Central zone histology of the prostate: a mimicker of high-grade prostatic intraepithelial neoplasia.
The central zone (CZ) is located at the base of the prostate adjacent to the seminal vesicles. Its histology as a potential mimicker of high-grade prostatic intraepithelial neoplasia (PIN) has not been formally studied. Three groups were evaluated. Group 1 comprised 30 consecutive radical prostatectomy specimens assessed for the extent of CZ and of Roman arch and/or cribriform formation in the CZ. Group 2 comprised 100 consecutive cases of nonconsult prostate needle biopsies, screened in a random blinded fashion to identify CZ histology and the specificity of its identification on biopsy. Group 3 comprised 34 consult cases (1984 to the present) with CZ histology on needle biopsy. For group 1, the average maximum diameter of CZ histology was 5 mm. Two cases (6.7%) did not contain the classic features of CZ histology. The average amount of cribriform and/or Roman arch formation in the areas with CZ histology was 16.5%. In group 2, 10% of prostate needle biopsy cases had CZ histology. Of these, 80% were located on biopsy specimens designated as the base of the prostate, 10% were located in the base and midportion of the prostate, and 10% were located in the midportion of the prostate. For group 3, CZ histology occupied on average 32% of the involved core. The 2 most common histologic features were eosinophilic cytoplasm (97%) and location at the end of a core (97%). Other features were Roman arch formation (59%), a prominent basal cell layer (32%), cribriform formation (26%), and associated thick muscle bundles typical of bladder neck (24%). On average, cribriform and/or Roman arch formation occupied 22% of the CZ area seen on biopsy. Twenty-six of the consult cases were sent in with preliminary outside diagnoses. Of these, 21 (81%) were either PIN or atypical: 11 (42%) high-grade PIN, 7 (27%) PIN, and 3 (12%) atypical glands. Our findings show that CZ histology is distinctive, as seen in radical prostatectomy specimens. Less frequently it is found on needle biopsy, where the presence of Roman arch and/or cribriform formation mimics PIN. Recognition of the distinctive features of CZ histology (i.e., tall columnar cells with eosinophilic cytoplasm, prominent basal cell layer, and lack of cytologic atypia) can help avoid a misdiagnosis of PIN or "atypia" on needle biopsy.


Glial line-derived neurotrophic factor (GDNF): Biological activities.
Glial cell line-derived neurotrophic factor (GDNF) was initially discovered as a neurotrophic factor that enhances survival of midbrain dopaminergic neurons. Findings in 1994 and 1995 extended the spectrum of biological activities of GDNF to different populations of neurons (motor and sensory). Recent findings revealed that GDNF, Neurturin (NTN), Persephin (PSP), and Artemin (ARTN) are members of the GDNF protein family and are structurally related to transforming growth factor protein family. They are survival factors for peripheral and central neurons, for oligodendrocytes and can promote morphogenesis of kidney in vitro.


The effect of an escape room game on college nursing students' learning attitude and game flow experiences in teaching safe medication care for the elderly: an intervention educational study.
In the context of an aging population, the Gerontological Nursing course is becoming more and more important. Escape room games have been shown to have a positive effect on nursing education, but they have not been applied in the Gerontological Nursing course. The purpose of this study was to investigate the effects of adding an escape room game-based learning activity at the end of classroom teaching in a Gerontological Nursing course on nursing students' learning attitude and game flow experience. In April 2023, a total of 84 nursing students from two classes at a medical school in Northeast China were selected for the study, and the classes were divided into a test group (n = 41) and a control group (n = 43). Both groups received regular classroom teaching on "Safe Medication Care for the Elderly", and the test group participated in an escape room game at the end of the classroom teaching. General information about the nursing students in both groups was collected prior to participation; learning attitude were measured before and after participation; and game flow experience was measured before and after participation in the test group. Data were analyzed using independent samples t-tests and paired samples t-tests. There was no statistically significant difference in the general information and learning attitude of nursing students between the two groups before participation. After participation, the total learning attitude score of nursing students in the test group was (73.17 ± 1.67) and that of the control group was (61.63 ± 2.66), and the difference was statistically significant (p < 0.001, Cohen's d = 5.196). The game flow experience of nursing students in the test group before and after participation was (63.27 ± 2.48) and (81.29 ± 2.49), respectively, and the difference between before and after was statistically significant (p < 0.001, Cohen's d = 5.253). During the teaching process of the Gerontological Nursing course, an escape room game added at the end of classroom teaching can improve nursing students' learning attitude and also help them to have a good game flow experience. These findings suggest that teaching activities based on the escape room game have considerable practical application value.


The PIWI proteins SMEDWI-2 and SMEDWI-3 are required for stem cell function and piRNA expression in planarians.
PIWI proteins are expressed in germ cells in a wide variety of metazoans, where they participate in the synthesis and function of a novel class of small RNAs called PIWI associated RNAs (piRNAs). One function of piRNAs is to preserve the integrity of the germline genome by silencing transposons, though they also participate in epigenetic and post-transcriptional gene regulation. In the planarian Schmidtea mediterranea, the PIWI proteins SMEDWI-1 and SMEDWI-2 are expressed in neoblasts and SMEDWI-2 is required for regeneration and homeostasis. Here, we identify a diverse population of approximately 32-nucleotide small RNAs that strongly resemble vertebrate and insect piRNAs and map to hundreds of thousands of loci in the S. mediterranea genome. The expression of these RNAs occurs predominantly in neoblasts and is not restricted to the germline. RNAi knockdown of either SMEDWI-2 or a newly identified PIWI protein, SMEDWI-3, impairs regeneration and homeostasis and decreases the levels of both piRNAs and neoblasts. Therefore, SMEDWI-2 and SMEDWI-3 are required for piRNA expression, regeneration, and neoblast function in S. mediterranea.


β-C-H Allylation of Trialkylamines with Allenes Promoted by Synergistic Borane/Palladium Catalysis.
Functionalization of the C(sp3)-H bonds of trialkylamines is challenging, especially for reactions at positions other than the α position. Herein, we report a method for β-C(sp3)-H allylation of trialkylamines. In these reactions, which involve synergistic borane/palladium catalysis, an enamine intermediate is first generated from the amine via α,β-dehydrogenation promoted by B(C6F5)3 and a base, and then the enamine undergoes palladium-catalyzed reaction with an allene to give the allylation product. Because the hydride and the proton resulting from the initial dehydrogenation are ultimately shuttled to the product by B(C6F5)3 and the palladium catalyst, respectively, these reactions show excellent atom economy. The establishment of this method paves the way for future studies of C-H functionalization of trialkylamines by means of synergistic borane/transition-metal catalysis.


Cardiovascular protection by ginsenosides and their nitric oxide releasing action.
1. In an animal model in vivo, ginsenosides (GS), saponins from Panax ginseng, were shown to protect against myocardial ischaemia/reperfusion damage with concomitant increased 6-keto-PGF1 alpha and decreased lipid peroxidation. 2. In perfused rabbit lung in situ and isolated rabbit aortic rings, GS protected the pulmonary and aortic endothelium against electrolysis-induced free radical injury. Purified components of GS, Rb1 and especially Rg1, relaxed pulmonary vessels and this effect was eliminated by nitro-L-arginine, an inhibitor of nitric oxide (NO) synthase. 3. In cultured bovine aortic endothelial cells, GS enhanced the conversion of [14C]-L-arginine to [14C]-L-citrulline, indicating an increased release of NO. 4. As the neurotransmitter inducing penile erection, NO release was shown to be enhanced by GS in rabbit corpus cavernosum (CC) in vitro. Ginsenosides enhanced both acetylcholine-induced and transmural nerve stimulation-activated relaxation associated with increased tissue cGMP. The latter effect was eliminated by tetrodotoxin and was associated with decreased tissue cGMP. Ginsenoside-enhanced CC relaxation was attenuated by nitro-L-arginine and oxyhaemoglobin, and enhanced by superoxide dismutase. 5. It is postulated that cardiovascular protection by GS may be partly mediated by the release of NO, a potent antioxidant, and that the GS-enhanced release of NO from endothelial cells, especially from perivascular nitric oxidergic nerves in the CC, may partly account for the aphrodisiac effect of Panax ginseng used in traditional Chinese medicine.


[Lipid variation in oocytes of the jellyfish Stomolophus meleagris (Scyphozoa: Rhizostomeae) from Las Guasimas Lagoon, Mexico, during gonadal development].
The jellyfish Stomolophus meleagris has potential for commercial exploitation but there is little information on their reproductive biology. This paper seeks to evaluate some biochemical and demographic characteristics of the species. Samples were taken monthly during 2005 and 2006. Jellyfish collected in 2005 were used to describe the characteristics and quantity of oocyte triglycerides and phospholipids with the Sudan black technique, and to ascertain the degree of gonadal development and sex ratio by the hematoxylin-eosin technique. The 2006 jellyfish were used to determine the size at first maturity and protein and total lipids contents. Four stages of development in both sexes were determined, with a continuous gamete development. The highest percentage of mature organisms was recorded in April. The proportion of sexes was 0.7:1.3. We found higher concentrations of triglycerides than phospholipids in the cytoplasm. There was a positive correlation between triglycerides and the diameter of the oocyte. The size at first maturity for both sexes was 105 mm. The highest protein and lipids contents were obtained in April and March respectively.


Isokinetic Fatigue Ratio of Shoulder Rotators in Elite Softball Players With and Without Rotator Cuff Tendinopathy, and its Association With the Subacromial Space.
Fatigue of the shoulder rotators may cause reduction of the subacromial space (SAS) and contribute to rotator cuff tendinopathy. To compare the isokinetic peak torques and fatigue ratios of shoulder external rotators (ER) and internal rotators (IR) between elite softball athletes with and without rotator cuff tendinopathy and to investigate their associations with the SAS. Cross-sectional study. University laboratory. Twenty-five elite softball players and 31 asymptomatic sedentary controls participated in this study. Isokinetic concentric IR and ER peak torque and fatigue ratio were measured at 60°/s and at 180°/s, respectively; and ultrasound measurement of the SAS was measured during 0° and 60° of shoulder abduction. Athletes with rotator cuff tendinopathy demonstrated lower peak torque in shoulder concentric ER when compared with their healthy counterparts (37.8 [5.8%] vs 43.6 [8.5%]). No significant difference was found in the fatigue ratios of ER, IR, and ER/IR when compared between elite softball athletes with and without rotator cuff tendinopathy (all P > .24). In asymptomatic athletes, greater IR peak torque (r = .583, P = .03), lower ER/IR strength ratio (r = -.605, P = .02), and greater ER/IR fatigue ratio (r = .575, P = .03) were moderately associated with more reduction of the SAS during 0° and 60° of shoulder abduction. Decreased strength ratio and fatigue ratio of ER/IR were related to reduction of the SAS.


