-PET showed metabolic complete response in 17 metastases (44,7%), partial response in 9 metastases (38%). SBRT is effective and safe for lymph node metastases. PET is important in identification of gross tumor and evaluation of the response.


Association between non-HDLC and 1-year prognosis in patients with spontaneous intracerebral haemorrhage: a prospective cohort study from 13 hospitals in Beijing.
Previous studies suggested an inverse association between lipoprotein cholesterols and bleeding risk, while limited data were available about the predictive value of lipoproteins on intracerebral haemorrhage (ICH). Our recent research series showed that higher non-high-density lipoprotein cholesterol (non-HDLC) was an independent predictor of favourable 3-month outcome in ICH patients, we thus aimed to further investigate the association between non-HDLC levels and 1-year functional outcomes after ICH. Prospective multicentre cohort study. 13 hospitals in Beijing, China. A total of 666 ICH patients were included between December 2014 and September 2016. Non-HDLC was calculated by subtracting HDL-C from total cholesterol. Patients were then grouped by non-HDLC levels into three categories: <3.4 mmol/L, 3.4-4.2 mmol/L and ≥4.2 mmol/L. Both the univariate and multivariate logistic regressions were used to assess the association between non-HDLC levels and 1-year unfavourable functional outcomes (modified Rankin Scale ≥3) in ICH patients. Moreover, sensitivity analysis was performed in ICH patients without statin use after admission. There were 33.5% (223/666) ICH patients identified with unfavourable functional outcomes at 1-year follow-up. In the univariate analysis, patients who achieved non-HDLC levels above 4.2 mmol/L had a 49% decreased risk of 1-year poor prognosis (OR 0.51, 95% CI 0.33 to 0.81). However, non-HDLC did not retain its independent prognostic value in multivariate analysis, the fully adjusted OR values were 1.00 (reference), 1.06 (0.63, 1.79) and 0.83 (0.45, 1.54) from the lowest to the highest non-HDLC group. Moreover, statin use after ICH onset made no difference to the long-term prognosis. Non-HDLC was not an independent predictor for 1-year functional outcome in ICH patients, irrespective of poststroke statin use. The predictive value of well-recognised confounding factors was more dominant than non-HDLC on long-term prognosis.


Human saliva as a source of biochemical genetic markers. II. Genetic interpretations and possible utilization.
Human saliva enzymes are compared to analogous blood enzymes. The genetic interpretations for variants of several saliva proteins are reviewed. The possible use of human saliva enzymes and proteins in population genetic studies and disease diagnosis is discussed.


The effect of ethanol and haloperidol on dopamine receptor (D2) density.
The study was performed to investigate the influence of ethanol on haloperidol-induced changes of the dopamine (D2) receptors in rat striatal membrane preparations. Subchronic administration of the neuroleptic in the drinking water resulted in an increase of the number of binding sites in a dose-dependent manner. Simultaneous treatment with both haloperidol and ethanol prevented the rise of D2 receptors.


Mechanical, biocompatibility and antibacterial studies of gelatin/polyvinyl alcohol/silkfibre polymeric scaffold for bone tissue engineering.
The current study focuses on the incorporation of natural polymers (gelatin, silk fibre) and synthetic (polyvinyl alcohol) polymer towards the fabrication of a novel composite for bone tissue engineering. The Electrospinning method was used to fabricate the novel gelatin/polyvinyl alcohol/silk fibre scaffold. XRD, FTIR and SEM-EDAX analysis was performed to characterize the composite. The characterized composite was investigated for its physical properties (porosity and mechanical studies) and biological studies (antimicrobial activity, hemocompatibility, bioactivity). The fabricated composite showed high porosity and the highest tensile strength of 34 MPa, with elongation at a break of 35.82 for the composite. The antimicrobial activity of the composite was studied and the zone of inhibition was measured around 51 ± 0.54 for E. coli, 48 ± 0.48 for S. aureus and 50 ± 0.26 for C. albicans. The hemolytic % was noted around 1.36 for the composite and the bioactivity assay revealed the formation of apatite on composite surfaces.


Analysis of a gas-liquid film plasma reactor for organic compound oxidation.
A pulsed electrical discharge plasma formed in a tubular reactor with flowing argon carrier gas and a liquid water film was analyzed using methylene blue as a liquid phase hydroxyl radical scavenger and simultaneous measurements of hydrogen peroxide formation. The effects of liquid flow rate, liquid conductivity, concentration of dye, and the addition of ferrous ion on dye decoloration and degradation were determined. Higher liquid flow rates and concentrations of dye resulted in less decoloration percentages and hydrogen peroxide formation due to initial liquid conductivity effects and lower residence times in the reactor. The highest decoloration energy yield of dye found in these studies was 5.2g/kWh when using the higher liquid flow rate and adding the catalyst. The non-homogeneous nature of the plasma discharge favors the production of hydrogen peroxide in the plasma-liquid interface over the chemical oxidation of the organic in the bulk liquid phase and post-plasma reactions with the Fenton catalyst lead to complete utilization of the plasma-formed hydrogen peroxide.


