Sedative hypnotic use among veterans with a newly reported mental health disorder.
This study compared sedative hypnotic use by type of mental health diagnosis and determined factors associated with use among older veterans (65+ years) with a newly reported mental health disorder. This study used data from veterans who received primary care services at VA Pittsburgh Healthcare System (VAPHS) from January 1, 2007 to December 31, 2011 (n = 879). Sedative hypnotics were commonly used in older veterans within 12-months following a newly reported mental health disorder (19.9%), particularly amongst those with insomnia (41.7%). The number of newly reported mental health disorders was a significant factor associated with sedative hypnotic use, with the odds of use increasing by more than 200% in older adults with two newly reported disorders compared to those with one newly reported mental health disorder. Continued efforts are needed to improve provider and patient awareness of the risks associated with sedative hypnotic use in older adults, as well as to increase access to and receipt of non-pharmacological mental health treatments for this vulnerable population.


Molecular cloning and characterization of gilthead sea bream (Sparus aurata) growth hormone receptor (GHR). Assessment of alternative splicing.
The full-length growth hormone receptor (GHR) of gilthead sea bream (Sparus aurata) was cloned and sequenced by RT-PCR and rapid amplification of 5'and 3'ends. The open reading frame codes for a mature 609 amino acid protein with a hydrophobic transmembrane region and all the characteristic motifs of GHRs. Sequence analysis revealed a 96 and 76% of amino acid identity with black sea bream (Acanthopagrus schlegeli) and turbot (Scophthalmus maximus) GHRs, respectively, but this amino acid identity decreases up to 52% for goldfish (Carassius auratus) GHR. By means of real-time PCR assays, concurrent changes in the hepatic expression of GHRs and insulin-like growth factor-I (IGF-I) was evidenced. Moreover, their regulation occurred in conjunction with the summer spurt of growth rates and circulating levels of GH and IGF-I. Search of alternative splicing was carried out exhaustively for gilthead sea bream GHR, but Northern blot and 3' RACE failed to demonstrate the occurrence of short alternative messengers. Besides, RT-PCR screening did not reveal deletions or insertions that could lead to alternative reading frames. In agreement with this, cross-linking assays only evidenced two protein bands that match well with the size of glycosylated and non-glycosylated forms of the full-length GHR. If so, it appears that alternative splicing at the 3'end does not occur in gilthead sea bream, although different messengers for truncated or longer GHR variants already exist in turbot and black sea bream, respectively. The physiological relevance of this finding remains unclear, but perhaps it points out large inter-species differences in the heterogeneity of the GHR population.


Structure of the orthorhombic form of Mn(2)Al(7), Fe(2)Al(7), and (Mn(0.7)Fe(0.3))(2)Al(7) that by twinning produces grains with decagonal point-group symmetry.
Analysis of electron diffraction photographs of grains of Mn(2)Al(7), Fe(2)Al(7), and (Mn(0.7)Fe(0.3))(2)Al(7) leads to the conclusion that they are 5-fold twins of a 1664-atom orthorhombic crystal with a = 32.86 A, b = 31.23 A, and c = 24.80 A and with 16 icosahedral clusters of 104 atoms in positions shifted by small amounts from those of the cubic beta-tungsten structure.


Prognostic value of proliferation index and expression of the RNA component of human telomerase (hTR) in papillary meningiomas.
Papillary meningioma is a rare subtype of meningioma that often behaves aggressively. In order to characterize factors that may influence this behavior, we chose to compare MIB-1 labeling index (LI) and telomerase RNA localization (hTR) in papillary meningiomas, meningiomas, and atypical meningiomas. LI is now often used to supplement histologic grade in the evaluation of these lesions. More recent studies indicate that increased expression of hTR is detected in many neoplastic cells, and may play an essential role in cell immortalization. The study group consisted of five papillary meningiomas (and a recurrence in one case), 11 conventional meningiomas, and eight atypical meningiomas. Conventional meningiomas showed either negative or 1 + hTR. Atypical meningiomas showed 1 + hTR. Papillary meningiomas showed the highest hTR (five of six, including recurrence, 2-3+ and one 1+). Generally, the LI was very low for conventional meningiomas (< 2%). The LI of atypical meningiomas ranged from 3-19%, mean 12%, and from 5.5-17.5%, mean 11.75% for papillary meningiomas. LI differentiated between meningiomas, and papillary or atypical meningiomas. hTR further delineated papillary (moderate to high) from atypical meningiomas (low). The combined variable of LI and hTR expression could be a useful independent prognostic indicator in patients with papillary meningioma.


Acanthosis nigricans as an indicator of insulin resistance in Chilean adult population.
Insulin resistance (IR) is associated with a higher risk of multiple diseases and its early detection would allow to minimize the associated risk; the presence of acanthosis nigricans (AN) it's associated to the presence of IR. To evaluate the sensibility and specificity of AN to diagnose IR in a group of Chilean patients. We designed a cross-sectional study and it was included subjects that were attended at the Center for the Attention of Metabolic Diseases at the Faculty of Medicine, University of Chile. Sixty subjects (18-60 years age) were included. It was determined BMI and diagnosed AN and skin phototype; blood samples were taken and calculated the HOMA-IR. The normality of the variables where analyzed by Kolmogorov-Smirnov test. There were used χ² and the diagnostic concordance between AN and IR was determined using the Kappa index and Pearson's correlation. Sensibility, specificity, positive and negative predictive value were calculated and accepted p<0.05. The IR diagnose was 67% and AN was 43%. The major proportion of subjects diagnosed as positive for IR were also positive for AN (84.6%). The sensibility of AN to find IR was an 84% and specificity was 100%. Positive and negative predictive values were 100% and 89% respectively. It was observed a positive association between BMI and HOMA-IR (r=0.674; r²=0.454; p<0.001). To detect acanthosis nigricans in Chilean population may be effective for the early diagnose of insulin resistance and, therefore, reduce the associated cost of the late treatment of glucose metabolic disturbances.


Mouse model of OPRM1 (A118G) polymorphism has sex-specific effects on drug-mediated behavior.
A single nucleotide polymorphism (SNP) in the human mu-opioid receptor gene (OPRM1 A118G) has been widely studied for its association in a variety of drug addiction and pain sensitivity phenotypes; however, the extent of these adaptations and the mechanisms underlying these associations remain elusive. To clarify the functional mechanisms linking the OPRM1 A118G SNP to addiction and analgesia phenotypes, we derived a mouse model possessing the equivalent nucleotide/amino acid substitution in the Oprm1 gene. Mice harboring this SNP (A112G) demonstrated several phenotypic similarities to humans carrying the A118G SNP, including reduced mRNA expression and morphine-mediated antinociception. We found additional phenotypes associated with this SNP including significant reductions of receptor protein levels, morphine-mediated hyperactivity, and the development of locomotor sensitization in mice harboring the G112 allele. In addition, we found sex-specific reductions in the rewarding properties of morphine and the aversive components of naloxone-precipitated morphine withdrawal. Further cross-species analysis will allow us to investigate mechanisms and adaptations present in humans carrying this SNP.


Effects of mutations in de novo designed synthetic amphiphilic β-sheet peptides on self-assembly of fibrils.
The self-assembly of two similar amphiphilic peptides into fibril structures is described. Molecular dynamic simulations show that both can organize similarly in a monolayer, but in the fibril bilayer, one prefers a single organization while the other forms two conformational variants. This assembly difference correlates well with our experimental results.