Effect of mixing on the formation of complexes of hyperbranched cationic polyelectrolytes and anionic surfactants.
The effect of different mixing protocols on the charged nature and size distribution of the aqueous complexes of hyperbranched poly(ethylene imine) (PEI) and sodium dodecyl sulfate (SDS) was investigated by electrophoretic mobility and dynamic light scattering measurements at different pH values, polyelectrolyte concentrations, and ionic strengths. It was found that at large excess of the surfactant a colloidal dispersion of individual PEI/SDS nanoparticles forms via an extremely rapid mixing of the components by means of a stop-flow apparatus. However, the application of a less efficient mixing method under the same experimental conditions might result in large clusters of the individual PEI/SDS particles as well as in a more extended precipitation regime compared with the results of stop-flow mixing protocol. The study revealed that the larger the charge density and concentration of the PEI, the more pronounced the effect of mixing becomes. It can be concluded that an efficient way to avoid precipitation in the solutions of oppositely charged polyelectrolytes and surfactants might be provided by extending the range of kinetically stable colloidal dispersion of polyelectrolyte/surfactant nanoparticles via the application of appropriate mixing protocols.


Pregnancy Exposure to Perfluoroalkyl Substances and Associations With Prolactin Concentrations and Breastfeeding in the Odense Child Cohort.
Human exposure to perfluoroalkyl substances (PFAS) has been associated with reduced duration of breastfeeding, although not consistently so, and mechanisms by which PFAS might affect breastfeeding are unknown. To examine the association between early pregnancy serum-PFAS concentrations and breastfeeding termination and to elucidate the potential role of serum-prolactin concentrations in pregnancy. Pregnant women from the Odense Child Cohort provided blood samples for analysis of 5 major PFAS (n = 1300) and prolactin concentrations (n = 924). They subsequently provided information about the duration of breastfeeding in questionnaires at 3 and 18 months postpartum, and a subgroup also provided breastfeeding information via weekly cell phone text messages. Associations between serum-PFAS concentrations and breastfeeding termination were analyzed using Cox regressions, while linear regression was used to assess associations between serum-PFAS and prolactin concentrations. Increased serum concentrations of perfluorooctane sulfonic acid, perfluorooctanoic acid, perfluorononanoic acid, and ∑PFAS were associated with a 16% (95% CI: 4%-30%), 14% (95% CI: 2%-26%), 14% (95% CI: 3%-27%), and 20% (95% CI: 6%-36%), respectively, increased risk of terminating breastfeeding at any given time after childbirth. Serum-PFAS concentrations were not associated with serum-prolactin concentrations. These findings are of public health importance due to the global exposures to PFAS. Because breastfeeding is crucial to promote both child health and maternal health, adverse PFAS effects on the ability to breastfeed may have long-term health consequences.


Pharmacogenomic and pharmacokinetic determinants of erlotinib toxicity.
To assess the pharmacogenomic and pharmacokinetic determinants of skin rash and diarrhea, the two primary dose-limiting toxicities of the epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor erlotinib. A prospective clinical study of 80 patients with non-small-cell lung cancer, head and neck cancer, and ovarian cancer was performed. Detailed pharmacokinetics and toxicity of erlotinib were assessed. Polymorphic loci in EGFR, ABCG2, CYP3A4, and CYP3A5 were genotyped, and their effects on pharmacokinetics and toxicities were evaluated. A novel diplotype of two polymorphic loci in the ABCG2 promoter involving -15622C/T and 1143C/T was identified, with alleles conferring lower ABCG2 levels associated with higher erlotinib pharmacokinetic parameters, including area under the curve (P = .019) and maximum concentration (P = .006). Variability in skin rash was best explained by a multivariate logistic regression model incorporating the trough erlotinib plasma concentration (P = .034) and the EGFR intron 1 polymorphism (P = .044). Variability in diarrhea was associated with the two linked polymorphisms in the EGFR promoter (P < .01), but not with erlotinib concentration. Although exploratory in nature, this combined pharmacogenomic and pharmacokinetic model helps to define and differentiate the primary determinants of skin and gastrointestinal toxicity of erlotinib. The findings may be of use both in designing trials targeting a particular severity of rash and in considering dose and schedule modifications in patients experiencing dose-limiting toxicities of erlotinib or similarly targeted agents. Further studies of the relationship between germline polymorphisms in EGFR and the toxicity and efficacy of EGFR inhibitors are warranted.


Hearing loss in skull fractures.
One hundred three cases of skull fractures in or around the temporal bone were reviewed for hearing loss. Of these, 100 patients had skull series, 66 had computed tomographic head scans, and 44 had polytomographic studies of the temporal bone. Hearing loss in head trauma can be grouped into four categories: conductive hearing loss, peripheral sensorineural hearing loss, central sensorineural hearing loss, and combinations of these hearing losses. The cause of conductive hearing loss and peripheral sensorineural hearing loss was usually identified by the type of temporal bone fracture. However, the cause of the central sensorineural hearing loss was more difficult to correlate with the brain lesions shown in the computed tomographic scans.


High-resolution structures and orientations of antimicrobial peptides piscidin 1 and piscidin 3 in fluid bilayers reveal tilting, kinking, and bilayer immersion.
While antimicrobial peptides (AMPs) have been widely investigated as potential therapeutics, high-resolution structures obtained under biologically relevant conditions are lacking. Here, the high-resolution structures of the homologous 22-residue long AMPs piscidin 1 (p1) and piscidin 3 (p3) are determined in fluid-phase 3:1 phosphatidylcholine/phosphatidylglycerol (PC/PG) and 1:1 phosphatidylethanolamine/phosphatidylglycerol (PE/PG) bilayers to identify molecular features important for membrane destabilization in bacterial cell membrane mimics. Structural refinement of (1)H-(15)N dipolar couplings and (15)N chemical shifts measured by oriented sample solid-state NMR and all-atom molecular dynamics (MD) simulations provide structural and orientational information of high precision and accuracy about these interfacially bound α-helical peptides. The tilt of the helical axis, τ, is between 83° and 93° with respect to the bilayer normal for all systems and analysis methods. The average azimuthal rotation, ρ, is 235°, which results in burial of hydrophobic residues in the bilayer. The refined NMR and MD structures reveal a slight kink at G13 that delineates two helical segments characterized by a small difference in their τ angles (<10°) and significant difference in their ρ angles (~25°). Remarkably, the kink, at the end of a G(X)4G motif highly conserved among members of the piscidin family, allows p1 and p3 to adopt ρ angles that maximize their hydrophobic moments. Two structural features differentiate the more potent p1 from p3: p1 has a larger ρ angle and less N-terminal fraying. The peptides have comparable depths of insertion in PC/PG, but p3 is 1.2 Å more deeply inserted than p1 in PE/PG. In contrast to the ideal α-helical structures typically assumed in mechanistic models of AMPs, p1 and p3 adopt disrupted α-helical backbones that correct for differences in the amphipathicity of their N- and C-ends, and their centers of mass lie ~1.2-3.6 Å below the plane defined by the C2 atoms of the lipid acyl chains.


A Stabilized Feedback Episodic Memory (SF-EM) and Home Service Provision Framework for Robot and IoT Collaboration.
The automated home referred to as Smart Home is expected to offer fully customized services to its residents, reducing the amount of home labor, thus improving human beings' welfare. Service robots and Internet of Things (IoT) play the key roles in the development of Smart Home. The service provision with these two main components in a Smart Home environment requires: 1) learning and reasoning algorithms and 2) the integration of robot and IoT systems. Conventional computational intelligence-based learning and reasoning algorithms do not successfully manage dynamic changes in the Smart Home data, and the simple integrations fail to fully draw the synergies from the collaboration of the two systems. To tackle these limitations, we propose: 1) a stabilized memory network with a feedback mechanism which can learn user behaviors in an incremental manner and 2) a robot-IoT service provision framework for a Smart Home which utilizes the proposed memory architecture as a learning and reasoning module and exploits synergies between the robot and IoT systems. We conduct a set of comprehensive experiments under various conditions to verify the performance of the proposed memory architecture and the service provision framework and analyze the experiment results.


Short report: further evidence for hepatitis E in the Brazilian Amazon.
During an investigation of a hepatitis outbreak occurring in a small village in the Brazilian Amazon, serum samples from 16 recent hepatitis cases and 66 of their asymptomatic relatives were tested for the presence of hepatitis A, B, C, and E markers. Sanitation is poor and organized disposal of sewage is absent in the village. Two of the 16 hepatitis cases were non-A, non-B and non-C hepatitis, but their sera reacted to hepatitis E antibodies of the IgG class (anti-HEV). Likewise, sera from seven of the 66 asymptomatic relatives were positive for anti-HEV. Four of the nine anti-HEV positive sera had their reactivity confirmed by a neutralization test using synthetic peptides based on the nucleotide sequences of open reading frames 2 (ORF2) and 3 (ORF3) encoded in the HEV genome. To our knowledge, this is the first report suggesting the occurrence of acute E hepatitis cases in the Brazilian Amazon.


[Effect of monovalent anions of various nature on conformation of DNA molecules in a water-salt solution].
Methods of intrinsic viscosity [eta] and beam flow birefringence were used to study the effects of some single-charged ions (F-, Cl-, Br-, J-, NO2-, NO3-, ClO4-, SCN-, CH3COO-) on the size and thermodynamic rigidity of DNA molecule in aqueous solutions of sodium salts in a broad interval of ionic strength mu when temperature T is changed. It has been shown that the close interactions in a macromolecule and the resulting persistent length a of DNA are independent of the type of the salt anion over the whole interval of mu. On the contrary, specific volume of DNA molecule in solution, proportional to [eta] value, is quite sensitive to the anionic composition of a solvent which is due to the effect of anions and their hydration on the remote interactions in the macromolecule. The presence of polyatomic and halide anions is manifested differently in the [eta] value of DNA. Possible factors responsible for the observed effect and the role of structural alterations of water upon anion hydration are discussed.


Asymmetric velocity correlations in shearing media.
A model of soft frictionless disks in two dimensions at zero temperature is simulated with a shearing dynamics to study various kinds of asymmetries in sheared systems. We examine both single particle properties, the spatial velocity correlation function, and a correlation function designed to separate clockwise and counterclockwise rotational fields from one another. Among the rich and interesting behaviors we find that the velocity correlation along the two different diagonals corresponding to compression and dilation, respectively, are almost identical and, furthermore, that a feature in one of the correlation functions is directly related to irreversible plastic events.