Emergence of Solvent-Separated Na+-Cl- Ion Pair in Salt Water: Photoelectron Spectroscopy and Theoretical Calculations.
Solvation of salts in water is a fundamental physical chemical process, but the underlying mechanism remains unclear. We investigated the contact ion pair (CIP) to solvent-separated ion pair (SSIP) transition in NaCl(H2O)n clusters with anion photoelectron spectroscopy and ab initio calculations. It is found that the SSIP type of structures show up at n = 2 for NaCl-(H2O)n anions. For neutral NaCl(H2O)n, the CIP structures are dominant at n < 9. At n = 9-12, the CIP structures and SSIP structures of NaCl(H2O)n are nearly degenerate in energy, coincident to the H2O:NaCl molar ratio of NaCl saturated solution and implying that the CIP and SSIP structures can coexist in concentrated solutions. These results are useful for understanding the solvation of salts at the molecular level.


Engineering improved bio-jet fuel tolerance in Escherichia coli using a transgenic library from the hydrocarbon-degrader Marinobacter aquaeolei.
Recent metabolic engineering efforts have generated microorganisms that can produce biofuels, including bio-jet fuels, however these fuels are often toxic to cells, limiting production yields. There are natural examples of microorganisms that have evolved mechanisms for tolerating hydrocarbon-rich environments, such as those that thrive near natural oil seeps and in oil-polluted waters. Using genomic DNA from the hydrocarbon-degrading microbe Marinobacter aquaeolei, we constructed a transgenic library that we expressed in Escherichia coli. We exposed cells to inhibitory levels of pinene, a monoterpene that can serve as a jet fuel precursor with chemical properties similar to existing tactical fuels. Using a sequential strategy with a fosmid library followed by a plasmid library, we were able to isolate a region of DNA from the M. aquaeolei genome that conferred pinene tolerance when expressed in E. coli. We determined that a single gene, yceI, was responsible for the tolerance improvements. Overexpression of this gene placed no additional burden on the host. We also tested tolerance to other monoterpenes and showed that yceI selectively improves tolerance. The genomes of hydrocarbon-tolerant microbes represent a rich resource for tolerance engineering. Using a transgenic library, we were able to identify a single gene that improves E. coli's tolerance to the bio-jet fuel precursor pinene.


A nonlinear relationship between systemic inflammation response index and short-term mortality in patients with acute myocardial infarction: a retrospective study from MIMIC-IV.
This investigation aimed to evaluate the efficacy of the Systemic Inflammatory Response Index (SIRI) in prognosticating short-term all-cause mortality among patients diagnosed with acute myocardial infarction (AMI) in the intensive care unit (ICU). Clinical data were obtained from the Medical Information Mart for Intensive Care-IV (MIMIC-IV) database. A total of 4,291 patients were included in the cohort. Results from multivariate regression analyses showed that the quartile of the natural logarithm of SIRI (ln-SIRI) was independently associated with mortality. Compared to patients in the first quartile (Q1), patients in the second quartile (Q2) and fourth quartile (Q4) were significantly associated with an increased risk of 30-day (HR = 2.031, 95% CI: 1.604-2.571, p < 0.001 and HR = 1.703, 95% CI: 1.32-2.195, p < 0.001) and 90-day all-cause mortality (HR = 2.063, 95% CI: 1.68-2.532, p < 0.001 and HR = 1.788, 95% CI: 1.435-2.227, p < 0.001), which is consistent with the results of the Kaplan-Meier analysis and the results of multivariate regression analyses by classifying into 12 groups based on dodeciles of SIRI. Curve fitting showed a curvilinear relationship and further threshold saturation effects showed that, for 90-day mortality, each unit increased in ln-SIRI, when the ln-SIRI level is less than 2.9, the patient's mortality increases by 23.2% (OR: 1.232; 95% CI: 1.111-1.367; p < 0.001); when the ln-SIRI is greater than 2.9 and less than 4.6, the patient's mortality decreases by 44.4% (OR: 0.554; 95% CI: 0.392-0.789; p = 0.001); when ln SIR > 4.6, the patient's mortality increases by 24.7% (OR: 1.247; 95% CI: 1.108-1.404; p < 0.001). Moreover, the length of stay in the hospital was lower in patients in the third quartile (Q3) (coefficient: -1.999; 95% CI: -2.834 - -1.165, p < 0.001). The length of stay in the ICU was higher in patients in Q2 and Q4 (coefficient: 0.685;95% CI: 0.243-1.128; p = 0.0024 and coefficient: 0.989;95% CI: 0.528-1.451; p < 0.001). Furthermore, SIRI may outperform NLR in predicting short-term mortality. SIRI is an independent risk factor for 30- and 90-day mortality, and length of stay in ICU for critical AMI patients.


Preoperative Assessment of Risk Factors.
Hemostasis is essential during endoscopic sinus and skull base surgery. Patients must be adequately assessed for bleeding risk to appropriately consent to surgery. The patient and the surgeon must be aware of the individual bleeding risk for a given procedure. A thorough history and physical examination is the best screening methodology available to determine whether a patient requires further hematologic work-up. Included in this assessment should be any medications and herbals that the patient consumes. This ensures a safe evaluation of the patient, streamlines appropriate consultation and testing when necessary, and confers accurate surgical risk assessment.