Minimally invasive approach compared to resternotomy for mitral valve surgery in patients with prior cardiac surgery: retrospective multicentre study based on the Netherlands Heart Registration.
Mitral valve (MV) surgery after prior cardiac surgery is conventionally performed through resternotomy and associated with increased morbidity and mortality. Alternatively, MV can be approached minimally invasively [minimally invasive mitral valve surgery (MIMVS)], but longer-term follow-up of this approach for MV surgery after prior cardiac surgery is lacking. Therefore, the aim of the current study is to evaluate short- and mid-term outcomes of MIMVS versus MV surgery through resternotomy in patients with prior sternotomy, using a nationwide registry. Patients undergoing isolated MV surgery after prior cardiac surgery between 2013 and 2018 were included. Primary outcomes were short-term morbidity and mortality and mid-term survival. Cox proportional hazard analysis was used to investigate the association between surgical approach and mortality. Propensity score matching was used to correct for potential confounders. In total, 290 patients underwent MV surgery after prior cardiac surgery, of whom 205 patients were operated through resternotomy and 85 patients through MIMVS. No significant differences in 30-day mortality (3.4% vs 2%, P = 0.99) were observed between both groups. Five-year survival was 86.3% in the resternotomy group, compared to 89.4% in the MIMVS group (log-rank P = 0.45). In the multivariable analysis, surgical approach showed no relation with mid-term mortality [hazard ratio 0.73 (0.34-1.60); P = 0.44]. A lower incidence of prolonged intubation and new-onset arrhythmia was observed in MIMVS. MV surgery after prior cardiac surgery has excellent short- and mid-term results in the Netherlands, and MIMVS and resternotomy appear to be equally efficacious. MIMVS is associated with a lower incidence of new-onset arrhythmia and prolonged intubation.


Fusion events lead to truncation of FOS in epithelioid hemangioma of bone.
Epithelioid hemangioma of bone is a locally aggressive vascular neoplasm. It can be challenging to diagnose because of the wide histological spectrum, which can make it difficult to differentiate from other vascular neoplasms such as epithelioid hemangioendothelioma or epithelioid angiosarcoma. COBRA-FISH karyotyping identified a balanced t(3;14) translocation. Transcriptome sequencing of the index case and two other epithelioid hemangiomas revealed a recurrent translocation breakpoint involving the FOS gene, which was fused to different partners in all three cases. The break was observed in exon 4 of the FOS gene and the fusion event led to the introduction of a stop codon. In all instances, the truncation of the FOS gene would result in the loss of the transactivation domain (TAD). Using FISH probes we found a break in the FOS gene in two additional cases, in none of these cases a recurrent fusion partner could be identified. In total, FOS was split in 5/7 evaluable samples. We did not observe point mutations leading to early stop codons in any of the 10 cases where RNA was available. Detection of FOS rearrangement may be a useful diagnostic tool to assist in the often difficult differential diagnosis of vascular tumors of bone. Our data suggest that the translocation causes truncation of the FOS protein, with loss of the TAD, which is thereby a novel mechanism involved in tumorigenesis.


Surface Acoustic Waves to Control Droplet Impact onto Superhydrophobic and Slippery Liquid-Infused Porous Surfaces.
Superhydrophobic coatings and slippery liquid-infused porous surfaces (SLIPS) have shown their potentials in self-cleaning, anti-icing, anti-erosion, and antibiofouling applications. Various studies have been done on controlling the droplet impact on such surfaces using passive methods such as modifying the lubricant layer thickness in SLIPS. Despite their effectiveness, passive methods lack on-demand control over the impact dynamics of droplets. This paper introduces a new method to actively control the droplet impact onto superhydrophobic and SLIPS surfaces using surface acoustic waves (SAWs). In this study, we designed and fabricated SLIPS on ZnO/aluminum thin-film SAW devices and investigated different scenarios of droplet impact on the surfaces compared to those on similar superhydrophobic-coated surfaces. Our results showed that SAWs have insignificant influences on the impact dynamics of a porous and superhydrophobic surface without an infused oil layer. However, after infusion with oil, SAW energy could be effectively transferred to the droplet, thus modifying its impact dynamics onto the superhydrophobic surface. Results showed that by applying SAWs, the spreading and retraction behaviors of the droplets are altered on the SLIPS surface, leading to a change in a droplet impact regime from deposition to complete rebound with altered rebounding angles. Moreover, the contact time was reduced up to 30% when applying SAWs on surfaces with an optimum oil lubricant thickness of ∼8 μm. Our work offers an effective way of applying SAW technology along with SLIPS to effectively reduce the contact time and alter the droplet rebound angles.


The division of linguistic labour for offloading conceptual understanding.
The division of linguistic labour (DLL), initially theorized by philosophers, has gained the attention of cognitive scientists in the last decade. Contrary to some controversial philosophical accounts of DLL, we propose that it is an extended mind strategy of offloading conceptual understanding onto other people. In this article, we empirically explore this proposal by providing an exploratory experimental paradigm to search for the mechanisms underwriting DLL and how they may work in practice. We developed a between-subjects experiment in which participants had to categorize two pairs of highly confusable dog breeds after receiving categorization training on just one pair of breeds. In the treatment group, participants were grouped in dyads and were allowed to interact with each other by means of the labels of these four dog breeds. In their queries to trained 'experts', novices frequently used labels to refer to breeds that they could not identify themselves. Experts were highly responsive to their paired novices' queries, and the rates of querying for the two members within a dyad were positively correlated. Independent categorization failure and offloading categorization success lead to subsequent increases in querying by novices, indicating adaptive use of offloading. Self-reports of breed knowledge were higher for experts within a dyad compared to isolated experts. This article is part of the theme issue 'Concepts in interaction: social engagement and inner experiences'.


Expression and amplification of the HER-2/neu (c-erbB-2) protooncogene in epithelial ovarian tumors and cell lines.
Amplification of the c-erbB-2 protooncogene has been associated with a poor prognosis in human breast and ovarian cancers. Our study was undertaken to examine whether amplification, rearrangement, or overexpression of c-erbB-2 and other protooncogenes was frequently observed in epithelial ovarian cancers. c-erbB-2 was expressed in 87% of 22 ovarian cancers analyzed, but expression was significantly increased in only one of the 22 tumor specimens. In this case elevated c-erbB-2 expression was associated with dramatic amplification of the gene. In another tumor a 3.8 kb EcoRI fragment was found, in addition to the usual 4.4 and 6.0 kb fragments; this is consistent with a possible gene rearrangement or a restriction fragment length polymorphism. To place these results in perspective, expression of several other protooncogenes has been examined in ovarian carcinomas. The c-fos, c-myc, n-myc, c-fms, and c-Ha-ras protooncogenes were expressed in different fractions of tumors, but expression of l-myc, c-erbB, c-myb, c-sis, and c-mos was not detectable. Aside from c-erbB-2, neither amplification nor rearrangement was observed among the other protooncogenes studied. Expression of c-erbB-2, c-fms, c-myc, n-myc, c-fos, and c-Ha-ras deserves further evaluation as a prognostic factor in ovarian cancer.