Expression of connective tissue growth factor in male breast cancer: clinicopathologic correlations and prognostic value.
Connective tissue growth factor (CTGF/CCN2) is a member of the CCN family of secreted proteins that are believed to play an important role in the development of neoplasia. In particular, CTGF has been reported to play an important role in mammary tumorigenesis and to have prognostic value in female breast cancer (FBC). The aim of the present study was to investigate clinicopathologic correlations and prognostic value of CTGF in male breast cancer (MBC) and to compare these findings with FBC. For this, we studied CTGF protein expression by immunohistochemistry in 109 MBC cases and 75 FBC cases. In MBC, stromal CTGF expression was seen in the majority of the cases 78% (85/109) with high expression in 31/109 cases (28.4%), but expression in tumor cells was only seen in 9.2% (10/109) of cases. High stromal CTGF expression correlated with high grade and high proliferation index (>15%) assessed by MIB-1 immunohistochemical staining. CTGF expression in tumor epithelial cells did not correlate with any of the clinicopathologic features. In FBC, stromal CTGF expression positively correlated with mitotic count and tumor CTGF expression was associated with triple negative status of the tumor (p = 0.002). Neither stromal nor tumor epithelial cell CTGF expression had prognostic value in MBC and FBC. In conclusion, stromal CTGF expression was seen in a high percentage of MBC and was correlated with high grade and high proliferation index. In view of the important role of the microenvironment in cancer progression, this might suggest that stromal CTGF could be an interesting target for novel therapies and molecular imaging. However, the lack of association with prognosis warrants caution. The potential role of CTGF as a therapeutic target for triple negative FBC deserves to be further studied.


Phenotype, function, and differentiation potential of human monocyte subsets.
Human monocytes have been grouped into classical (CD14++CD16-), non-classical (CD14dimCD16++), and intermediate (CD14++CD16+) subsets. Documentation of normal function and variation in this complement of subtypes, particularly their differentiation potential to dendritic cells (DC) or macrophages, remains incomplete. We therefore phenotyped monocytes from peripheral blood of healthy subjects and performed functional studies on high-speed sorted subsets. Subset frequencies were found to be tightly controlled over time and across individuals. Subsets were distinct in their secretion of TNFα, IL-6, and IL-1β in response to TLR agonists, with classical monocytes being the most producers and non-classical monocytes the least. Monocytes, particularly those of the non-classical subtype, secreted interferon-α (IFN-α) in response to intracellular TLR3 stimulation. After incubation with IL-4 and GM-CSF, classical monocytes acquired monocyte-derived DC (mo-DC) markers and morphology and stimulated allogeneic T cell proliferation in MLR; intermediate and non-classical monocytes did not. After incubation with IL-3 and Flt3 ligand, no subset differentiated to plasmacytoid DC. After incubation with GM-CSF (M1 induction) or macrophage colony-stimulating factor (M-CSF) (M2 induction), all subsets acquired macrophage morphology, secreted macrophage-associated cytokines, and displayed enhanced phagocytosis. From these studies we conclude that classical monocytes are the principal source of mo-DCs, but all subsets can differentiate to macrophages. We also found that monocytes, in particular the non-classical subset, represent an alternate source of type I IFN secretion in response to virus-associated TLR agonists.


Nuclear matrix protein SMAR1 represses c-Fos-mediated HPV18 E6 transcription through alteration of chromatin histone deacetylation.
Matrix attachment region (MAR)-binding proteins have been implicated in the transcriptional regulation of host as well as viral genes, but their precise role in HPV-infected cervical cancer remains unclear. Here we show that HPV18 promoter contains consensus MAR element in the LCR and E6 sequences where SMAR1 binds and reinforces HPV18 E6 transcriptional silencing. In fact, curcumin-induced up-regulation of SMAR1 ensures recruitment of SMAR1-HDAC1 repressor complex at the LCR and E6 MAR sequences, thereby decreasing histone acetylation at H3K9 and H3K18, leading to reorientation of the chromatin. As a consequence, c-Fos binding at the putative AP-1 sites on E6 promoter is inhibited. E6 depletion interrupts degradation of E6-mediated p53 and lysine acetyl transferase, Tip60. Tip60, in turn, acetylates p53, thereby restoring p53-mediated transactivation of proapoptotic genes to ensure apoptosis. This hitherto unexplained function of SMAR1 signifies the potential of this unique scaffold matrix-associated region-binding protein as a critical regulator of E6-mediated anti-apoptotic network in HPV18-infected cervical adenocarcinoma. These results also justify the candidature of curcumin for the treatment of HPV18-infected cervical carcinoma.


Bone tissue and hyperhomocysteinemia.
Bone tissue quality is determined not only by multiple architectural variables, but also by the mechanical properties of collagen type 1. Homocysteinuria is a genetic disease whose manifestations include severe hyperhomocysteinemia and decreased bone strength. The effects of smaller homocysteine elevations on bone tissue are difficult to demonstrate in clinical studies. Studies in animals and in humans suggest that homocysteine may weaken collagen crosslinks and, if present in large amounts, interfere with bone remodeling. Whether routine homocysteine assays should be performed to detect bone frailty remains unclear. In clinical practice, the focus should be on identifying patients with potential causes of homocysteine elevation (e.g., medications), who should then be given vitamin D and folic acid supplementation if needed. This approach may improve not only bone health, but also vascular and general health.


A dynamic anchor domain in slc13 transporters controls metabolite transport.
Metabolite transport across cellular membranes is required for bioenergetic processes and metabolic signaling. The solute carrier family 13 (slc13) transporters mediate transport of the metabolites succinate and citrate and hence are of paramount physiological importance. Nevertheless, the mechanisms of slc13 transport and regulation are poorly understood. Here, a dynamic structural slc13 model suggested that an interfacial helix, H4c, which is common to all slc13s, stabilizes the stationary scaffold domain by anchoring it to the membrane, thereby facilitating movement of the SLC13 catalytic domain. Moreover, we found that intracellular determinants interact with the H4c anchor domain to modulate transport. This dual function is achieved by basic residues that alternately face either the membrane phospholipids or the intracellular milieu. This mechanism was supported by several experimental findings obtained using biochemical methods, electrophysiological measurements in Xenopus oocytes, and fluorescent microscopy of mammalian cells. First, a positively charged and highly conserved H4c residue, Arg108, was indispensable and crucial for metabolite transport. Furthermore, neutralization of other H4c basic residues inhibited slc13 transport function, thus mimicking the inhibitory effect of the slc13 inhibitor, slc26a6. Our findings suggest that the positive charge distribution across H4c domain controls slc13 transporter function and is utilized by slc13-interacting proteins in the regulation of metabolite transport.


Characterising modulatory effects of high-intensity high frequency transcranial random noise stimulation using the perceptual template model.
Neural noise is an inherent property of all nervous systems. However, our understanding of the mechanisms by which noise influences perception is still limited. To elucidate this relationship, we require techniques that can safely modulate noise in humans. Transcranial random noise stimulation (tRNS) has been proposed to induce noise into cortical processing areas according to the principles of stochastic resonance (SR). Specifically, it has been demonstrated that small to moderate intensities of noise improve performance. To date, however, high intensity tRNS effects on neural noise levels have not been directly quantified, nor have the detrimental effects proposed by SR been demonstrated in early visual function. Here, we applied 3 mA high-frequency tRNS to primary visual cortex during an orientation-discrimination task across increasing external noise levels and used the Perceptual Template Model to quantify the mechanisms by which noise changes perceptual performance in healthy observers. Results show that, at a group level, high-intensity tRNS worsened perceptual performance. Our computational analysis reveals that this change in performance was underpinned by an increased amount of additive noise and a reduced ability to filter external noise compared to sham stimulation. Interestingly, while most observers experienced detrimental effects, a subset of participants demonstrated improved performance. Preliminary evidence suggests that differences in baseline internal noise levels might account for these individual differences. Together, these results refine our understanding of the mechanisms underlying the influence of neural noise on perception and have important implications for the application of tRNS as a research tool.


Effects of denture adhesives and mouth moisturizers to human oral fibroblast and human keratinocyte cells using direct and indirect cell culture systems.
The purpose of this study was to evaluate the effects of commercialized denture adhesives and mouth moisturizers using direct and indirect cell cultures for in vitro examinations with human fibroblast and epithelial cells. Denture adhesives (Faston, Poligrip Powder, New Poligrip Free, Tafugurippu Kurimu, Polident Adhesive, Tafugurippu Tomei) and mouth moisturizers (Concool Mouth Gel, Biotene Oral Balance Gel) were subjected to live and dead detection and pH level determination. The mouth moisturizers showed higher cytotoxicity effects comparing with control on every cell cultures and cells, and pH level did not show any significant differences. However, there was no correlation of type of denture adhesive or mouth moisturizer with cytotoxicity. We concluded that cytotoxicity affects human cells regardless of type of material, though some dependence was noted.


Estrogen receptor regulation of quinone reductase in breast cancer: implications for estrogen-induced breast tumor growth and therapeutic uses of tamoxifen.
Antiestrogens have found widespread use in the treatment of breast cancer (reviewed in ref. 1). There is also interest in the use of tamoxifen as a preventive agent for breast cancer. However, the mechanism for the antitumor effects of antiestrogens is relatively unknown. For the most part it is thought that the basis for the anticancer action of antiestrogens is the inhibition of estradiol (E2)-stimulated tumor growth. We have observed however that antiestrogens can activate detoxifying enzymes, like quinone reductase (NQO1), which protect cells against the toxic and tumor-promoting effects of carcinogens (2). Studies characterizing the molecular mechanisms behind the regulation of NQO1 by the Estrogen Receptor (ER) support an important role of the ER in pathways regulating antioxidant defenses. Moreover these findings represent a novel mechanism through which antiestrogens function. The activation of NQO1 may contribute to the beneficial anticancer and antioxidant activity of antiestrogens in breast cancer and possibly other estrogen target tissues. It is possible that the basis for some of the anticancer action of antiestrogens is that the induction of NQO1 inhibits the genotoxic effects induced by the oxidative metabolism of estrogens.