Transcriptional regulation of the open reading frame 35 encoded by Kaposi's sarcoma-associated herpesvirus.
Kaposi's sarcoma-associated herpesvirus (KSHV) is a member of the Gammaherpesvirinae and is causally associated with Kaposi's sarcoma, primary effusion lymphoma, and multicentric Castleman's disease. The KSHV genome encodes over 85 genes; the function of some is entirely unknown. We have characterized the transcriptional regulation of a conserved and uncharacterized Gammaherpesvirinae open reading frame, orf35, which lies in a cluster of several overlapping genes, orf34 to orf38. We identified the transcription start site and analyzed upstream sequences. We found that expression of the KSHV lytic replication and transcription activator (RTA) strongly increased the orf35 promoter activity through a 46-nucleotide region which includes a conserved AP-1 binding site. Electrophoretic mobility shift assay demonstrated direct binding of cJUN and cFOS to the predicted AP-1 binding site. Finally, using a mutated promoter lacking the AP-1 site and dominant-negative cFOS, we established that the RTA-mediated orf35 transactivation is AP-1-dependent.


Metabolic flux phenotyping of secondary metabolism in cyanobacteria.
Cyanobacteria generate energy from photosynthesis and produce various secondary metabolites with diverse commercial and pharmaceutical applications. Unique metabolic and regulatory pathways in cyanobacteria present new challenges for researchers to enhance their product yields, titers, and rates. Therefore, further advancements are critically needed to establish cyanobacteria as a preferred bioproduction platform. Metabolic flux analysis (MFA) quantitatively determines the intracellular flows of carbon within complex biochemical networks, which elucidate the control of metabolic pathways by transcriptional, translational, and allosteric regulatory mechanisms. The emerging field of systems metabolic engineering (SME) involves the use of MFA and other omics technologies to guide the rational development of microbial production strains. This review highlights the potential of MFA and SME to optimize the production of cyanobacterial secondary metabolites and discusses the technical challenges that lie ahead.


Distinguishing optimal esophagectomy candidates in elderly patients: A nomogram based on propensity score matching.
A survival benefit from esophagectomy was observed in elderly patients. But it's unclear how to identify specific patients who can benefit. Thus, we aimed to establish a predictive model to identify optimal candidates for esophagectomy. Patients (age ≥75 years) with esophageal cancer in Surveillance, Epidemiology and End Results (SEER) database were used to establish the predictive model. Propensity-score matching (PSM) was applied to eliminate the imbalance between esophagectomy group and non-esophagectomy group. We hypothesized that elderly patients could benefit from esophagectomy with longer cancer specific survival (CSS) time than those who did not receive esophagectomy. Patients received surgery were divided into beneficial group and non-beneficial group according to the median CSS time of non-esophagectomy group. Prognostic factors affecting patients' long-term survival were identified. Among esophagectomy group, a logistic regression model based on these factors was established to build a nomogram. A total of 7,025 eligible patients were extracted from the SEER database, with 831 patients received esophagectomy. Surgery was independently associated with better long-term survival (median CSS time in the matched population: 35 vs. 8 months, p < 0.001). As a result, 361 (68.6%) patients were divided into beneficial group (CSS >8 months). Factors including age, tumor site, histology, differentiation grade, TNM stage, and tumor size were used to formulate the nomogram, which was named as esophagectomy candidates screening score (ECSS). The validation from two aspects showed the model a useful and stable one. A predictive model was established to distinguish optimal candidates for esophagectomy among elderly patients with EC.


An integrated model for Gpr124 function in Wnt7a/b signaling among vertebrates.
Within the central nervous system, Wnt7a/b are unambiguously discriminated from other Wnt ligands by an endothelial receptor complex made of the glycosylphosphatidylinositol (GPI)-anchored Reck and the adhesion G protein-coupled receptor (GPCR) Gpr124. Reck is a Wnt7a/b-specific receptor, while Gpr124 facilitates the delivery of Reck-bound Wnt7a/b ligands to Frizzled, through partially characterized mechanisms. We report that, in zebrafish, the Gpr124-Frizzled interactions are dominated by intracellular scaffolds that exploit the striking molecular mimicry between Gpr124 and Frizzled intracellular domains (ICDs): an internal Dvl-binding motif and a C-terminal ETTV motif that recruits Dlg4 and Magi3. By contrast, mammalian Gpr124 receptors exhibit an ICD-independent interaction mechanism governed by species-specific attributes of their transmembrane and extracellular domains. This mechanism seemingly evolved to replace the Dvl-mediated mechanism. By contrasting zebrafish, mouse, and human Gpr124, this study provides insights into the evolution of Gpr124/Reck function across the vertebrate clade, a receptor complex uniquely implicated in Wnt ligand-specific cellular responses.


[Significance of clinically used gnotobiotechnics in the prophylaxis and during therapy of granulocytopenic infections].
Besides a literature survey own results by using the method of selective decontamination in the induction attendance of patients suffering from acute leucaemia are represented. These patients had an extreme infection disposition. The infection rate, the fever days, and the amount of systemic prescribed antibiotics could be decreased statistically significant. The results of selective decontamination, of granulocytes transfusion, and of isolation of patients in the life island achieved in our clinic are confronted. The selective decontamination is of central importance for prophylaxis in the same way as in the attendance of hospital infected defense diminished patients. Additionally, in the case of infections combinations of bactericidic antibiotics are indicated. On the other hand, granulocytes transfusion are not necessary. The effectivity of selective decontamination of the gastrointestinal tract underlines the significance of gnotobiotic methods within clinical practice.