The mental representation of hand movements after parietal cortex damage.
Recent neuroimagery findings showed that the patterns of cerebral activation during the mental rehearsal of a motor act are similar to those produced by its actual execution. This concurs with the notion that part of the distributed neural activity taking place during movement involves internal simulations, but it is not yet clear what specific contribution the different brain areas involved bring to this process. Here, patients with lesions restricted to the parietal cortex were found to be impaired selectively at predicting, through mental imagery, the time necessary to perform differentiated finger movements and visually guided pointing gestures, in comparison to normal individuals and to a patient with damage to the primary motor area. These results suggest that the parietal cortex is important for the ability to generate mental movement representations.


Feeding Angptl4-/- mice trans fat promotes foam cell formation in mesenteric lymph nodes without leading to ascites.
Angiopoietin-like 4 (ANGPTL4) regulates plasma triglyceride levels by inhibiting LPL. Inactivation of ANGPTL4 decreases plasma triglycerides and reduces the risk of coronary artery disease. Unfortunately, targeting ANGPTL4 for the therapeutic management of dyslipidemia and atherosclerosis is hampered by the observation that mice and monkeys in which ANGPTL4 is inactivated exhibit lipid accumulation in the mesenteric lymph nodes (MLNs). In mice these pathological events exclusively unfold upon feeding a high saturated FA diet and are followed by an ultimately lethal pro-inflammatory response and chylous ascites. Here, we show that Angptl4-/- mice fed a diet rich in trans FAs develop numerous lipid-filled giant cells in their MLNs, yet do not have elevated serum amyloid and haptoglobin, do not exhibit ascites, and survive, unlike Angptl4-/- mice fed a saturated FA-rich diet. In RAW264.7 macrophages, the saturated FA, palmitate, markedly increased markers of inflammation and the unfolded protein response, whereas the trans-unsaturated elaidate and the cis-unsaturated oleate had the opposite effect. In conclusion, trans and saturated FAs have very distinct biological effects in macrophages. Furthermore, lipid accumulation in MLNs is uncoupled from activation of an acute-phase response and chylous ascites, suggesting that ANGPTL4 should not be fully dismissed as target for dyslipidemia.


Tungsten oxide buffer layers fabricated in an inert sol-gel process at room-temperature for blue organic light-emitting diodes.
WO3 deposition from tungsten ethoxide precursor solutions at room temperature is demonstrated. The W(OEt)6 precursor can be converted under inert conditions and hence avoids sample contamination with oxygen, opening a pathway to more stable devices. The stoichiometry of all WO3 layers and the optoelectronic performance of the respective SMOLEDs well match thermally evaporated WO3 and its corresponding SMOLEDs. The solution processed WO3 hole injection layers enable the fabrication of blue phosphorescent OLEDs with low onset voltage and current efficiencies of up to 14 cd A(-1) .


Use of complementary and alternative medicine during pregnancy and the postpartum period: an analysis of the National Health Interview Survey.
Complementary and alternative medicine (CAM) is commonly used among women, but few national data exist regarding CAM use during pregnancy or the postnatal period. Data from the 2007 National Health Interview Survey were analyzed for women ages between the ages of 18 and 49 years who were pregnant or had children less than 1 year old. CAM use was identified based on standard definitions of CAM from the National Institutes of Health's National Center for Complementary and Alternative Medicine. CAM use among women who were pregnant or with a child less than 1 year was compared with the other similarly aged female responders. CAM use was examined among these women stratified by sociodemographics, health conditions, and conventional medicine use through bivariable and multivariable logistic regression models. Among pregnant and postpartum women from the ages of 19 to 49 years in the United States, 37% of pregnant women and 28% of postpartum women reported using CAM in the last 12 months compared with 40% of nonpregnant/non-postpartum women. Mind-body practices were the most common CAM modality reported, with one out of four women reporting use. Biological therapies, excluding vitamins and minerals, during the postpartum period were used by only 8% of women. Using multivariable regression modeling, we report no significant difference in CAM use among pregnant compared with non-pregnant women (adjusted odds ratio [AOR], 0.88; [95% confidence interval 0.65-1.20]), but lower CAM use among postpartum women compared with non-pregnant women (AOR 0.67; [0.52-0.88]), while adjusting for sociodemographics. CAM use among pregnancy similar to women who are not pregnant, while postpartum CAM use decreases. Further evaluation of CAM therapies among pregnant and postpartum women is necessary to determine the costs and benefits of integrative CAM therapies in conventional care.


Gene mutation profiling and clinical significances in patients with renal cell carcinoma.
The pathological mechanisms of patients with Renal Cell Carcinoma (RCC) remain defined. This study aimed to evaluate relationships between the landscape of gene mutations and their clinical significance in RCC patients. Tissue and peripheral blood samples of 42 patients with RCC were collected and performed for the Next Generation Sequencing (NGS) with Geneseeq PrimeTM 425-gene panel probes. Their landscapes of gene mutation were analyzed. We also carried out an evaluation of Tumor-Node-Metastasis (TNM) staging, RENAL nephelometry score, surgery, and targeted drug treatment of patients. Then we compared the correlations of landscape in gene mutations and the prognosis. The most common gene alternations, including BAP1, PBRM1, SETD2, CSF1R, NPM1, EGFR, POLE, RB1, and VHL genes, were identified in tissue and blood samples of 75% of patients. EGFR, POLE, and RB1 gene mutations frequently occurred in relapsed and metastatic patients. BAP1, CCND2, KRAS, PTPN11, ERBB2/3, JAK2, and POLE were presented in the patients with > 9 RENAL nephelometry score. Univariable analysis indicated that SETD2, BAP1, and PBRM1 genes were key factors for Disease-Free Survival (DFS). Multivariable analysis confirmed that mutated SETD1, NPM1, and CSF1R were critical factors for the Progression Free Survival (PFS) of RCC patients with target therapy. Wild-type PBRM1 and mutated BAP1 in patients with RCC were strongly associated with the outcomes of the patient. The PFS of the patients with SETD2, NPM1, and CSF1R mutations were significantly shorter than those patients without variants.


PREVAIL I Cluster Vaccination Study With rVSVΔG-ZEBOV-GP as Part of a Public Health Response in Liberia.
In November 2015, a 15-year-old boy received a diagnosis of Ebola virus disease (EVD) at the John F. Kennedy Medical Center in Monrovia, Liberia. Two additional family members received a diagnosis of EVD. The protocol for a phase 2 placebo-controlled trial of 2 Ebola vaccines was amended and approved; in 4 days, a single-arm cluster vaccination trial using the Merck rVSVΔG-ZEBOV-GP vaccine was initiated. Here, we evaluate the safety and immunogenicity of the vaccine and discuss challenges for its implementation in a small Ebola outbreak. We conducted a ring vaccination study among contacts and contacts of close contacts of EVD cases a in Monrovia. Participants were evaluated 1 and 6 months after vaccination. Among 650 close contacts and contacts of close contacts of EVD cases, 210 (32%) consented and were vaccinated with rVSVΔG-ZEBOV-GP. Of those vaccinated, 189 (90%) attended the month 1 follow-up visit; 166 (79%) attended the month 6 visit. No serious adverse events were reported. Among 88 participants without an elevated antibody level at baseline, 77.3% (95% confidence interval, 68.5-86.1) had an antibody response at 1 month. The Merck rVSVΔG-ZEBOV-GP vaccine appeared to be safe and immunogenic among the vaccinated individuals. However, fewer than one third of eligible individuals consented to vaccination. These data may help guide implementation decisions for of cluster vaccination programs in an Ebola cluster outbreak response situation.