Dislocation Shielding of a Nanocrack in Graphene: Atomistic Simulations and Continuum Modeling.
Combining atomistic simulations and continuum modeling, we studied dislocation shielding of a nanocrack in monolayer graphene under mode-I loading. Different crack-dislocation configurations were constructed and the shielding effects on the threshold stress intensity for crack propagation were examined. Excellent agreement between simulation results and linear-elastic fracture mechanics (LEFM) predictions was achieved. As the separation between the crack-tip and dislocation, that is, rR, varies (with respect to the crack size a), the shielding effect exhibits two different dependences on rR, scaling as 1/rR 1/2 for rR/a ≪ 1 (near-tip), whereas 1/rR for rR/a ≫ 1 (far-field), respectively. Particularly, the far-field 1/rR scaling was shown to be a direct manifestation of the stress field of dislocation in graphene. Our work presents a systematic study of nanoscale crackdislocation interactions in graphene, providing valuable information on defect engineering of graphene.


OLIgo mass profiling (OLIMP) of extracellular polysaccharides.
The direct contact of cells to the environment is mediated in many organisms by an extracellular matrix. One common aspect of extracellular matrices is that they contain complex sugar moieties in form of glycoproteins, proteoglycans, and/or polysaccharides. Examples include the extracellular matrix of humans and animal cells consisting mainly of fibrillar proteins and proteoglycans or the polysaccharide based cell walls of plants and fungi, and the proteoglycan/glycolipid based cell walls of bacteria. All these glycostructures play vital roles in cell-to-cell and cell-to-environment communication and signalling. An extraordinary complex example of an extracellular matrix is present in the walls of higher plant cells. Their wall is made almost entirely of sugars, up to 75% dry weight, and consists of the most abundant biopolymers present on this planet. Therefore, research is conducted how to utilize these materials best as a carbon-neutral renewable resource to replace petrochemicals derived from fossil fuel. The main challenge for fuel conversion remains the recalcitrance of walls to enzymatic or chemical degradation due to the unique glycostructures present in this unique biocomposite. Here, we present a method for the rapid and sensitive analysis of plant cell wall glycostructures. This method OLIgo Mass Profiling (OLIMP) is based the enzymatic release of oligosaccharides from wall materials facilitating specific glycosylhydrolases and subsequent analysis of the solubilized oligosaccharide mixtures using matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF/MS)(1) (Figure 1). OLIMP requires walls of only 5000 cells for a complete analysis, can be performed on the tissue itself(2), and is amenable to high-throughput analyses(3). While the absolute amount of the solubilized oligosaccharides cannot be determined by OLIMP the relative abundance of the various oligosaccharide ions can be delineated from the mass spectra giving insights about the substitution-pattern of the native polysaccharide present in the wall. OLIMP can be used to analyze a wide variety of wall polymers, limited only by the availability of specific enzymes(4). For example, for the analysis of polymers present in the plant cell wall enzymes are available to analyse the hemicelluloses xyloglucan using a xyloglucanase(5, 11, 12, 13), xylan using an endo-beta-(1-4)-xylanase (6,7), or for pectic polysaccharides using a combination of a polygalacturonase and a methylesterase (8). Furthermore, using the same principles of OLIMP glycosylhydrolase and even glycosyltransferase activities can be monitored and determined (9).


The DCDC2/intron 2 deletion and white matter disorganization: focus on developmental dyslexia.
The DCDC2 gene is involved in neuronal migration. Heterotopias have been found within the white matter of DCDC2-knockdown rats. A deletion in DCDC2/intron 2 (DCDC2d), which encompasses a regulatory region named 'regulatory element associated with dyslexia 1' (READ1), increases the risk for dyslexia. We hypothesized that DCDC2d can be associated to alterations of the white matter structure in general and in dyslexic brains. Based on a full-factorial analysis of covariance (ANCOVA) model, we investigated voxel-based diffusion tensor imaging (VB-DTI) data of four groups of subjects: dyslexia with/without DCDC2d, and normal readers with/without DCDC2d. We also tested DCDC2d effects upon correlation patterns between fractional anisotropy (FA) and reading scores. We found that FA was reduced in the left arcuate fasciculus and splenium of the corpus callosum in subjects with versus without DCDC2d, irrespective of dyslexia. Subjects with dyslexia and DCDC2d showed reduced FA, mainly in the left hemisphere and in the corpus callosum; their counterpart without DCDC2d showed similar FA alterations. Noteworthy, a conjunction analysis in impaired readers revealed common regions with lower FA mainly in the left hemisphere. When we compared subjects with dyslexia with versus without DCDC2d, we found lower FA in the inferior longitudinal fasciculus and genu of the corpus callosum, bilaterally. Normal readers with versus without DCDC2d had FA increases and decreases in both the right and left hemisphere. The major contribution of our study was to provide evidence relating genes, brain and behaviour. Overall, our findings support the hypothesis that DCDC2d is associated with altered FA. In normal readers, DCDC2-related anatomical patterns may mark some developmental cognitive vulnerability to learning disabilities. In subjects with dyslexia, DCDC2d accounted for both common - mainly located in the left hemisphere - and unique - a more severe and extended pattern - alterations of white matter fibre tracts.


Structure, backbone dynamics and interactions with RNA of the C-terminal RNA-binding domain of a mouse neural RNA-binding protein, Musashi1.
Musashi1 is an RNA-binding protein abundantly expressed in the developing mouse central nervous system. Its restricted expression in neural precursor cells suggests that it is involved in the regulation of asymmetric cell division. Musashi1 contains two ribonucleoprotein (RNP)-type RNA-binding domains (RBDs), RBD1 and RBD2. Our previous studies showed that RBD1 alone binds to RNA, while the binding of RBD2 is not detected under the same conditions. Joining of RBD2 to RBD1, however, increases the affinity to greater than that of RBD1 alone, indicating that RBD2 contributes to RNA-binding. We have determined the three-dimensional solution structure of the C-terminal RBD (RBD2) of Musashi1 by NMR. It folds into a compact alpha beta structure comprising a four-stranded antiparallel beta-sheet packed against two alpha-helices, which is characteristic of RNP-type RBDs. Special structural features of RBD2 include a beta-bulge in beta2 and a shallow twist of the beta-sheet. The smaller 1H-15N nuclear Overhauser enhancement values for the residues of loop 3 between beta2 and beta3 suggest that this loop is flexible in the time-scale of nano- to picosecond order. The smaller 15N T2 values for the residues around the border between alpha2 and the following loop (loop 5) suggest this region undergoes conformational exchange in the milli- to microsecond time-scale. Chemical shift perturbation analysis indicated that RBD2 binds to an RNA oligomer obtained by in vitro selection under the conditions for NMR measurements, and thus the nature of the weak RNA-binding of RBD2 was successfully characterized by NMR, which is otherwise difficult to assess. Mainly the residues of the surface composed of the four-stranded beta-sheet, loops and C-terminal region are involved in the interaction. The appearance of side-chain NH proton resonances of arginine residues of loop 3 and imino proton resonances of RNA bases upon complex formation suggests the formation of intermolecular hydrogen bonds. The structural arrangement of the rings of the conserved aromatic residues of beta2 and beta3 is suitable for stacking interaction with RNA bases, known to be one of the major protein-RNA interactions, but a survey of the perturbation data suggested that the stacking interaction is not ideally achieved in the complex, which may be related to the weaker RNA-binding of RBD2.


[Quantitative ultrasound for the diagnosis of osteoporosis].
Quantitative ultrasound (QUS) methods are promising tools for the assessment of the bone status in osteoporosis. The techniques are based on changes in speed and amplitude of a broadband ultrasound signal propagating through the bone. However, ultrasound propagation through the anisotropic bone is complex and cannot be described in a simple way. The devices are easy to use, inexpensive, portable, do not use ionizing radiation, and therefore have advantages compared to conventional densitometry. This review discusses the technical basics, current research, clinical applications, points of weakness, and future prospects of QUS. For better understanding ultrasound propagation through bone is visualized with a simulation software.


NMR metabolomic profiling reveals new roles of SUMOylation in DNA damage response.
Post-translational modifications by the Small Ubiquitin-like Modifier (SUMO) family of proteins have been established as critical events in the cellular response to a wide range of DNA damaging reagents and radiation; however, the detailed mechanism of SUMOylation in DNA damage response is not well understood. In this study, we used a nuclear magnetic resonance (NMR) spectroscopy-based metabolomics approach to examine the effect of an inhibitor of SUMO-mediated protein-protein interactions on MCF7 breast cancer cell response to radiation. Metabolomics is sensitive to changes in cellular functions and thus provides complementary information to other biological studies. The peptide inhibitor (SUMO interaction motif mimic, SIM) and a control peptide were stably expressed in MCF-7 cell line. Metabolite profiles of the cell lines before and after radiation were analyzed using solution NMR methods. Various statistical methods were used to isolate significant changes. Differences in the amounts of glutamine, aspartate, malate, alanine, glutamate and NADH between the SIM-expressing and control cells suggest a role for SUMOylation in regulating mitochondrial function. This is also further verified following the metabolism of (13)C-labeled glutamine. The inability of the cells expressing the SIM peptide to increase production of the antioxidants carnosine and glutathione after radiation damage suggests an important role of SUMOylation in regulating the levels of antioxidants that protect cells from free radicals and reactive oxygen species generated by radiation. This study reveals previously unknown roles of SUMOylation in DNA damage response.


Aggravation of brain injury after transient focal ischemia in p53-deficient mice.
The transcriptional factor p53 is a regulatory protein which contributes to the preservation of tissue integrity by promoting either DNA repair or apoptosis. To establish the pathophysiological role of this protein in ischemia, we produced 1 h transient middle cerebral artery (MCA) occlusion in normal and in p53-deficient mice and investigated the resulting tissue damage by multiparametric imaging. Possible genetic influences on the angioarchitecture of the MCA territory and blood flow were examined by intravascular latex infusion and laser-Doppler flowmetry. Wild-type (p53(+/+)), heterozygous (p53(+/-)) and homozygous (p53(-/-)) mice deficient for the p53 gene did not differ in respect to angioarchitecture or the effect of vascular occlusion on blood flow and general physiological parameters. Twenty-four hours after 1 h MCA occlusion, mice revealed a gene dose-dependent decline in the size of metabolic disturbances (ATP depletion and inhibition of protein synthesis) and histological injury (Cresyl Violet staining). DNA fragmentations detected by terminal deoxynucleotidyl transferase-mediated UTP nick end labeling (TUNEL) did not differ in the three groups and were only present in ATP-depleted tissue. Our findings suggest that after transient focal brain ischemia p53 prevents rather than aggravates brain injury, and that this effect is brought about by mechanisms that are unrelated to the pro-apoptotic properties of this gene.