Maternal Stress Combined with Terbutaline Leads to Comorbid Autistic-Like Behavior and Epilepsy in a Rat Model.
Human autism is comorbid with epilepsy, yet, little is known about the causes or risk factors leading to this combined neurological syndrome. Although genetic predisposition can play a substantial role, our objective was to investigate whether maternal environmental factors alone could be sufficient. We examined the independent and combined effects of maternal stress and terbutaline (used to arrest preterm labor), autism risk factors in humans, on measures of both autistic-like behavior and epilepsy in Sprague-Dawley rats. Pregnant dams were exposed to mild stress (foot shocks at 1 week intervals) throughout pregnancy. Pups were injected with terbutaline on postnatal days 2-5. Either maternal stress or terbutaline resulted in autistic-like behaviors in offspring (stereotyped/repetitive behaviors and deficits in social interaction or communication), but neither resulted in epilepsy. However, their combination resulted in severe behavioral symptoms, as well as spontaneous recurrent convulsive seizures in 45% and epileptiform spikes in 100%, of the rats. Hippocampal gliosis (GFAP reactivity) was correlated with both abnormal behavior and spontaneous seizures. We conclude that prenatal insults alone can cause comorbid autism and epilepsy but it requires a combination of teratogens to achieve this; testing single teratogens independently and not examining combinatorial effects may fail to reveal key risk factors in humans. Moreover, astrogliosis may be common to both teratogens. This new animal model of combined autism and epilepsy permits the experimental investigation of both the cellular mechanisms and potential intervention strategies for this debilitating comorbid syndrome.


Ca2+ oscillations in pancreatic acinar cells: spatiotemporal relationships and functional implications.
The pancreatic acinar cells are of particular interest for the study of cytosolic Ca2+ signals, since they are morphologically polarized and generate agonist-specific Ca2+ oscillation patterns. Recent data obtained by combining digital video imaging of Fura-2 fluorescence with patch-clamp whole-cell current recording have provided new information on the spatiotemporal relationships of the cytosolic Ca2+ signals and the Ca(2+)-activated ionic currents. Low agonist concentrations evoke repetitive short-lasting local Ca2+ spikes in the secretory pole region that activate shortlasting current spikes. In the case of acetylcholine stimulation the spikes are confined to this region. When cholecystokinin is used the shortlasting local spikes precede longer Ca2+ transients that spread to the whole of the cell. Infusion of non-metabolizable inositol trisphosphate analogues can mimic these responses. The shortlasting local Ca2+ spikes are particularly sensitive to blockade by the inositol trisphosphate receptor antagonist heparin. These results show that the secretory pole region has a particularly high sensitivity to inositol trisphosphate probably due to clustering of high affinity receptors.


Heat stress increases the effectiveness of early ischemic preconditioning in spinal cord protection.
This study was aimed to test the hypothesis that the combination of heat stress and early ischemic preconditioning (IP) applied before aortic occlusion would be protective against spinal cord ischemic injury. Thirty Whister-Albino rats were randomly divided into three groups. In group 1 (n=10), aorta was clamped just distal to the left renal artery and above the iliac bifurcation for 45 min. Group 2 (n=10) had 5 min of transient aortic occlusion and 30 min later underwent an additional 45 min. In group 3 (n=10), animals were heated to 41 degrees C and maintained at this temperature for 15 min. Twenty-four hours later, this hyperthermia pretreated group underwent the same early IP model of aortic occlusion. Neurologic status was assessed on postoperative 24 and 48 h by using the 15-point neurologic performance scale. Spinal cords were harvested for histopathological grading (1-4) and evaluated for the presence of heat shock protein-ubiquitin staining. At 24 and 48 h, the mean neurologic performance scores of the group 1 were found to be significantly lower than those of groups 2 and 3. Although the neurologic assessment of rats performed on the 24h did not reveal statistically significant difference between groups 2 and 3 (P=0.069); on 48 h, the mean neurologic scores of the group 3 were significantly higher than those of group 2 (P=0.005). At 48 h, a delayed neurologic deterioration was seen in groups 1 and 2 when compared to the results obtained at 24h. Histologic evaluation correlated well with the neurologic outcome with the least cellular damage in group 3. There were six rats with ubiquitin expression and this was detected only in animals pretreated with sublethal heat stress. An early IP model with a short reperfusion interval does not give the minimal required time for the HSPs expression and is associated with a delayed neurologic deterioration. Neuroprotection provided by heat stress combined with an early IP model lasts up to 48 h and heat shock protein-ubiquitin induction may be responsible in this phenomenon.


Electronic Substitution Effect on the Ground and Excited State Properties of Indole Chromophore: A Computational Study.
Indole, being the main chromophore of amino acid tryptophan and several other biologically relevant molecules like serotonin, melatonin, has prompted considerable theoretical and experimental interest. The current work focuses on the investigation of substitution effect on the ground and excited electronic states of indole using computational quantum chemistry. Having three close-lying excited electronic states, the vibronic coupling effect becomes extremely important yet challenging for the photophysics and photochemistry of indole. Here, we have evaluated the performance of time-dependent density functional theory against available experimental and ab initio results from the literature. The electronic effects on the excited states of indole and indole derivatives e. g. tryptophan, serotonin and melatonin are reported. A bathochromic shift has been observed in the absorption spectrum for the La state. The absorption wavelength increases in the order of indole<tryptophan <serotonin <melatonin. While the contribution of the in-plane small adjacent groups increases the electron density of the indole ring, the out-of-plane long substituent groups have minor effect. The absorption spectra calculated including the vibronic coupling are in good agreement with experiments. These results can be used to estimate the error in photophysical observables of indole derivatives calculated considering indole as a prototypical system.