A new study of intrauterine synechiae.
This study is based on a series of 37 hysteroscopies performed in the knee-chest on patients undergoing culdoscopy as part of an infertility work-up. Local anesthesia was used for the two procedures. All the patients had a thorough infertility work-up that was completely negative. Ruled-out by hysterogram prior to the procedure were congenital abnormalities of the uterus, endometrial polyps, and submucous myomas. There were several different types of endometrial scars in nine patients and this was the only intrauterine pathology discovered. They were intrauterine synechiae typical of the Asherman's syndrome in four cases, cesarean section scars in two, adhesions due to an infected IUD in two, and in one patient there were vertical linear scars secondary to an endometrial biopsy. In this study, the hysterogram was particularly accurate in predicting major endometrial abnormalities, but specific evidence as to the type of minor intrauterine pathology had to be obtained with a hysteroscope. The firmer adhesions that were not of the Asherman's type were difficult to remove and could not be broken up with a hysteroscope. The types of scar visualized are described in some detail. Intrauterine synechiae probably derive ultimately from any type of trauma to a decidual or predecidual endometrium and need not be pregnancy related.


The Role of Lymphatic Vascular Function in Metabolic Disorders.
In addition to its roles in the maintenance of interstitial fluid homeostasis and immunosurveillance, the lymphatic system has a critical role in regulating transport of dietary lipids to the blood circulation. Recent work within the past two decades has identified an important relationship between lymphatic dysfunction and patients with metabolic disorders, such as obesity and type 2 diabetes, in part characterized by abnormal lipid metabolism and transport. Utilization of several genetic mouse models, as well as non-genetic models of diet-induced obesity and metabolic syndrome, has demonstrated that abnormal lymphangiogenesis and poor collecting vessel function, characterized by impaired contractile ability and perturbed barrier integrity, underlie lymphatic dysfunction relating to obesity, diabetes, and metabolic syndrome. Despite the progress made by these models, the contribution of the lymphatic system to metabolic disorders remains understudied and new insights into molecular signaling mechanisms involved are continuously developing. Here, we review the current knowledge related to molecular mechanisms resulting in impaired lymphatic function within the context of obesity and diabetes. We discuss the role of inflammation, transcription factor signaling, vascular endothelial growth factor-mediated signaling, and nitric oxide signaling contributing to impaired lymphangiogenesis and perturbed lymphatic endothelial cell barrier integrity, valve function, and contractile ability in collecting vessels as well as their viability as therapeutic targets to correct lymphatic dysfunction and improve metabolic syndromes.


Microvascular decompression for trigeminal neuralgia: a single-center experience with 516 cases, including 32 patients with multiple sclerosis.
To evaluate the effectiveness and long-term pain relief of microvascular decompression (MVD) for "typical" trigeminal neuralgia (TN), including patients affected by multiple sclerosis (MS). Between January 2011 and December 2022, 516 consecutive patients presenting with trigeminal neuralgia and a diagnosed neurovascular conflict at MRI underwent microvascular decompression surgery in our neurosurgery department. Ten surgeons with different ages and experiences performed the surgical procedures. Pain improvement, re-operation rate, and complication rates were retrospectively collected and analyzed. 516 patients were included (214 males 302 females, ranging from 12 to 87 years), including 32 patients with multiple sclerosis. Neurovascular compression was found in all cases during surgery. Barrow Neurological Institute pain intensity scale with a score of I was achieved in 404 patients (78,29%), a score II or III was obtained in 100 cases (19,37%) and a score of IV and V in 12 patients (2,32%). In the multiple sclerosis subset of patients, a BNI score of I was achieved in 21/32 (65.62%). The pain recurrence rate of our series was 15.11%. The follow-up for all patients was at least of 13 months, with a mean follow-up of 41.93 months (± 17.75 months, range 13-91 months). Neither intraoperative mortality nor major intra-operative complications occurred in the analyzed series. The re-operation rate was 12.98%. Thermorhizotomy, percutaneous balloon compression, cyber-knife radiosurgery, or new MVD were the surgical techniques utilized for re-operations. MVD may be considered an effective and safe surgical technique for TN, and in patients affected by multiple sclerosis, it may be proposed even if a less favorable outcome has to be expected with respect to classic TN patients. Larger studies focusing on the relation of multiple sclerosis with neurovascular compression are required.


Liquid drops on a surface: using density functional theory to calculate the binding potential and drop profiles and comparing with results from mesoscopic modelling.
The contribution to the free energy for a film of liquid of thickness h on a solid surface due to the interactions between the solid-liquid and liquid-gas interfaces is given by the binding potential, g(h). The precise form of g(h) determines whether or not the liquid wets the surface. Note that differentiating g(h) gives the Derjaguin or disjoining pressure. We develop a microscopic density functional theory (DFT) based method for calculating g(h), allowing us to relate the form of g(h) to the nature of the molecular interactions in the system. We present results based on using a simple lattice gas model, to demonstrate the procedure. In order to describe the static and dynamic behaviour of non-uniform liquid films and drops on surfaces, a mesoscopic free energy based on g(h) is often used. We calculate such equilibrium film height profiles and also directly calculate using DFT the corresponding density profiles for liquid drops on surfaces. Comparing quantities such as the contact angle and also the shape of the drops, we find good agreement between the two methods. We also study in detail the effect on g(h) of truncating the range of the dispersion forces, both those between the fluid molecules and those between the fluid and wall. We find that truncating can have a significant effect on g(h) and the associated wetting behaviour of the fluid.


VEGF deprivation-induced apoptosis is a component of programmed capillary regression.
The pupillary membrane (PM) is a transient ocular capillary network, which can serve as a model system in which to study the mechanism of capillary regression. Previous work has shown that there is a tight correlation between the cessation of blood flow in a capillary segment and the appearance of apoptotic capillary cells throughout the segment. This pattern of cell death is referred to as synchronous apoptosis (Lang, R. A., Lustig, M., Francois, F., Sellinger, M. and Plesken, H. (1994) Development 120, 3395-3404; Meeson, A., Palmer, M., Calfon, M. and Lang, R. A. (1996) Development 122, 3929-3938). In the present study, we have investigated whether the cause of synchronous apoptosis might be a segmental deficiency of either oxygen or a survival factor. Labeling with the compound EF5 in a normal PM indicated no segmental hypoxia; this argued that oxygen deprivation was unlikely to be the cause of synchronous apoptosis. When rat plasma was used as a source of survival factors in an in vitro PM explant assay, inhibition of vascular endothelial growth factor (VEGF) all but eliminated the activity of plasma in suppressing apoptosis. This argued that VEGF was an important plasma survival factor. Furthermore, inhibition of VEGF in vivo using fusion proteins of the human Flk-1/KDR receptor resulted in a significantly increased number of capillaries showing synchronous apoptosis. This provides evidence that VEGF is necessary for endothelial cell survival in this system and in addition, that VEGF deprivation mediated by flow cessation is a component of synchronous apoptosis.