Chlorambucil plus rituximab with or without maintenance rituximab as first-line treatment for elderly chronic lymphocytic leukemia patients.
In a phase II trial, we evaluated chlorambucil and rituximab (CLB-R) as first-line induction treatment with or without R as maintenance for elderly chronic lymphocytic leukemia (CLL) patients. Treatment consisted of eight 28-day cycles of CLB (8 mg/m(2) /day, days 1-7) and R (day 1 of cycle 3, 375 mg/m(2) ; cycles 4-8, 500 mg/m(2) ). Responders were randomized to 12 8-week doses of R (375 mg/m(2) ) or observation. As per intention-to-treat analysis, 82.4% (95% CI, 74.25-90.46%) of 85 patients achieved an overall response (OR), 16.5% a complete response (CR), 2.4% a CR with incomplete bone marrow recovery. The OR was similar across Binet stages (A 86.4%, B 81.6%, and C 78.6%) and age categories (60-64 years, 92.3%; 65-69, 85.2%; 70-74, 75.0%; ≥75, 81.0%). CLB-R was well tolerated. After a median follow-up of 34.2 months, the median progression-free survival (PFS) was 34.7 months (95% CI, 33.1-39.5). TP53 abnormalities, complex karyotype, and low CD20 gene expression predicted lack of response; SF3B1 mutation and BIRC3 disruption low CR rates. IGHV mutations significantly predicted PFS. R maintenance tended towards a better PFS than observation and was safe and most beneficial for patients in partial response and for unmutated IGHV cases. CLB-R represents a promising option for elderly CLL patients.


Age related susceptibility of newborn pigs to the cutaneous application of chlorpyrifos.
An aerosol preparation containing 2.5% chlorpyrifos was applied to the tail and umbilicus of newborn pigs. Mortality was 7/7 pigs treated 0-3 hr after birth, 3/5 pigs treated at 24-30 hr, and 0/3 pigs treated 30-36 hr after birth. Clinical signs consistent with organophosphate (OP) toxicosis were demonstrated by pigs that subsequently died or were euthanatized in extremis. Blood and brain cholinesterase (ChE) activities were depressed in affected pigs compared to controls. Only 1/3 pigs treated 30-36 hr after birth had a diagnostically significant depression in blood ChE. These results indicate that piglets one day or less of age are susceptible to OP toxicosis by cutaneous absorption of chlorpyrifos.


Are healthcare professionals delivering opportunistic behaviour change interventions? A multi-professional survey of engagement with public health policy.
"Making Every Contact Count" (MECC), a public health policy in the UK, compels healthcare professionals to deliver opportunistic health behaviour change interventions to patients during routine medical consultations. Professionals' awareness of, and engagement with, the policy is unclear. This study examined (1) awareness of the MECC policy, and (2) the prevalence of MECC-related practice in relation to (a) perceived patient benefit, (b) how often healthcare professionals deliver interventions during routine consultations, and (c) the time spent on this activity. Cross-sectional national survey was administered in 2017 of 1387 healthcare professionals working in the UK's National Health Service (NHS). Descriptive statistics were used to assess awareness and practice consistent with the MECC policy. Chi-square was used to gauge the potential representativeness of our sample compared to NHS employment data. 31.4% of healthcare professionals reported having heard of the policy; nevertheless, healthcare professionals perceived a need to provide patients with opportunistic behaviour change interventions in 55.9% (32,946/58,906) of consultations. However, healthcare professionals did not deliver interventions on 50.0% of occasions in which they perceived a need. Where behaviour change interventions were delivered to patients, this constituted 35.3% of the appointment time. Policy makers must address the gap between the proportion of patients that healthcare professionals perceive would benefit from opportunistic behaviour change interventions and those receiving them (an estimated 50.0%; 16,473 additional patients could have benefited). Future research should consider how healthcare professionals identify patients who might benefit from opportunistic behaviour change interventions and developing training for efficient delivery of interventions.


Discovery of genes expressed in response to Perkinsus marinus challenge in Eastern (Crassostrea virginica) and Pacific (C. gigas) oysters.
The protozoan pathogen Perkinsus marinus is the causative agent of Dermo, a lethal disease of the eastern oyster Crassostrea virginica, but not the Pacific oyster Crassostrea gigas. To understand the response of these two oysters to parasite exposure, a suppression subtractive hybridization (SSH) method was employed to characterize genes up-regulated during parasite challenge in both hemocytes and gills. The number of differentially expressed gene sequences obtained was 107 for C. virginica and 69 for C. gigas, including 46 and 37 sequences, respectively, that matched known genes in GenBank. Most of the sequences have not been characterized in other molluscs. Nineteen genes involved in immune system and cell communication, protein regulation and transcription, cell cycle, respiratory chain and cytoskeleton were selected for expression analysis by semi-quantitative PCR. Although varying in magnitude and timing post exposure, all genes screened showed over-expression in challenged oysters in both species, validating the SSH method. Results of this study highlighted some differences in gene expression between the two oysters in response to P. marinus infection, providing candidate genes and pathways for further analysis.


Biphasic effects of baclofen on phrenic motoneurons: possible involvement of two types of gamma-aminobutyric acid (GABA) receptors.
Intravenous injections of baclofen have two general dose-dependent effects on phrenic motoneurons in anesthetized cats. Small doses (0.5-1.5 mg/kg) increase the frequency of action potentials recorded from single motoneurons and from the phrenic nerve, whereas large doses (2-10 mg/kg) reduce or abolish action potentials. The increase in frequency produced by small doses is accompanied by membrane depolarization and, in most experiments, by increased input resistance. Large doses hyperpolarize phrenic motoneurons and produce greater increases in input resistance. Extracellular recording during microelectrophoretic application of baclofen reveals only one effect, depression of cell firing, at all effective current strengths. The low dose stimulatory effect of i.v. baclofen is attributed to disinhibition, whereas the depression by large doses is attributed to disfacilitation. During incomplete inhibition by baclofen, CO2 administration further depresses phrenic nerve activity. Bicuculline (100-600 micrograms/kg i.v.) and picrotoxin (900 micrograms/kg i.v.) restore firing depressed by baclofen, whereas strychnine (80-1280 micrograms/kg) does not. 3-Aminopropanesulfonic acid (5-75 mg/kg i.v.) an agonist at gamma-aminobutyric acid-A receptor sites, depresses phrenic nerve activity. It is suggested that the low dose stimulatory effects are related to actions at gamma-aminobutyric acid-B receptors, whereas the high dose depressant effects are related, at least in part, to activation of gamma-aminobutyric acid-A receptors.


The relevance of PTEN-AKT in relation to NOTCH1-directed treatment strategies in T-cell acute lymphoblastic leukemia.
The tumor suppressor phosphatase and tensin homolog (PTEN) negatively regulates phosphatidylinositol 3-kinase (PI3K)-AKT signaling and is often inactivated by mutations (including deletions) in a variety of cancer types, including T-cell acute lymphoblastic leukemia. Here we review mutation-associated mechanisms that inactivate PTEN together with other molecular mechanisms that activate AKT and contribute to T-cell leukemogenesis. In addition, we discuss how Pten mutations in mouse models affect the efficacy of gamma-secretase inhibitors to block NOTCH1 signaling through activation of AKT. Based on these models and on observations in primary diagnostic samples from patients with T-cell acute lymphoblastic leukemia, we speculate that PTEN-deficient cells employ an intrinsic homeostatic mechanism in which PI3K-AKT signaling is dampened over time. As a result of this reduced PI3K-AKT signaling, the level of AKT activation may be insufficient to compensate for NOTCH1 inhibition, resulting in responsiveness to gamma-secretase inhibitors. On the other hand, de novo acquired PTEN-inactivating events in NOTCH1-dependent leukemia could result in temporary, strong activation of PI3K-AKT signaling, increased glycolysis and glutaminolysis, and consequently gamma-secretase inhibitor resistance. Due to the central role of PTEN-AKT signaling and in the resistance to NOTCH1 inhibition, AKT inhibitors may be a promising addition to current treatment protocols for T-cell acute lymphoblastic leukemia.


Neuron and Brain Maturation 2.0.
The mammalian central nervous system (CNS) is built up during embryogenesis by neural stem cells located in the periventricular germinal layers which undergo multiple division cycles [...].


Human biological adaptability. The ecological approach in physical anthropology.
Adaptation is an aspect of virtually all questions of human biology. Besides their interest in evolution through adaptive selection of the primates, including man, physical anthropologists are concerned with biological adaptability as a human attribute. In this sense adaptation has been examined at three overlapping levels: (i) those represented by differences in the extent of inherent capacities in subpopulations long exposed to different conditions, such as differences in the inherited determinants of body form and skin pigment in peoples in different climatic zones; (ii) adaptations acquired during the growth period of the individual such as residual stunting and reduced caloric needs in individuals receiving low caloric diets throughout childhood; and (iii) reversible acclimatization to the immediate conditions such as the changes which make it easier to work at high altitudes after the first few days there. Greater resilience to change is achieved if adaptations are reversible in each generation or within a lifetime. This implies an evolutionary tendency to shift human adaptability from genetic selection to ontogenetic plasticity to reversible adaptability.


Fluorometric assays of phospholipase A2 activity with three different substrates in biological samples of patients with schizophrenia.
The rationale of this study was to understand the complexity of kinetics of fluorogenic phospholipid substrates as well as contradictory findings of clinical papers measuring phospholipase A2 (PLA2) activity using different methodologies. The aim was to recommend to clinicians and researchers what substrate in conjunction with what assay should be used. Two methods, (i) continuous fluorometric assay and (ii) high performance thin layer chromatography (HPTLC) on microplates combined with quantitative image scanning, were studied with three different substrates (bis-BODIPY FL C11-PC, NBDC6-HPC, PED6). The study demonstrates that NBD-PC is not a suitable substrate to measure PLA2 activity using a spectrofluorometer. On the other hand, NBD-PC gives the highest and most reproducible integrated light intensities (ILls) in HPTLC studies. Slow time-dependent increases in fluorescence intensities recorded with biological samples in fluorometers, but not caused by substrate splitting, had to be classified as "perturbation kinetics". PLA2 activities in blood samples of 26 unmedicated schizophrenia patients and 26 age-matched healthy controls were measured by the spectrofluorometric method and then compared with the activity data obtained with the HPTLC method. A significant group difference was found only with the HPTLC. In order to get more reliable results, we recommend that clinicians and researchers use NBD-phosphatidylcholines as PLA2 substrates in biological samples and start with an analytical separation of reaction products followed by image analysis of the fluorescent spots.