Phygocytosis by rabbit polymorphonuclear leukocytes: the effect of albumin and polyamino acids on latex uptake.
Albumin in low concentrations (0.0001-0.01 weight percent) was found to be an effective inhibitor of phagocytosis of polystyrene latex beads by rabbit polymorphonuclear leukocytes. Polyglutamic acid proved to be an inhibitor of latex uptake at even lower concentrations. Polylysine stimulates phagocytosis, maximal stimulation occurring at 0.002% polylysine. These findings are discussed with reference to the surface properties of latex particles and leukocytes, and particularly with reference to electrostatic interactions in phagocytosis.


Performance of screening algorithms in systemic sclerosis-related pulmonary arterial hypertension: a systematic review.
Pulmonary arterial hypertension (PAH) is a major cause of mortality in systemic sclerosis (SSc). There is emerging evidence that screening may enable the earlier detection and treatment of SSc-PAH, and thereby improve survival. We undertook a systematic review to evaluate the performance of current screening algorithms in SSc-PAH. We searched the Medline and EMBASE databases to 31 March 2012. We selected studies if they applied a screening algorithm to consecutively enrolled SSc patients not known to have PAH; SSc-PAH had to be confirmed on right heart catheterisation (RHC). The performance of each screening algorithm and the methodological quality of each study was evaluated. Nine studies met the inclusion criteria with a total intent-to-screen population of 3504 participants. In studies of patients with prevalent disease, the positive predictive value (PPV) of screening for PAH was 20.4-87.0%. In studies of patients with incident disease, the PPV of screening for PAH was 20.0-30.7%. The PPV of algorithms using echocardiography alone, or in combination with other tests, was comparable. No study enabled an accurate determination of negative predictive value, sensitivity or specificity of the screening algorithm as only patients who screened positive underwent confirmatory testing with RHC. The optimal timing and frequency of repeat screening is unknown. The low to moderate PPV of current screening algorithms, coupled with the inability to determine accurately the negative predictive value, sensitivity and specificity, suggests that there is a need to validate further these algorithms before making recommendations regarding screening for SSc-PAH.


Has the distribution of smoking across young adult transition milestones changed over the past 20 years? Evidence from the 1970 British Cohort Study (1996) and Next Steps (2015-16).
Transitions into work and family life during young adulthood exacerbate differences in the progression of smoking over the life-course. Few have considered how changes in smoking and the transition to adulthood in the past two decades have influenced these relationships over time. We compared the distribution of smoking at ages 25-26 across transition milestones among 3764 men and 4568 women in the 1970 British Cohort study (1996) and 3426 men and 4281 women in the Next Steps study (2015-16). We regressed occasional and daily smoking status on educational attainment, economic activity, living arrangements, relationship status, and parenthood, adjusting for family background, socio-demographics, and smoking history. There were few differences in associations between the 1996 and 2015-16 samples. Young men and women were less likely to smoke if they had higher education, were homeowners, and cohabited with a partner. Women were less likely to smoke occasionally if they were full-time students, and men were less likely to smoke daily if they were employed full-time and not living with children. However, comparing associations in 2015-16 to 1996: 1) in men, higher education had a weaker negative association and living with a partner had a stronger negative association with daily smoking; 2) in women, independently renting had a weaker positive association with daily smoking. Despite considerable changes in smoking and the transition to adulthood over the past two decades, the distribution of smoking at ages 25-26 across transition milestones has been relatively stable during this time period in Great Britain.


Effects of asymmetric vertebral blood flow upon the vestibulo-ocular reflex of the rabbit.
Per-rotational nystagmus was recorded in rabbits with unilaterally narrowed vertebral arteries or following unilateral cervical sympathectomies. Asymmetry of per-rotational nystagmus could not be observed when the animal's systemic arterial blood pressure was within the normal range (about 90-120 mm Hg). However, directional preponderance of nystagmus occurred when blood pressure either increased or decreased beyond this level. The reason for the occurrence of directional preponderance can be interpreted as a failure of autoregulation of cerebral and/or inner ear blood flow.


Enhancers have more cofactor specificity than we think: A potential new way to classify enhancers based on their functional cofactor requirements.
By systematically assessing the effects of depleting eight cofactors on enhancer activity, Neumayr et al. (2022) found that different enhancers have different requirements for some perceived universal cofactors. While some cofactors influence enhancer strength, others affect enhancer-promoter specificity.


Cost-Utility of Rhegmatogenous Retinal Detachment Repair With Pars Plana Vitrectomy, Scleral Buckle, and Pneumatic Retinopexy: A Microsimulation Model.
To assess the cost-effectiveness of primary noncomplex rhegmatogenous retinal detachment (RRD) repair, comparing 3 different strategies, pars plana vitrectomy (PPV), scleral buckle (SB), and pneumatic retinopexy (PnR) from the health care payer perspective over a lifetime. Model-based cost-utility analysis. A simulated cohort of 100,000 adult patients (≥18 years old) requiring primary noncomplex RRD repair in theoretical surgical centers in the United States. Quality-adjusted life years (QALYs), lifetime costs (2022 United States dollars), and the incremental cost-effectiveness ratio (ICER) of the 3 interventions were projected over a lifetime horizon, with a cost-effectiveness threshold of ≤$50,000 per gained QALY. Based on inputted parameters, the primary anatomical success was highest for PPV (95.00%) compared to SB (91.76%) and PnR (63.41%). The QALYs associated with PPV, SB, and PnR were (11.87, SD 1.62), (11.84, SD 1.63), and (11.59, SD 1.72), respectively. The incurred lifetime costs of RRD repair and associated postoperative surgeries for PPV, SB, and PnR were $4445.72 (SD 655.75), $4518.04 (662.92), and $3978.45 (728.50), respectively. Parameter-level simulations suggested that PPV was most likely to be the most cost-effective therapy compared to SB and PnR beyond a threshold of $3000/QALY. The incremental cost-effectiveness ratio for PPV compared to PnR was $1693.54. SB was dominant in all scenarios. Threshold analyses indicated that the success rate of PnR would have to be 100% and/or the cost would have to be $2000 or less over lifetime for it to be more cost-effective than PPV. This study found PPV to be the most cost-effective primary procedure for RRD repair at a threshold of $50,000/QALY gained over a lifetime horizon from the health care payer perspective.