The therapeutic use of gene therapy in inflammatory demyelinating diseases of the central nervous system.
Gene therapy protocols aimed to deliver therapeutic molecules into the central nervous system may represent an alternative therapeutic strategy in patients affected by inflammatory demyelinating diseases of the central nervous system where systemic therapies have shown limited therapeutic efficacy possibly owing to the blood-brain barrier, a major obstacle for the entry of therapeutic molecules into the central nervous system. Among inflammatory demyelinating diseases of the central nervous system, gene therapy approaches have been so far developed almost exclusively for multiple sclerosis. However, the chronic/relapsing nature of the disease, the restriction to the central nervous system of the pathological process as well as the necessity to inhibit the ongoing inflammatory process but also to foster endogenous remyelinating pathways, have posed several questions which still need to be properly addressed for the development of a successful gene therapy strategy in multiple sclerosis patients. The gene therapy approaches for multiple sclerosis have been so far developed and tested only in rodents and monkeys with experimental autoimmune encephalomyelitis, the animal model of multiple sclerosis. The results of these studies clearly indicate that the delivery of therapeutic genes within the central nervous system is superior to the peripheral delivery. In particular, the intracerebral delivery of genes coding for anti-inflammatory and/or neurotrophic molecules, using gene vectors derived from non-replicative viruses, showed to inhibit not only the detrimental function of blood-borne mononuclear effector cells but also to foster proliferation and differentiation of surviving oligodendrocytes within demyelinated areas. Here, we summarize the most recent findings of this novel area of research.


The vascular control in liver resection: revisitation of a controversial issue.
Limiting intraoperative blood loss and the consequent need for whole blood transfusion is a widely accepted goal in liver resection. To achieve this goal, liver resection carried out under warm ischemia seems adequate. Methods used for this purpose can be categorized as follows: those with only an inflow control and the one that consists of total vascular exclusion. Liver resections under inflow vascular control are safer than those performed without. Furthermore, up to now the ischemia-reperfusion liver damage does not seem to affect the patients' course. The clinical evidence shows that intermittent warm ischemia seems to be safer than the continuous clamping and guarantees an effective control of the intraoperative bleeding. Conversely, total vascular exclusion is an invasive technique with not negligible morbidity; then its real indications should be restricted to exceptional cases, such as those with infiltration of the inferior vena cava which demands substitution of the involved vessel. In conclusion, up to now intermittent warm ischemia is the most appropriate approach to carry out safe liver resections.


Chondrosarcoma of the small bones of the hand: case report and review of the literature.
An unusually rare case of chondrosarcoma arising from an osteochondroma of a finger is presented. Chondrosarcomas of the hand in general are rare and almost always central in origin. Malignant degeneration of previously known enchondromas can occur and account for some but not all cases of chondrosarcoma of the hand. Histologic interpretation of cartilagenous lesions of the hand is difficult, and clinical behavior and radiographic appearance and appearance at surgery are often more reliable indicators of malignancy. Clinical suspicion should be aroused in an older individual with a previously quiescent lesion that becomes larger and/or more symptomatic. The clinical course of these tumors is slow and metastasis is late and usually to the lungs. Treatment of choice is amputation or ray resection of the affected part. Prognosis is good if metastasis has not occurred.


Body dysmorphic disorder. A survey of fifty cases.
Body dysmorphic disorder (BDD) consists of a preoccupation with an 'imagined' defect in appearance which causes significant distress or impairment in functioning. There has been little previous research into BDD. This study replicates a survey from the USA in a UK population and evaluates specific measures of BDD. Cross-sectional interview survey of 50 patients who satisfied DSM-IV criteria for BDD as their primary disorder. The average age at onset was late adolescence and a large proportion of patients were either single or divorced. Three-quarters of the sample were female. There was a high degree of comorbidity with the most common additional Axis l diagnosis being either a mood disorder (26%), social phobia (16%) or obsessive-compulsive disorder (6%). Twenty-four per cent had made a suicide attempt in the past. Personality disorders were present in 72% of patients, the most common being paranoid, avoidant and obsessive-compulsive. BDD patients had a high associated comorbidity and previous suicide attempts. BDD is a chronic handicapping disorder and patients are not being adequately identified or treated by health professionals.


Employment status and the association of sociocultural stress with sleep in the Hispanic Community Health Study/Study of Latinos (HCHS/SOL).
We examined the association of sociocultural stress severity (i.e. acculturation stress, ethnic discrimination) and chronic stress burden with multiple dimensions of sleep in a population-based sample of US Hispanics/Latinos. We also explored whether employment status modified stress-sleep associations. We conducted survey linear regressions to test the cross-sectional association of sociocultural stress severity and stress burden with sleep dimensions using data collected between 2010 and 2013 from individuals who participated in both the Hispanic Community Health Study/Study of Latinos Sueño and Sociocultural Ancillary studies (N = 1192). Greater acculturation stress (B = 0.75, standard error [SE] = 0.26, p < .01) and chronic psychosocial stress burden (B = 1.04, SE = 0.18, p < .001) were associated with greater insomnia symptoms but were not associated with actigraphic measures of sleep. Ethnic discrimination was not associated with any of the sleep dimensions. The association of acculturation stress with insomnia severity was greater in unemployed (B = 2.06, SE = 0.34) compared to employed (B = 1.01, SE = 0.31) participants (p-interaction = .08). Acculturation stress severity and chronic stress burden are important and consistent correlates of insomnia, but not actigraphically measured sleep dimensions. If replicated, future research should test whether interventions targeting the resolution of sociocultural stress improve sleep quality in Hispanics/Latinos.


Alterations in chemotactic factor-induced responses of neutrophils and monocytes from chronic dialysis patients.
Chronic renal failure patients on dialysis have an increased susceptibility to infection. Previous studies have demonstrated that these patients have a decreased in vitro neutrophil (PMN) chemotactic response and a reduction in C5a receptor availability on both PMN and monocytes. This study was designed to determine if other chemotactic factor-mediated responses of PMN and monocytes from hemodialysis (HD) and continuous ambulatory peritoneal dialysis (CAPD) patients are abnormal. The responses investigated included in vitro chemotaxis, superoxide generation, H2O2 production, and myeloperoxidase (MPO) release. These studies showed that PMN from HD and CAPD patients are significantly decreased in their chemotactic response to both C5a and fMLP when compared to normal controls. The response of HD patient's PMN to C5a was decreased by an average of 55.1% (p less than 0.005) and for CAPD patients by 49.7% (p less than 0.01). Similarly, chemotactic responses to fMLP were decreased by an average of 44.7% (p less than 0.005) for HD patients and 36.3% (p less than 0.02) for CAPD patients. Superoxide anion production by PMN and monocytes from HD and CAPD patients in response to C5a and fMLP was also significantly decreased compared to controls. PMN superoxide production in response to C5a was decreased by an average of 36.5% (p less than 0.001) for HD patients and 32.0% (p less than 0.001) for CAPD patients. fMLP-stimulated production of superoxide was also decreased but to a lesser degree with a mean decrease of 18.0% (p less than 0.01) for HD patients and 24.1% decrease (p less than 0.01) for CAPD patients. This decreased responsiveness was restricted to C5a- and fMLP-stimulated superoxide production since phorbol myristate acetate (PMA)-stimulated responses were comparable to controls. A similar pattern of decreased superoxide production was found with monocytes from these patients. Comparable decreases in chemotactic factor-stimulated responses were also observed in a flow cytometric assay of H2O2 production in both PMN and monocytes and an in vitro assay of MPO release from PMN. Analysis of the binding of fluorescent C5a to PMN showed a direct correlation between decreased C5a binding and decreased O2- production and MPO release. Since all of these chemotactic factor-stimulated events are involved in the inflammatory process and the killing of microorganisms, alterations in these WBC functions in dialysis patients may contribute to their increased susceptibility to infection.