Auditory and somatosensory evoked potentials in coma following spontaneous cerebral hemorrhage: early prognosis and outcome.
The aim of this study was to check the prognostic power of auditory brain-stem responses (ABRs) and somatosensory evoked potentials (SEPs) in coma following spontaneous cerebral hemorrhage. Seventy patients comatose following subarachnoidal or hypertensive hemorrhage were submitted to ABR and SEP recordings during the acute phase of clinical course. Twenty-one patients survived (30%), two remained vegetative (2.9%) and 47 died (68.1%). The Glasgow Coma Score (GCS) was significantly related to the outcome (P < 0.001), but showed a low sensitivity, since about 50% of patients with GCS = 5-8 died or remained vegetative. ABRs and SEPs showed a much closer correlation with outcome (P < 0.001): their combined use allowed there to be a sensitivity of 96%, a specificity of 90% and a predictive power of 96%; the relative risk of poor outcome in patients with at least one abnormal modality was equal to 223 times the one for patients with normal evoked potentials. Moreover, in surviving patients a significant relationship appeared to exist between abnormalities of SEPs during the acute phase and the severity of disability. Our results confirm the prognostic effectiveness of short latency evoked potentials in cerebral hemorrhage: they are far superior to clinical data, being able to yield a marked decrease of falsely optimistic predictions.


Preventing sharps, splash, and needlestick injuries in dentistry: a comprehensive overview.
This article presents a comprehensive collection of precautions and suggestions for preventing sharps, splash, and needlestick injuries in dentistry. The authors looked at studies of sharps and splash injuries in dentistry to determine which of these injuries are most common. They then assembled a set of precautions to prevent these injuries based on published literature, tips learned from other dentists, and their own clinical observations. Dentists must remember and apply many precautions to prevent the broad spectrum of sharps and splash injuries that could occur during the delivery of dental care.


Long-term data from the Swiss pulmonary hypertension registry.
Registries are important for real-life epidemiology on different pulmonary hypertension (PH) groups. To provide long-term data of the Swiss PH registry of 1998-2012. PH patients have been classified into 5 groups and registered upon written informed consent at 5 university and 8 associated hospitals since 1998. New York Heart Association (NYHA) class, 6-min walk distance, hemodynamics and therapy were registered at baseline. Patients were regularly followed, and therapy and events (death, transplantation, endarterectomy or loss to follow-up) registered. The data were stratified according to the time of diagnosis into prevalent before 2000 and incident during 2000-2004, 2005-2008 and 2009-2012. From 996 (53% female) PH patients, 549 had pulmonary arterial hypertension (PAH), 36 PH due to left heart disease, 127 due to lung disease, 249 to chronic thromboembolic PH (CTEPH) and 35 to miscellaneous PH. Age and BMI significantly increased over time, whereas hemodynamic severity decreased. Overall, event-free survival was 84, 72, 64 and 58% for the years 1-4 and similar for time periods since 2000, but better during the more recent periods for PAH and CTEPH. Of all PAH cases, 89% had target medical therapy and 43% combination therapy. Of CTEPH patients, 14 and 2% underwent pulmonary endarterectomy or transplantation, respectively; 87% were treated with PAH target therapy. Since 2000, the incident Swiss PH patients registered were older, hemodynamically better and mostly treated with PAH target therapies. Survival has been better for PAH and CTEPH diagnosed since 2008 compared with earlier diagnosis or other classifications.


Extensive mutagenesis of a transcriptional activation domain identifies single hydrophobic and acidic amino acids important for activation in vivo.
C1 is a transcriptional activator of genes encoding biosynthetic enzymes of the maize anthocyanin pigment pathway. C1 has an amino terminus homologous to Myb DNA-binding domains and an acidic carboxyl terminus that is a transcriptional activation domain in maize and yeast cells. To identify amino acids critical for transcriptional activation, an extensive random mutagenesis of the C1 carboxyl terminus was done. The C1 activation domain is remarkably tolerant of amino acid substitutions, as changes at 34 residues had little or no effect on transcriptional activity. These changes include introduction of helix-incompatible amino acids throughout the C1 activation domain and alteration of most single acidic amino acids, suggesting that a previously postulated amphipathic alpha-helix is not required for activation. Substitutions at two positions revealed amino acids important for transcriptional activation. Replacement of leucine 253 with a proline or glutamine resulted in approximately 10% of wild-type transcriptional activation. Leucine 253 is in a region of C1 in which several hydrophobic residues align with residues important for transcriptional activation by the herpes simplex virus VP16 protein. However, changes at all other hydrophobic residues in C1 indicate that none are critical for C1 transcriptional activation. The other important amino acid in C1 is aspartate 262, as a change to valine resulted in only 24% of wild-type transcriptional activation. Comparison of our C1 results with those from VP16 reveal substantial differences in which amino acids are required for transcriptional activation in vivo by these two acidic activation domains.


Glutamate NMDA receptor dysregulation in Parkinson's disease with dyskinesias.
Levodopa-induced dyskinesias are a common complication of long-term therapy in Parkinson's disease. Although both pre- and post-synaptic mechanisms seem to be implicated in their development, the precise physiopathology of these disabling involuntary movements remains to be fully elucidated. Abnormalities in glutamate transmission (over expression and phosphorylation of N-methyl-D-aspartate receptors) have been associated with the development of levodopa-induced dyskinesias in animal models of Parkinsonism. The role of glutamate function in dyskinetic patients with Parkinson's disease, however, is unclear. We used (11)C-CNS 5161 [N-methyl-3(thyomethylphenyl)cyanamide] positron emission tomography, a marker of activated N-methyl-D-aspartate receptor ion channels, to compare in vivo glutamate function in parkinsonian patients with and without levodopa-induced dyskinesias. Each patient was assessed with positron emission tomography twice, after taking and withdrawal from levodopa. Striatal and cortical tracer uptake was calculated using a region of interest approach. In the 'OFF' state withdrawn from levodopa, dyskinetic and non-dyskinetic patients had similar levels of tracer uptake in basal ganglia and motor cortex. However, when positron emission tomography was performed in the 'ON' condition, dyskinetic patients had higher (11)C-CNS 5161 uptake in caudate, putamen and precentral gyrus compared to the patients without dyskinesias, suggesting that dyskinetic patients may have abnormal glutamatergic transmission in motor areas following levodopa administration. These findings are consistent with the results of animal model studies indicating that increased glutamatergic activity is implicated in the development and maintenance of levodopa-induced dyskinesias. They support the hypothesis that blockade of glutamate transmission may have a place in the management of disabling dyskinesias in Parkinson's disease.


Physician-Directed Diabetes Education without a Medication Change and Associated Patient Outcomes.
When patients with diabetes mellitus (DM) are first referred to a hospital from primary health care clinics, physicians have to decide whether to administer an oral hypoglycemic agent (OHA) immediately or postpone a medication change in favor of diabetes education regarding diet or exercise. The aim of this study was to determine the effect of diabetes education alone (without alterations in diabetes medication) on blood glucose levels. The study was conducted between January 2009 and December 2013 and included patients with DM. The glycosylated hemoglobin (HbA1c) levels were evaluated at the first visit and after 3 months. During the first medical examination, a designated doctor also conducted a diabetes education session that mainly covered dietary management. Patients were divided into those who received no diabetic medications (n=66) and those who received an OHA (n=124). Education resulted in a marked decrease in HbA1c levels in the OHA group among patients who had DM for <1 year (from 7.0%±1.3% to 6.6%±0.9%, P=0.0092) and for 1 to 5 years (from 7.5%±1.8% to 6.9%±1.1%, P=0.0091). Those with DM >10 years showed a slightly lower HbA1c target achievement rate of <6.5% (odds ratio, 0.089; P=0.0024). For patients who had DM for more than 5 years, higher doses or changes in medication were more effective than intensive active education. Therefore, individualized and customized education are needed for these patients. For patients with a shorter duration of DM, it may be more effective to provide initial intensive education for diabetes before prescribing medicines, such as OHAs.


[Follow-up of the patient with pacemakers: Interrogation and basic programming].
Permanent pacemakers are a frequently used therapeutic modality. Its use has had a great impact on the morbidity and mortality and quality of life of patients with heart rhythm disturbances, with an exponential increase observed in recent decades. The use of this strategy presents different phases, in which follow-up throughout the useful life of the device is a fundamental and determinant pillar of the efficacy and safety of this therapeutic modality. This review seeks to provide a clear and structured update of the fundamental aspects to consider in the follow-up of all patients with pacemakers. The follow-up of the patient with a pacemaker must follow a complete, systematic and periodic protocol, evaluating aspects and parameters related to the patient and the pacemaker, in order to ensure the proper and safe operation of the device adapted to the person.


In vivo imaging of C. elegans ASH neurons: cellular response and adaptation to chemical repellents.
ASH sensory neurons are required in Caenorhabditis elegans for a wide range of avoidance behaviors in response to chemical repellents, high osmotic solutions and nose touch. The ASH neurons are therefore hypothesized to be polymodal nociceptive neurons. To understand the nature of polymodal sensory response and adaptation at the cellular level, we expressed the calcium indicator protein cameleon in ASH and analyzed intracellular Ca(2+) responses following stimulation with chemical repellents, osmotic shock and nose touch. We found that a variety of noxious stimuli evoked strong responses in ASH including quinine, denatonium, detergents, heavy metals, both hyper- and hypo-osmotic shock and nose touch. We observed that repeated chemical stimulation led to a reversible reduction in the magnitude of the sensory response, indicating that adaptation occurs within the ASH sensory neuron. A key component of ASH adaptation is GPC-1, a G-protein gamma-subunit expressed specifically in chemosensory neurons. We hypothesize that G-protein gamma-subunit heterogeneity provides a mechanism for repellent-specific adaptation, which could facilitate discrimination of a variety of repellents by these polymodal sensory neurons.


Super Antiwetting Surfaces for Mitigating Drag-Out of Deep Eutectic Solvents.
Deep eutectic solvents (DESs) are, at room temperature, about dozens to hundreds of times more viscous than water, which brings pretty thick residues on solid surfaces, for example, causing drag-out and weight loss in the transfer process. Unfortunately, until now little work had been done for solving this knotty problem. In this study, the super antiwetting surface, i.e., super-DES-phobic surface (defined as DES contact angle > 150°) is proposed and fabricated successfully by a facile coating technique. Hierarchical silver dendrites on copper foam substrate provide effective dual-roughness surfaces showing stable superDESphobicity. The superDESphobic surface can repel the DESs and their derived solutions even under elevated temperature of about 120 °C and the impact attack of drops. It is also found that the superDESphobic surface can significantly delay the DESs freezing and reduce the adhesion strength of the frozen DESs. Interestingly, the superDESphobic surface can be applied as an effective tool for gauging the density of DES using an ∼2 μL droplet in virtue of its super antiwetting property. The super antiwetting surfaces show promise for potential applications in DES self-cleaning and antifreezing.