Activation of an adipogenic program in adult myoblasts with age.
Myoblasts isolated from mouse hindlimb skeletal muscle demonstrated increased adipogenic potential as a function of age. Whereas myoblasts from 8-month-old adult mice did not significantly accumulate terminal markers of adipogenesis regardless of culture conditions, myoblasts from 23-month-old mice accumulated fat and expressed genes characteristic of differentiated adipocytes, such as the fatty acid binding protein aP2. This change in differentiation potential was associated with a change in the abundance of the mRNA encoding the transcription factor C/EBPalpha, and in the relative abundance of PPARgamma2 to PPARgamma1 mRNAs. Furthermore, PPARgamma activity appeared to be regulated at the level of phosphorylation, being more highly phosphorylated in myoblasts isolated from younger animals. Although adipogenic gene expression in myoblasts from aged animals was activated, presumably in response to PPARgamma and C/EBPalpha, unexpectedly, myogenic gene expression was not effectively repressed. The Wnt signaling pathway may also alter differentiation potential in muscle with age. Wnt-10b mRNA was more abundantly expressed in muscle tissue and cultured myoblasts from adult compared with aged mice, resulting in stabilization of cytosolic beta-catenin, that may potentially contribute to inhibition of adipogenic gene expression in adult myoblasts. The changes reported here, together with those reported in bone marrow stroma with age, suggest that a default program may be activated in mesenchymal cells with increasing age resulting in a more adipogenic-like phenotype. Whether this change in differentiation potential contributes to the increased adiposity in muscle with age remains to be determined.


A rapid and quantitative coat protein complex II vesicle formation assay using luciferase reporters.
The majority of protein export from the endoplasmic reticulum (ER) is facilitated by coat protein complex II (COPII). The COPII proteins deform the ER membrane into vesicles at the ER exit sites. During the vesicle formation step, the COPII proteins load cargo molecules into the vesicles. Formation of COPII vesicles has been reconstituted in vitro in yeast and in mammalian systems. These in vitro COPII vesicle formation assays involve incubation of microsomal membranes and purified COPII proteins with nucleotides. COPII vesicles are separated from the microsomes by differential centrifugation. Interestingly, the efficiency of the COPII vesicle formation with purified recombinant mammalian COPII proteins is lower than that with cytosol, suggesting that an additional cytosolic factor(s) is involved in this process. Indeed, other studies have also implicated additional factors. To facilitate biochemical identification of such regulators, a rapid and quantitative COPII vesicle formation assay is necessary because the current assay is lengthy. To expedite this assay, we generated luciferase reporter constructs. The reporter proteins were packaged into COPII vesicles and yielded quantifiable luminescent signals, resulting in a rapid and quantitative COPII vesicle formation assay.


Evaluation of the effect of various main elements on the PrPSc detection by real-time quaking-induced conversion assay.
In order to definitively diagnosis sporadic Creutzfeldt‑Jakob disease (sCJD), brain tissue is currently required. Therefore, there is a great need for tests that can detect sCJD in body fluids or other types of tissues. Different variables, including the amount of recombinant celluar prion protein (rPrPC), salt, cleaning surfactants and thioflavin T (ThT), in human cerebrospinal fluid (CSF) were evaluated. The reagent concentrations of 1X PBS, 170 mM NaCl, 1 mM EDTA, 0.01 mM ThT and 0.001% SDS, and the amounts of 10 µg rPrPC and 10 µl CSF were considered to be optimal for the real‑time quaking‑induced conversion (RT‑QuIC) assay. Using these conditions, the RT‑QuIC assay for prion protein (PrPSc) detection was observed to be sensitive to 10‑8 diluted brain homogenates of hamsters infected with the 263K scrapie strain. Furthermore, CSF samples from 70 probable sCJD cases and 48 non‑CJD cases were preliminarily screened. A substantial proportion of sCJD samples (57.14%) tested positive by RT‑QuIC, with a short lag phase (<50 h post‑reaction) and high peak ThT values (>25,000 relative fluorescence units). By contrast, only a small number of non‑CJD samples displayed weakly positive results, and these were detected at a later stage (>50 h post‑reaction) and had much lower ThT values. In conclusion, the RT‑QuIC assay in CSF samples reported in the present study may provide a useful pre‑mortem tool for the diagnosis of sCJD, particularly in China where postmortem examination is rarely conducted.