HTLV-1-host interactions on the development of adult T cell leukemia/lymphoma: virus and host gene expressions.
Adult T-cell leukemia/lymphoma (ATLL) is a lymphoproliferative disorder of HTLV-1-host interactions in infected TCD4+ cells. In this study, the HTLV-1 proviral load (PVL) and HBZ as viral elements and AKT1, BAD, FOXP3, RORγt and IFNλ3 as the host factors were investigated. The study was conducted in ATLLs, HTLV-1-associated myelopathy/tropical spastic paraparesis patients (HAM/TSPs) and HTLV-1-asympthomatic carriers (ACs). The DNA and mRNA from peripheral blood mononuclear cells were extracted for gene expression assessments via qRT-PCR, TaqMan assay, and then confirmed by western blotting. As it was expected, the HTLV-1-PVL were higher in ATLLs than ACs (P = 0.002) and HAM/TSP (P = 0.041). The HBZ expression in ATLL (101.76 ± 61.3) was radically higher than in ACs (0.12 ± 0.05) and HAM/TSP (0.01 ± 0.1) (P = 0.001). Furthermore, the AKT1 expression in ATLLs (13.52 ± 4.78) was higher than ACs (1.17 ± 0.27) (P = 0.05) and HAM/TSPs (0.72 ± 0.49) (P = 0.008). However, BAD expression in ATLL was slightly higher than ACs and HAM/TSPs and not significant. The FOXP3 in ATLLs (41.02 ± 24.2) was more than ACs (1.44 ± 1) (P = 0.007) and HAM/TSP (0.45 ± 0.15) (P = 0.01). However, RORγt in ATLLs (27.43 ± 14.8) was higher than ACs (1.05 ± 0.32) (P = 0.02) but not HAM/TSPs. Finally, the IFNλ3 expression between ATLLs (31.92 ± 26.02) and ACs (1.46 ± 0.63) (P = 0.01) and ACs and HAM/TSPs (680.62 ± 674.6) (P = 0.02) were statistically different, but not between ATLLs and HAM/TSPs. The present and our previous study demonstrated that HTLV-1-PVL and HBZ and host AKT1 and Rad 51 are novel candidates for molecular targeting therapy of ATLL. However, high level of RORγt may inhibit Th1 response and complicated in ATLL progressions.


Cortical Asymmetries and Connectivity Patterns in the Valence Dimension of the Emotional Brain.
Understanding the neurophysiology of emotions, the neuronal structures involved in processing emotional information and the circuits by which they act, is key to designing applications in the field of affective neuroscience, to advance both new treatments and applications of brain-computer interactions. However, efforts have focused on developing computational models capable of emotion classification instead of on studying the neural substrates involved in the emotional process. In this context, we have carried out a study of cortical asymmetries and functional cortical connectivity based on the electroencephalographic signal of 24 subjects stimulated with videos of positive and negative emotional content to bring some light to the neurobiology behind emotional processes. Our results show opposite interhemispheric asymmetry patterns throughout the cortex for both emotional categories and specific connectivity patterns regarding each of the studied emotional categories. However, in general, the same key areas, such as the right hemisphere and more anterior cortical regions, presented higher levels of activity during the processing of both valence emotional categories. These results suggest a common neural pathway for processing positive and negative emotions, but with different activation patterns. These preliminary results are encouraging for elucidating the neuronal circuits of the emotional valence dimension.


Development and Evaluation of Serum CST1 Detection for Early Diagnosis of Esophageal Squamous Cell Carcinoma.
Our pilot study has shown that cystatin SN (CST1) protein is highly expressed in esophageal squamous cell carcinoma (ESCC) tissues. We intend to develop a chemiluminescent enzyme immunoassay (CLEIA) available for serum CST1 detection and define the diagnostic value of CST1 detection for early ESCC patients, and establish a panel of CST1 with traditional tumor markers to improve the diagnostic sensitivity for early ESCC. Detection performance of CLEIA for CST1 was evaluated by linearity, detection limit, accuracy, precision, anti-interference and stability. Diagnostic performance of CST1 for early ESCC was evaluated by detecting CST1 of 112 early ESCC, 107 esophageal benign lesions (EBL), and 151 healthy controls (HC). CEA, CYFRA21-1 and SCC-Ag were detected by chemiluminescence immunoassay (CLIA). The linear range and detection limit of CLEIA for CST1 were 6.25-400 pg/mL and 1.35 pg/mL, respectively; the average recovery rate was 102.65%; CVs of intra-batch precision and inter-batch precision were <1/4 TEa and <1/3 TEa, respectively; 8 interferents including 7 common interferents and CST4 had no interference on CST1 detection; stability evaluation showed good sample and reagent stability. The level and positive rate of CST1 in early ESCC group were significantly higher than those in EBL/HC groups (P<0.05). The diagnostic sensitivity of CST1 for early ESCC was 31.25% (specificity 92.64%, AUC 0.654). The diagnostic sensitivity of traditional tumor markers ranged from 16.07% to 28.57%, at >93.0% specificity, and SCC-Ag showed the highest AUC (0.709). Combination of CST1 and CEA, SCC-Ag exhibited the highest AUC up to 0.736 (sensitivity 49.11%, specificity 89.53%). CLEIA has excellent detection performance for CST1. CST1 might be a prospective serological biomarker for early diagnosis of ESCC, while combination of CST1 and CEA, SCC-Ag might improve the early diagnostic performance.


Efferocytosis creates a tumor microenvironment supportive of tumor survival and metastasis.
Programmed cell death, or apoptosis, occurs in nearly all tissues of all multi-cellular organisms. In order to avoid leakage of intracellular contents, which could generate tissue damaging inflammation, apoptotic cells are cleared from tissues by phagocytes, which then dispatch the engulfed dying cell through the lysosomal pathway. Phagocytic clearance of apoptotic cells is referred to as efferocytosis. One key feature of efferocytosis is the production and release of wound healing cytokines by the phagocyte, which acts to resolve inflammation, and promote tissue repair. Phagocytic engulfment of apoptotic cells coupled with cytokine modulation aimed at immune suppression ensures that physiological programmed cell death does not induce inflammation and tissue damage. However, cytokines involved in wound healing and immune suppression are notorious for their role in the tumor microenvironment, increasing tumor cell motility and promoting evasion of anti-tumor immunity. Therefore, current and future studies aimed at targeting important players of efferocytosis should reveal new and efficacious therapeutic approaches for limiting cancer progression and relapse.