Intestinal helminth infection impacts the systemic distribution and function of the naive lymphocyte pool.
Homeostasis is a fundamental principle of biological systems. A paradigm of immune homeostasis is the remarkably constant number of naive T and B lymphocytes in the body that continuously circulate through the secondary lymphoid organs to maximize immune surveillance. Whether the dynamics and distribution of the systemic naive lymphocyte pool is affected following organ-specific infection is not known. Here we show that, following infection of mice with an enteric helminth, naive T and B lymphocytes accumulate in the T helper type 2-reactive mesenteric lymph node while they are concurrently depleted from non-draining peripheral lymph nodes. This systemic redistribution of naive lymphocytes is sustained into the chronic phase of the infection, requires lymphotoxin beta receptor-dependent signals and is associated with a reduced ability of parasitized animals to mount antigen-specific cellular and humoral immune responses to heterologous immunization or infection at peripheral sites. Our data suggest that the function of the homeostatic naive lymphocyte pool can be modulated by its systemic distribution following infection and may provide a novel concept underlying compromised immune responsiveness at peripheral sites in helminth-infected individuals.


Isolation of specialized transducing bacteriophages carrying deletions of the regulatory region of the Escherichia coli K-12 tryptophan operon.
A lysogen of a wild-type strain of Escherichia coli K-12 carrying a heat-inducible lambda-phi80 hybrid prophage was induced to yield transducing phages carrying all of the structural genes of the tryptophan operon. The presence or absence of elements of the trp regulatory region was determined by examining the effects of lambda genes N and cI on trp gene expression. The phages were further characterized by transduction studies and by examining anthranilate synthetase (EC 18.104.22.168) (TRYPE+D) synthesis in the presence of the lambda cI product. A number of phages deleted for the trp promoter were found. Recombination studies between trpOc bacteria and the transducing phages have yielded information that can be used to order the trp end points of some phages and to provide an estimate of the size of the trp promoter region.


The GBS PI-2a pilus is required for virulence in mice neonates.
Streptococcus agalactiae (Group B Streptococcus) is a leading cause of sepsis and meningitis in newborns. Most bacterial pathogens, including gram-positive bacteria, have long filamentous structures known as pili extending from their surface. Although pili are described as adhesive organelles, they have been also implicated in many other functions including thwarting the host immune responses. We previously characterized the pilus-encoding operon PI-2a (gbs1479-1474) in strain NEM316. This pilus is composed of three structural subunit proteins: PilA (Gbs1478), PilB (Gbs1477), and PilC (Gbs1474), and its assembly involves two class C sortases (SrtC3 and SrtC4). PilB, the bona fide pilin, is the major component whereas PilA, the pilus associated adhesin, and PilC the pilus anchor are both accessory proteins incorporated into the pilus backbone. In this study, the role of the major pilin subunit PilB was tested in systemic virulence using 6-weeks old and newborn mice. Notably, the non-piliated ΔpilB mutant was less virulent than its wild-type counterpart in the newborn mice model. Next, we investigated the possible role(s) of PilB in resistance to innate immune host defenses, i.e. resistance to macrophage killing and to antimicrobial peptides. Phagocytosis and survival of wild-type NEM316 and its isogenic ΔpilB mutant in immortalized RAW 264.7 murine macrophages were not significantly different whereas the isogenic ΔsodA mutant was more susceptible to killing. These results were confirmed using primary peritoneal macrophages. We also tested the activities of five cationic antimicrobial peptides (AMP-1D, LL-37, colistin, polymyxin B, and mCRAMP) and found no significant difference between WT and ΔpilB strains whereas the isogenic dltA mutant showed increased sensitivity. These results question the previously described role of PilB pilus in resistance to the host immune defenses. Interestingly, PilB was found to be important for virulence in the neonatal context.


Risk of Pneumonitis Associated with Programmed Cell Death 1 Inhibitors in Cancer Patients: A Meta-analysis.
Pneumonitis, a rare but potentially life-threatening adverse event in cancer patients receiving programmed death 1 (PD-1) or programmed death ligand 1 (PD-L1) inhibitors, has been reported in case reports, clinical trials, and retrospective studies. We performed a systematic review and meta-analysis to calculate the RR of pneumonitis associated with the use of PD-1/L1 inhibitors in randomized clinical trials (RCT). We searched MEDLINE, Embase, the Cochrane Central Register of Controlled Trials, trial registers, conference proceedings, review articles, and reference lists of trial publications for all relevant RCTs comparing PD-1/L1 inhibitors to control with available data on pneumonitis. The pooled incidence, RR, and 95% confidence intervals (CI) were calculated using fixed effects or random effects model according to the heterogeneity of included trials. Twelve RCTs were eligible for the meta-analysis, yielding a total of 5,775 patients included in trials evaluating a PD-1 inhibitor; no eligible trials evaluated a PD-L1 inhibitor. The pooled incidence of all-grade pneumonitis for patients treated with PD-1 inhibitors was 3.2% (95% CI, 2.3-4.5), and that of high-grade pneumonitis was 1.1% (95% CI, 0.7-1.7). The RR of all-grade and high-grade pneumonitis was 4.36 (95% CI, 2.58-7.38) and 2.86 (95% CI, 1.30-6.31), respectively. In a sensitivity analysis, PD-1 inhibitors were also associated with significantly increased risk of pneumonitis per person-month (for all grade, RR = 3.37; 95% CI, 1.97-5.76; for high grade, RR = 2.25; 95% CI, 1.03-4.94). PD-1 inhibitors were associated with a significant increase of all-grade and high-grade pneumonitis both per treatment episode and per person-month. Mol Cancer Ther; 16(8); 1588-95. ©2017 AACR.


The effect of amlodipine on respiratory and pulmonary vascular responses to hypoxia in mountaineers.
Calcium antagonists are known to reduce the incidence of high-altitude pulmonary oedema, but the mechanism is unclear. The aim of this study was to examine the effects of the calcium antagonist, amlodipine, on cardiac and respiratory responses in normoxia and hypoxia. Fourteen normal subjects aged 31+/-4 yrs who had climbed to altitudes of 5,000-7,500 m without problems were randomly assigned to a double-blind crossover trial of amlodipine versus placebo, using sea-level inspiratory hypoxia to simulate altitude. Doppler echocardiographic estimates of resting pulmonary haemodynamics and cycle ergometer test results of cardiorespiratory responses to exercise were recorded in normoxia and hypoxia. It was found that, although hypoxic pulmonary vasoconstriction (HPV) was not significantly reduced by amlodipine, the effect of the drug on HPV was inversely related to the serum level of amlodipine. Amlodipine did not alter left ventricular function measured echocardiographically. During exercise, amlodipine increased breathlessness, measured using standard scales, in both normoxia and hypoxia but had no effect on ventilatory variables. It was concluded that amlodipine has the potential to block hypoxic pulmonary vasoconstriction as evidenced by a drug concentration-related decrease in resting tricuspid regurgitation jet velocity without any change in resting myocardial contractility. However, with amlodipine, the subjects felt more breathless during exercise. The reasons for this increase in breathlessness are not clear.


[Postoperative care following hip fracture in a hospital or a psychogeriatric nursing home? A comparative study of short or long-stay demented hospitalized elderly].
In this article the question under discussion is, whether a short stay in hospital, for an inmate of a psychogeriatric nursing home with a hip-fracture, shows better results for mortality, morbidity and mobility than a long stay. Two matched groups, of 27 inmates each, have been compared retrospectively. The first remained in hospital for a week or more (long stay), the second for a period of less than a week (short stay). There was no significant difference in mortality risk between both groups. There were less urinary infections in the short-stay group and one month after the operation mobility was better. Decubitus, wound infection and bronchopneumonia appeared equally frequent. The results justify to continue the policy in this nursing home. More research in other nursing homes is pleaded.


Area and shape changes of the carpal tunnel in response to tunnel pressure.
Carpal tunnel mechanics is relevant to our understanding of median nerve compression in the tunnel. The compliant characteristics of the tunnel strongly influence its mechanical environment. We investigated the distensibility of the carpal tunnel in response to tunnel pressure. A custom balloon device was designed to apply controlled pressure. Tunnel cross sections were obtained using magnetic resonance imaging to derive the relationship between carpal tunnel pressure and morphological parameters at the hook of hamate. The results showed that the cross-sectional area (CSA) at the level of the hook of hamate increased, on average, by 9.2% and 14.8% at 100 and 200 mmHg, respectively. The increased CSA was attained by a shape change of the cross section, displaying increased circularity. The increase in CSA was mainly attributable to the increase of area in the carpal arch region formed by the transverse carpal ligament. The narrowing of the carpal arch width was associated with an increase in the carpal arch. We concluded that the carpal tunnel is compliant to accommodate physiological variations of the carpal tunnel pressure, and that the increase in tunnel CSA is achieved by increasing the circularity of the cross section.


Production and characterization of a monoclonal anti-anti-idiotype antibody against fumonisin B(1).
A monoclonal anti-anti-idiotype antibody (mAb3) against fumonisin B(1) (FmB1) was produced from the hybridoma cell line 7C7F4, which was generated by the fusion of P3/NS-1/1-AG4-1 myeloma cells with spleen cells isolated from a Balb/c mouse that had been immunized with the Fab fragments of affinity-purified anti-idiotype antibodies. The mAb3 belongs to the immunoglobulin M, kappa light chain. A direct competitive enzyme-linked immunosorbent assay (dc-ELISA) and an indirect competitive ELISA (idc-ELISA) were established for antibody characterization and toxin analysis. In an idc-ELISA using FmB1-ovalbumin (OVA) as the coating antigen, the concentrations causing 50% inhibition of binding (IC(50)) of mAb3 to the solid-phase FmB1-OVA by free FmB1, FmB2, and FmB3 were found to be 75, 95, and 450 ng/mL, respectively. In the dc-ELISA, the concentration causing IC(50) of FmB1-horseradish peroxidase to the solid-phase mAb3 by free FmB1 was found to be 233 ng/mL. Analysis of 12 samples naturally contaminated with fumonisins with mAb3-based idc-ELISA and polyclonal-based dc-ELISA showed a good correlation between these two methods with a correlation coefficient of 0.76 at p < 0.02. The linear regression slope was found to be y[polyclonal ELISA] = 0.87x[mAb3 ELISA] - 52 ppb.