Vangl-dependent Wnt/planar cell polarity signaling mediates collective breast carcinoma motility and distant metastasis.
In light of the growing appreciation for the role of collective cell motility in metastasis, a deeper understanding of the underlying signaling pathways will be critical to translating these observations to the treatment of advanced cancers. Here, we examine the contribution of Wnt/planar cell polarity (Wnt/PCP), one of the non-canonical Wnt signaling pathways and defined by the involvement of the tetraspanin-like proteins Vangl1 and Vangl2, to breast tumor cell motility, collective cell invasiveness and mammary tumor metastasis. Vangl1 and Vangl2 knockdown and overexpression and Wnt5a stimulation were employed to manipulate Wnt/PCP signaling in a battery of breast cancer cell lines representing all breast cancer subtypes, and in tumor organoids from MMTV-PyMT mice. Cell migration was assessed by scratch and organoid invasion assays, Vangl protein subcellular localization was assessed by confocal fluorescence microscopy, and RhoA activation was assessed in real time by fluorescence imaging with an advanced FRET biosensor. The impact of Wnt/PCP suppression on mammary tumor growth and metastasis was assessed by determining the effect of conditional Vangl2 knockout on the MMTV-NDL mouse mammary tumor model. We observed that Vangl2 knockdown suppresses the motility of all breast cancer cell lines examined, and overexpression drives the invasiveness of collectively migrating MMTV-PyMT organoids. Vangl2-dependent RhoA activity is localized in real time to a subpopulation of motile leader cells displaying a hyper-protrusive leading edge, Vangl protein is localized to leader cell protrusions within leader cells, and actin cytoskeletal regulator RhoA is preferentially activated in the leader cells of a migrating collective. Mammary gland-specific knockout of Vangl2 results in a striking decrease in lung metastases in MMTV-NDL mice, but does not impact primary tumor growth characteristics. We conclude that Vangl-dependent Wnt/PCP signaling promotes breast cancer collective cell migration independent of breast tumor subtype and facilitates distant metastasis in a genetically engineered mouse model of breast cancer. Our observations are consistent with a model whereby Vangl proteins localized at the leading edge of leader cells in a migrating collective act through RhoA to mediate the cytoskeletal rearrangements required for pro-migratory protrusion formation.


Evaluation of 13N-amines as tracers.
The organ distribution and the metabolic fate of the 13N-amines 13N-beta-phenethylamine, 13N-n-octylamine, and 13N-3,4-dimethoxyphenethylamine, were studied in detail. After administration 13N-amines were rapidly transferred to tissues and oxidized by MAO. 13N-ammonia formed thereby was converted into amino acids (mainly glutamine by glutamine synthetase) and trapped. 13N-amines were found to be potential metabolic trapping tracers for the study of disposition and metabolism of amines.


NCLX pumps up the heat.
Mitochondrial Ca2+ signaling is a well-appreciated regulator of cell metabolism and energy production. A major function of mitochondria in brown adipose tissue (BAT) is thermogenesis. Assali et al. offer new insights into how the mitochondrial Ca2+ extrusion mediator NCLX is crucial for BAT survival and thermogenesis.


Responding to a challenge: nursing care and AIDS.
Those providing nursing services have been at the forefront in responding to the AIDS epidemic. This paper poses the question as to what extent AIDS work makes unique demands of nursing staff. It explores the implications of AIDS-related nursing work and considers these within the broader context of the role of nurses and their work environment. Although intense, many of the demands of AIDS-related work are also features of nursing in other contexts. There is thus potential to draw on already formulated training responses and to contribute significantly to ongoing debates about nursing and nurse education.


Scope of the organocatalysed asymmetric reductive amination of ketones with trichlorosilane.
A highly active organocatalyst has been shown to affect the asymmetric reductive amination of ketones producing both aromatic and aliphatic amines. At 1 mol% catalyst loading, a series of structurally diverse chiral amines were quickly and economically prepared with good enantioselectivity and generally useful yield. The efficient synthesis of the calcimimetic (+)-NPS R-568 (67%, 89% ee) demonstrated the synthetic applicability of this methodology.


Refractive keratotomy using a footplateless knife.
This article describes a diamond knife designed for safer, more precise extension of pre-existing refractive keratotomy incisions. The knife has a blade with a sharp vertical cutting edge whose progress is limited by a dull safety stop. The stop prevents extension of a wound by more than 500 microns at one time, minimizing the possibility of overextending the keratotomy incision into the optical zone. Because it requires no footplate, the knife improves visibility, allowing for more precise surgery.


Laparoscopic cholecystectomy in acute cholecystitis.
In the light of laparoscopic cholecystectomy increasingly applied to all forms of cholecystitis, this study aimed at evaluating the safety of laparoscopic cholecystectomy applied to all cases of acute cholecystitis, and at determining factors associated with the risk of conversion to open cholecystectomy. The clinical, biochemical, radiologic, and operative data from 124 consecutive cases of acute cholecystitis were analyzed retrospectively to determine the complications and morbidity after operation. The data were analyzed further by univariate and multivariate analysis to identify factors associated with conversion. No major bile duct injury or mortality occurred. Bile leak from the stump of the cystic duct developed in four patients. These were managed successfully by endoscopic biliary stent placement. The mean duration of hospital stay was 3.8 days in the laparoscopic group and 8.2 days in the open group. Of the 124 patients (18.5%), 23 underwent conversion to open cholecystectomy. Univariate analysis identified the following factors as associated with conversion: common duct dilation greater than 7 mm observed on ultrasound, (p < 0.05), pericholecystic collection seen on ultrasound (p < 0.0001), emphysematous cholecystitis (p < 0.01), endoscopic retrograde cholangiopancreatographic evidence of Mirizzi syndrome (p < 0.05), and pericholecystic collection at operation (p < 0.0001). On multivariate analysis, only pericholecystic collection (p < 0.015) and gallbladder wall thickness greater than 5 mm (p < 0.013) were statistically significant. Laparoscopic cholecystectomy for acute cholecystitis can be applied safely to all comers, offering the advantage of a shortened hospital stay. Pericholecystic collection, as observed on ultrasound, is associated with a high risk of conversion to open cholecystectomy.