Dynamic Distortion of Orientation Representation after Learning in the Mouse Primary Visual Cortex.
Learning is an essential cognitive mechanism allowing behavioral adaptation through adjustments in neuronal processing. It is associated with changes in the activity of sensory cortical neurons evoked by task-relevant stimuli. However, the exact nature of those modifications and the computational advantages they may confer are still debated. Here, we investigated how learning an orientation discrimination task alters the neuronal representations of the cues orientations in the primary visual cortex (V1) of male and female mice. When comparing the activity evoked by the task stimuli in naive mice and the mice performing the task, we found that the representations of the orientation of the rewarded and nonrewarded cues were more accurate and stable in trained mice. This better cue representation in trained mice was associated with a distortion of the orientation representation space such that stimuli flanking the task-relevant orientations were represented as the task stimuli themselves, suggesting that those stimuli were generalized as the task cues. This distortion was context dependent as it was absent in trained mice passively viewing the task cues and enhanced in the behavioral sessions where mice performed best. Those modifications of the V1 population orientation representation in performing mice were supported by a suppression of the activity of neurons tuned for orientations neighboring the orientations of the task cues. Thus, visual processing in V1 is dynamically adapted to enhance the reliability of the representation of the learned cues and favor generalization in the task-relevant computational space.SIGNIFICANCE STATEMENT Performance improvement in a task often requires facilitating the extraction of the information necessary to its execution. Here, we demonstrate the existence of a suppression mechanism that improves the representation of the orientations of the task stimuli in the V1 of mice performing an orientation discrimination task. We also show that this mechanism distorts the V1 orientation representation space, leading stimuli flanking the task stimuli orientations to be generalized as the task stimuli themselves.


Interventions for reducing alcohol consumption among general hospital inpatient heavy alcohol users: a systematic review.
There is growing interest in pro-active detection and provision of interventions for heavy alcohol use in the general hospital inpatient population. We aimed to determine, from the available evidence, the effectiveness of interventions in reducing alcohol consumption among general hospital inpatient heavy alcohol users. The following databases were searched for completed and on-going randomised and non-randomised controlled studies published up to November 2012: MEDLINE; C2-SPECTR; CINAHL; The Cochrane Library; Conference Proceedings Citation Index: Science; EMBASE; HMIC; PsycInfo; Public Health Interventions Cost Effectiveness Database (PHICED); and ClinicalTrials.gov. Studies were screened independently by two reviewers. Data extraction was performed by one reviewer and independently checked by a second. Twenty-two studies which met the inclusion criteria enrolled 5307 participants in total. All interventions were non-pharmacological and alcohol focused. Results from single session brief interventions and self-help literature showed no clear benefit on alcohol consumption outcomes, with indications of benefit from some studies but not others. However, results suggest brief interventions of more than one session could be beneficial on reducing alcohol consumption, especially for non-dependent patients. No active intervention was found superior over another on alcohol consumption and other outcomes. Brief interventions of more than one session could be beneficial on reducing alcohol consumption among hospital inpatients, especially for non-dependent patients. However, additional evidence is still needed before more definitive conclusions can be reached.


Challenges experienced and resources identified by young to midlife couples 1-3 years post-cancer diagnosis.
The purpose of this study was to explore what young to midlife couples viewed as their strengths as a couple and the greatest challenges in their experience with cancer 1-3 years post-diagnosis. We used qualitative content analysis to extract common themes from open-ended questions from 42 cancer survivors and their partners (aged 27-58). Patterns of themes by age and gender of the survivor were also explored. Couples described both positive and negative impacts of the cancer experience: (1) strengthened the relationship, bringing couples closer together; (2) brought emotional strain to many areas of life, especially for partners; (3) created positive changes in lifestyle and new priorities for the couple; (4) created strain in the couple's relationship and intimacy; and (5) altered the role of family in supporting the couple. Couples also described four key strengths in dealing with the cancer experience: (1) drawing strength from shared love and mutuality; (2) communicating openly, even about the difficult stuff; (3) working together as a team to support each other; and (4) drawing strength from shared values and goals. Couples reported unmet needs related to the emotional and relational strain of the cancer experience, managing longer term survivor symptoms, fertility and physical intimacy, and lack of support or attention to the partner who often assumed the role of care partner. Themes are discussed in light of current dyadic concepts and importance of couple-based interventions.


Does the expression of granzyme B participate in inflammation, fibrosis, and fertility of hydatid cysts?
Echinococcus granulosus (sensu lato), a cestode that is endemic in Egypt, causes cystic echinococcosis (CE), a significant but neglected zoonotic disease that is prevalent throughout the world. Infected hydatid cysts are classified as fertile or non-fertile based on the presence of protoscoleces; nevertheless, the mechanism of non-fertile CE cysts remains unknown. The study aimed to assess whether granzyme B (GrB) expression and CD4 + /CD8 + could be related to the induction of non-fertile CE cysts. A total of fifty-eight individuals diagnosed with visceral hydatid cysts were selected, and they were further divided according to cyst fertility into fertile and non-fertile. Immunohistochemistry for CD4, CD8, and GrB was done. According to the results, hydatid cysts are common in adults and have no gender preference. The same clinical and laboratory data were shared by patients with fertile and non-fertile cysts (p = 0.186). GrB expression was not impacted by the fibrous deposition inside the hydatid cyst wall (p = 0.85); however, GrB was significantly correlated with the inflammatory density (p = 0.005). GrB expression was also found to be significantly higher in non-fertile cysts (p = 0.04). GrB expression is positively correlated with CD4 and CD8 expression. In conclusion, the expression of GrB in hydatid cysts may exacerbate the inflammatory response and impede cyst fertility while not affecting the fibrous deposition in the cyst wall.


Comparison of Speech Recognition and Hearing Preservation Outcomes Between the Mid-Scala and Lateral Wall Electrode Arrays.
To assess speech recognition and hearing preservation (HP) outcomes with the Advanced Bionics Mid-Scala and SlimJ electrodes. Retrospective cohort. Tertiary referral center. A total of 237 adult patients implanted between 2013 and 2020 (Mid-Scala, n = 136; SlimJ, n = 101). Consonant-nucleus-consonant (CNC) and AzBio (Arizona Biomedical) scores at 6 and 12 months; postoperative HP, defined as low-frequency pure-tone average ≤ 80 dB HL; scalar position. Mean CNC scores did not significantly differ between Mid-Scala and SlimJ recipients at 6 (45.8% versus 46.0%, p = 0.962) and 12 (51.9% versus 48.8%, p = 0.363) months. Similarly, mean AzBio in quiet scores were equivalent for both groups at 6 (55.1% versus 59.2%, p = 0.334) and 12 (60.6% versus 62.3%, p = 0.684) months. HP rates were significantly higher with the SlimJ (48.4%) than the Mid-Scala (30.8%; p = 0.033). Scalar translocations were 34.8 and 16.1% for the Mid-Scala and SlimJ groups, respectively ( p = 0.019). Ears with postoperative HP had significantly fewer scalar translocations (16.7% versus 37.2%, p = 0.048), and postoperative HP was associated with higher AzBio in noise scores at the most recent follow-up interval (38.7% versus 25.1%, p = 0.042). CNC, AzBio in quiet and noise, low-frequency pure-tone average shifts, and PTA at 6 and 12 months were not significantly different between patients with scala tympani insertions of the SlimJ versus the Mid-Scala ( p > 0.05). Compared with the Mid-Scala, the lateral wall electrode has superior HP rates and fewer scalar translocations, whereas speech recognition scores are equivalent between both electrode arrays. These findings can help providers with electrode selection and patient counseling.