[Complaint to the disciplinary board about a resident].
We describe the course of two complaints that were filed by patients to the Dutch Medical Disciplinary Board against two internal medicine residents. In the procedure following the complaints the supervisor and the teacher were actively involved, which resulted in one complaint being dropped. We describe the importance of adequate moral support in such cases, as the complaint may lead to loss of work satisfaction or self-esteem, especially for those in training. We make some recommendations on how the resident and the supervisor/head of the department should engage in complaints filed to the Medical Disciplinary Board. In addition, we suggest that routine 'error-meetings' may help to provide an open atmosphere where disclosure of errors and the various procedures at the hospital or disciplinary boards are promoted.


Periodic limb movement in a community population detected by a new actigraphy technique.
Periodic limb movements (PLMs) have been studied in both community and sleep clinic populations using polysomnography. An alternative detection method is actigraphy. Our aims were to determine the frequency of PLMs, measured by actigraphy in a community sample, and to assess the relationships of PLMs with age, gender, and reported sleep-related symptoms. Volunteers had bilateral foot actigraphy (Cambridge Neurotechnology) at home and completed sleep questionnaires. Actigraphy was scored for PLMs per hour in bed (PLMI) and statistical analysis performed to assess possible associations. PLMI (mean of two nights) ranged from 0 to 60.3 and 37% of the sample had a PLMI> or =5. Men had significantly higher PLMIs than females (P=0.003) but PLMI was not correlated with age. There was a modest but significant correlation between subjectively reported restless leg severity and PLMI (r=0.238; P=0.003), but none with reported sleepiness. This actigraphy technique is a practical and reliable tool for community studies. A large proportion of this community sample, particularly men, had PLMs. PLMI was not correlated with age or Epworth Sleepiness Score.


Sex steroid hormones and breast cancer: is there a link with oral contraceptives and hormone replacement therapy?
To determine whether use of sex steroid hormones for contraception and hormone replacement therapy alters the risk of breast cancer, and whether the risk varies with their composition, duration of use, the period of a woman's life when the hormones are used, and after successful treatment for breast cancer. The results of important epidemiological reports, readily available from the English literature and published since 1981, were evaluated, using reports of basic scientific work as a background to the problem. An attempt was made to obtain most of the relevant reports. Twenty case-control and seven cohort studies were available on the oral contraceptive pill (OCP) and eleven case-control and five cohort studies on hormone replacement therapy (HRT). The relative risk estimates for breast cancer (and their 95% confidence intervals) determined by each report were tabulated according to the specific conditions of analysis, for example users under age 25, duration of use. Results by meta-analysis from previous studies were also used to determine risk. A significant positive association was present when the risk estimate exceeded 1.0 and the 95% confidence interval did not cross 1.0. Among OCP users, the vast majority of reports showed no significant risk of breast cancer--overall, longest duration of use, and use before first full-term pregnancy. However, a positive association between breast cancer and users under age 25 was found in three of eight reports. Similarly, the majority of reports showed no significant risk of breast cancer among HRT users, overall as well as in relation to duration of use and interval since first use. There was no increased risk with additional progestogen; it may be protective. An improved prognosis was found in users who developed breast cancer. On the limited data, use of hormones for postmenopausal symptoms did not appear to be harmful to women who had been successfully treated for breast cancer. The review revealed good evidence that use of sex steroid hormones had no significant effect on the risk of breast cancer, whether given for contraception or hormone replacement. There was some concern about increased risk with prolonged use of the OCP, especially in younger women. At present, use of these hormones is a matter of informed choice, with individual considerations of the risk-benefit ratio.


Effect of neuronal excitotoxicity on Munc18-1 distribution in nuclei of rat hippocampal neuron and primary cultured neuron.
Munc18-1 has an important role in neurotransmitter release, and controls every step in the exocytotic pathway in the central nervous system. In the present study, whether epileptic seizure causes a change of Munc18 localization in neuronal nuclei was analyzed. Epilepsy models were established by injection of kainic acid (KA) solution into hippocampus of Sprague-Dawley (SD) rats or intraperitoneal injection of KA in Kunming mice. The hippocampal neurons were prepared from embryonic day 18 SD rats, and cultured in neurobasal medium, followed by treatment with glutamate for 3 h. Neuronal and glial nuclei of hippocampus were separated by sucrose density gradient centrifugation. The nucleus-enriched fractions were stained with 0.1% Cresyl Violet for morphological assay. Immunochemistry and immunoelectron microscopy with anti-Munc18-1 antibody were used to determine the nuclear localization of Munc18-1. Immunoblotting was used to detect the protein level of Munc18-1. The localization of Munc18-1 in nucleus of rat hippocampal neuron was confirmed by immunochemistry, immunoelectron microscopy, and immunoblotting detection of neuronal nucleus fraction. In animals receiving intrahippocampal or intraperitoneal injection of KA, immunostaining revealed that the expression of Munc18-1 decreased in pyramidal cell layer of CA regions, as well as in hilus and granular cell layer of dentate gyrus in hippocampus. Moreover, immunoblotting analysis showed that the expression level of Munc18-1 in nucleus fraction of hippocampus significantly decreased in KA-treated animals. The relationship between the change of Munc18-1 expression in neuronal nuclei and neuronal over-activation was also tested in primary cultured neurons. After treatment with 50 μmol/L glutamate acid for 3 h, Munc18-1 level was decreased in nucleus fraction and increased in cytoplasmic fraction of primary cultured neurons. These results suggest that excitatory stimulation can induce the distribution change of Munc18-1 in neuron, which may subsequently modulate neuronal functions in brain.


[Biological value of soy protein concentrate].
The chemical score techinique was employed in animal experiments to study the biological value of the protein soybean concentrate. Net utilization of protein, the protein efficacy ratio were determined as were nitrogen balance and its assimilability. The animals' general status and body weight were observed over time. It was discovered that the protein soybean concentrate appeared inferior to casein used as control. The relative biological value of the product under study was found to be high enough, amounting to 82.66% with regard to casein.


From fecal microbiota transplantation toward next-generation beneficial microbes: The case of Anaerobutyricum soehngenii.
The commensal gut microbiota is important for human health and well-being whereas deviations of the gut microbiota have been associated with a multitude of diseases. Restoration of a balanced and diverse microbiota by fecal microbiota transplantation (FMT) has emerged as a potential treatment strategy and promising tool to study causality of the microbiota in disease pathogenesis. However, FMT comes with logistical challenges and potential safety risks, such as the transfer of pathogenic microorganisms, undesired phenotypes or an increased risk of developing disease later in life. Therefore, a more controlled, personalized mixture of cultured beneficial microbes might prove a better alternative. Most of these beneficial microbes will be endogenous commensals to the host without a long history of safe and beneficial use and are therefore commonly referred to as next-generation probiotics (NGP) or live biotherapeutic products (LBP). Following a previous FMT study within our group, the commensal butyrate producer Anaerobutyricum spp. (previously named Eubacterium hallii) was found to be associated with improved insulin-sensitivity in subjects with the metabolic syndrome. After the preclinical testing with Anaerobutyricum soehngenii in mice models was completed, the strain was produced under controlled conditions and several clinical studies evaluating its safety and efficacy in humans were performed. Here, we describe and reflect on the development of A. soehngenii for clinical use, providing practical guidance for the development and testing of NGPs and reflecting on the current regulatory framework.


Effect of dietary linoleate content on the metabolic response of rats to Escherichia coli endotoxin.
Dietary fat influences many aspects of immune function. Escherichia coli endotoxin is a potent stimulator of interleukin 1 production from macrophages. The present study examines the effect of feeding with fat diets rich (corn oil) and poor (coconut oil) in linoleate at high and low concentrations on responses to endotoxin. Spleen phosphatidylcholine linoleate contents were higher in the corn oil than in the coconut oil group and arachidonate concentrations were highest in the group fed a high concentration of corn oil. Coconut oil completely abolished the responses to endotoxin. The inhibitory effects of coconut oil could largely be due to reduced prostaglandin and leukotriene synthesis.


SPOCK1, as a potential prognostic and therapeutic biomarker for lung adenocarcinoma, is associated with epithelial-mesenchymal transition and immune evasion.
The occurrence of epithelial-mesenchymal transition (EMT) and immune evasion is considered to contribute to poor prognosis in lung adenocarcinoma (LUAD). Therefore, this study aims to explore the key oncogenes that promote EMT and immune evasion and reveal the expression patterns, prognostic value, and potential biological functions. Firstly, we identified gene modules associated with EMT and Tumor Immune Dysfunction and Exclusion (TIDE) through weighted gene co-expression network analysis (WGCNA). Next, we utilized differential analysis and machine learning to identify the key genes and validate them. Moreover, we analyzed the correlation between key genes and tumor microenvironment remodeling, drug sensitivity, as well as mutation frequency. Furthermore, we explored and validated their malignant biological characteristics through in vitro experiments and clinical samples. Finally, potential drugs for LUAD were screened based on CMap and validated through experiments. Firstly, WGCNA analysis revealed that red and green modules were highly correlated with EMT and TIDE. Among them, upregulated expression of SPOCK1 was observed in lung adenocarcinoma tissues and was associated with poor prognosis. Additionally, patients in the high SPOCK1 group showed more activation of malignant oncogenic pathways, higher infiltration of immunosuppressive components, and a higher frequency of mutations. The knockdown of SPOCK1 suppressed invasion and metastasis capabilities of lung adenocarcinoma cells, and the high expression of SPOCK1 was associated with low infiltration of CD8+ T cells. Therapeutic aspects, SPOCK1 can be a candidate indicator for drug sensitivity and CMap showed that VER-155008 was the drug candidate with the largest perturbation effect on the SPOCK1 expression profile. In vitro and in vivo experiments validated the cancer-inhibitory effect of VER-155008 in LUAD. This study revealed through comprehensive bioinformatics analysis and experimental analysis that SPOCK1 can promote EMT and immune escape in LUAD, and it may serve as a promising candidate prognostic biomarker and therapeutic target for LUAD.


Is adaptation to climate change really constrained in niche specialists?
Species with restricted distributions make up the vast majority of biodiversity. Recent evidence suggests that Drosophila species with restricted tropical distributions lack genetic variation in the key trait of desiccation resistance. It has therefore been predicted that tropically restricted species will be limited in their evolutionary response to future climatic changes and will face higher risks of extinction. However, these assessments have been made using extreme levels of desiccation stress (less than 10% relative humidity (RH)) that extend well beyond the changes projected for the wet tropics under climate change scenarios over the next 30 years. Here, we show that significant evolutionary responses to less extreme (35% RH) but more ecologically realistic levels of climatic change and desiccation stress are in fact possible in two species of rainforest restricted Drosophila. Evolution may indeed be an important means by which sensitive rainforest-restricted species are able to mitigate the effects of climate change.