Dual versus triple antithrombotic therapy after percutaneous coronary intervention or acute coronary syndrome in patients with indication for anticoagulation: an updated meta-analysis.
For patients who have an indication for anticoagulation, it is controversial whether dual therapy with an oral anticoagulant and single antiplatelet agent can be used after percutaneous coronary intervention (PCI) or acute coronary syndrome (ACS) instead of triple therapy with an oral anticoagulant and dual antiplatelet therapy. Twelve observational studies and four clinical trials were identified from three electronic databases from their inception to December, 2017. Pooled estimates were calculated using a random-effects model for meta-analysis. Compared with the triple therapy, dual therapy was associated with significantly lower risk of major bleeding [relative risk (RR), 0.63; 95% confidence interval (CI), 0.50-0.80] without statistically significant increase in major adverse cardiac events (RR, 1.04; 95% CI, 0.84-1.29), all-cause death (RR, 1.15; 95% CI, 0.77-1.71), cardiac death (RR, 1.04; 95% CI, 0.67-1.61), myocardial infarction (RR, 1.25; 95% CI, 0.98-1.59), stroke (RR, 1.27; 95% CI, 0.79-2.06), stent thrombosis (RR, 1.52; 95% CI, 0.96-2.41), and repeat revascularization (RR, 1.15; 95% CI, 0.87-1.52). Although risks of myocardial infarction and stent thrombosis were marginally higher in the dual therapy group, this trend was attenuated after excluding studies that exclusively included patients undergoing PCI for ACS, but not stable coronary artery disease. Dual therapy may be a reasonable alternative to triple therapy after PCI in patients with indication for chronic anticoagulation. However, further studies are needed to investigate efficacy of dual therapy, especially in the patients with higher ischemic risk, such as in ACS.


Expectancy biases in fear and anxiety and their link to biases in attention.
Healthy individuals often exhibit prioritized processing of aversive information, as manifested in enhanced orientation of attention to threatening stimuli compared with neutral items. In contrast to this adaptive behavior, anxious, fearful, and phobic individuals show exaggerated attention biases to threat. In addition, they overestimate the likelihood of encountering their feared stimulus and the severity of the consequences; both are examples of expectancy biases. The co-occurrence of attention and expectancy biases in fear and anxiety raises the question about causal influences. Herein, we summarize findings related to expectancy biases in fear and anxiety, and their association with attention biases. We suggest that evidence calls for more comprehensive research strategies in the investigation of mutual influences between expectancy and attention biases, as well as their combined effects on fear and anxiety. Moreover, both types of bias need to be related to other types of distorted information processing commonly observed in fear and anxiety (e.g., memory and interpretation biases). Finally, we propose new research directions that may be worth considering in developing more effective treatments for anxiety disorders.


miR-448 is a novel prognostic factor of lung squamous cell carcinoma and regulates cells growth and metastasis by targeting DCLK1.
MicroRNA-448 (miR-448) has been showed to be low-expressed and function as tumor suppressor in most human cancers. However, there are limited reports on the clinical significance and biological function of miR-448 in lung squamous cell carcinoma. In this study, we observed that miR-448 expression was decreased in lung squamous cell carcinoma tissues and cell lines. Meanwhile, miR-448 expression associated with differentiated degree, T classification (tumor size), N classification (lymph node metastasis), M classification (distant metastasis), clinical stage and prognosis of lung squamous cell carcinoma patients. In survival analysis, low expression of miR-448 was a poor independent prognostic factor for lung squamous cell carcinoma patients. Moreover, gain-of-function and loss-of-function studies showed miR-448 acted as a tumor suppressor regulating lung squamous cell carcinoma cells growth and metastasis. Furthermore, DCLK1 has been identified as a potential target for miR-448 to regulate lung squamous cell carcinoma cells growth and metastasis. In conclusion, miR-448 low-expression was a poor prognostic factor for lung squamous cell carcinoma patients, and miR-448 served as a tumor suppressor in lung squamous cell carcinoma cells via targeting DCLK1.


[Simultaneous subacute thrombosis in bare metal stents implanted into right coronary artery and left anterior descending artery without coexistence of resistance to antiplatelet therapy].
In-stent thrombosis is a rare but devastating complication of coronary stent implantation, occurring in 0.5% to 1.9% of patients with bare metal stents (BMS). The most frequent clinical manifestation of stent thrombosis is ST elevation myocardial infarction (STEMI) and 30 day mortality is 50%. In-stent thrombosis can present as acute (within 24 h), subacute (within 30 days), late or very late after stent placement. We describe a case of a patient presented with STEMI due to subacute stent thrombosis, which occurred simultaneously in BMS, 3 days after implantation. The patient was successfully treated with balloon coronary angioplasty and discharged from a hospital in good condition.