[Inferential evaluation of intimacy based on observation of interpersonal communication].
How do people inferentially evaluate others' levels of intimacy with friends? We examined the inferential evaluation of intimacy based on the observation of interpersonal communication. In Experiment 1, participants (N = 41) responded to questions after observing conversations between friends. Results indicated that participants inferentially evaluated not only goodness of communication, but also intimacy between friends, using an expressivity heuristic approach. In Experiment 2, we investigated how inferential evaluation of intimacy was affected by prior information about relationships and by individual differences in face-to-face interactional ability. Participants (N = 64) were divided into prior- and no-prior-information groups and all performed the same task as in Experiment 1. Additionally, their interactional ability was assessed. In the prior-information group, individual differences had no effect on inferential evaluation of intimacy. On the other hand, in the no-prior-information group, face-to-face interactional ability partially influenced evaluations of intimacy. Finally, we discuss the fact that to understand one's social environment, it is important to observe others' interpersonal communications.


Is the silvering process similar to the effects of pressure acclimatization on yellow eels?
To reproduce eels need to migrate over 6000 km and at pressure but before this migration they metamorphose into silver eels (silvering). The question raised in this study is to determine whether and how the silvering process contributes to pressure resistance. As migration represents a long swimming activity mainly performed with slow muscles, the red muscle energetics of pressure exposed silver eels was studied. By comparing these results to what has already been shown in yellow eels, we point out that the effects of the silvering process on pressure resistance are similar to the effects of pressure acclimatization in yellow eels. As previously shown, success of pressure acclimatization depends on membrane fluidity, but we raise the hypothesis that the high-pressure resistance of silver eels is due to more fluid membranes.


Event-related potentials in alcoholic men: P3 amplitude reflects family history but not alcohol consumption.
Multilead event-related potentials (ERPs), elicited by auditory and visual stimuli requiring a button press response and by a startling noise requiring no response, were recorded from male alcoholics and age-matched male controls (26-60 years old). Single-trial analyses of blink responses to the startling stimuli indicated that alcoholics startle less frequently but with equivalent amplitude as the controls. In contrast, single-trial analyses of P3 indicated that alcoholics generate a P3 as often as controls, but that their individual P3s are smaller. Alcoholics who reported a positive family history of problem drinking had larger startle blink amplitudes and smaller auditory and visual P3s than did alcoholics who reported a negative family history. Hierarchical regression analysis was used to demonstrate that smaller P3s in family history positive alcoholics were independent of lifetime alcohol consumption.


Drug-coated balloons versus drug-eluting stents in patients with acute myocardial infarction undergoing percutaneous coronary intervention: an updated meta-analysis with trial sequential analysis.
Drug-coated balloons (DCBs) are an established strategy for coronary artery disease. However, the new generation drug-eluting stent (DES) is recommended for patients with Acute myocardial infarction (AMI) for coronary artery revascularization. Our aim is to provide a comprehensive appraisal of the efficacy of DCBs in patients with AMI undergoing PCI. We searched the WOS, PubMed, Scopus, and Cochrane CENTRAL till March 2023, for studies that compared DCBs versus DES in patients with AMI undergoing PCI. We used a random-effects model to compare major adverse cardiac events (MACE), cardiac death, all-cause death, myocardial infarction, target lesion revascularization (TLR), stent thrombosis, Late lumen Loss (LLL), and minimum lumen diameter (MLD) between the two groups. Thirteen studies comprising 2644 patients were included. The pooled OR showed non-inferiority of DCB over DES in terms of MACE (OR = 0.89, 95% CI [0.57 to 1.40], p = 0.63). When we defined MACE as a composite of cardiac death, MI, and TLR; the pooled OR favored DCB over DES (OR = 0.50, 95% CI [0.28 to 0.9], p = 0.02). Moreover, DCB was not inferior to DES in terms of all-cause mortality (OR = 0.88, 95% CI: 0.43 to 1.8, p = 0.73), cardiac mortality, (OR = 0.59, 95% CI: 0.22 to 1.56, p = 0.29), MI (OR = 0.88, 95% CI: 0.34 to 2.29, p = 0.79), stent thrombosis (OR = 1.21, 95% CI: 0.35 to 4.23, p = 0.76), TLR (OR = 0.9, 95% CI: 0.43 to 1.93, p = 0.8), LLL (MD = -0.6, 95% CI: -0.3 to 0.19, p = 0.64), or MLD (MD = -0.4, 95% CI: -0.33 to 0.25, p = 0.76). Our meta-analysis indicated that DCB intervention was not inferior to DES in the PCI setting in patients with AMI, and can be recommended as a feasible strategy in AMI. CRD42023412757.


Spermidine biosynthesis in Escherichia coli: promoter and termination regions of the speED operon.
Two enzymes, S-adenosylmethionine decarboxylase and spermidine synthase, are essential for the biosynthesis of spermidine in Escherichia coli. We have previously shown that the genes encoding these enzymes (speD and speE) form an operon and that the area immediately upstream from the speE gene is necessary for the expression of both the speE and speD genes. We have now studied the upstream promoter and the downstream terminator regions of this operon more completely. We have shown that the major mRNA initiation site (Ia) of the operon is located 475 base pairs (bp) upstream from the speE gene and that there is an open reading frame that encodes for a polypeptide of 115 amino acids between the Ia site and the ATG start codon for the speE gene. Downstream from the stop codon for the speD gene is a potential hairpin structure immediately followed by an mRNA termination site, t. An additional mRNA termination site, t', is present about 110 bp downstream from t and is stronger than t. By comparing our DNA fragments with those prepared from this region of the E. coli chromosome by Kohara et al., we have located the speED operon on the physical map of the E. coli chromosome. We have shown that the orientation of the speED operon is counterclockwise and that the operon is located 137.5 to 140 kbp (2.9 minutes) clockwise from the zero position of the E. coli chromosomal map.


Oxyhemoglobin-induced apoptosis in cultured endothelial cells.
Oxyhemoglobin (OxyHb) is one of the most important spasmogens for cerebral vasospasm that follows aneurysmal subarachnoid hemorrhage. The cytotoxic effect of OxyHb has been documented in endothelial and smooth-muscle cells; however, the pattern of cell death--necrosis or apoptosis--as the final stage of cell damage has not been demonstrated. This study was undertaken to determine if OxyHb induces apoptotic changes in cultured bovine aortic endothelial cells. Confluent bovine aortic endothelial cells were treated with OxyHb in a concentration- and time-dependent manner. Cell density was assayed by counting the number of cells that attached to culture dishes after exposure to OxyHb. To identify apoptotic changes, the investigators used three specific methods: DNA fragmentation (electrophoreses), the apoptotic body (transmission electron microscopy), and cleavage of poly (adenosine diphosphate ribose) polymerase (PARP [Western blotting]). Oxyhemoglobin decreased cell density in a concentration- and time-dependent manner. Analysis of DNA showed a pattern of internucleosomal cleavage characteristic of apoptosis (DNA ladder). Transmission electron microscopy demonstrated condensation of nuclei and apoptotic bodies in OxyHb-treated endothelial cells. Western blotting with the PARP antibody revealed that the 116-kD PARP was cleaved to the 85-kD apoptosis-related fragment. These results for the first time demonstrated that the OxyHb induces apoptosis in cultured endothelial cells.


TRB3, a novel ER stress-inducible gene, is induced via ATF4-CHOP pathway and is involved in cell death.
C/EBP homologous protein (CHOP) is a stress-inducible nuclear protein that is crucial for the development of programmed cell death and regeneration; however, the regulation of its function has not been well characterized. Slbo, a Drosophila homolog of C/EBP (CCAAT/enhancer binding protein), was shown to be unstabilized by tribbles. Here, we identified TRB3 as a tribbles ortholog in humans, which associated with CHOP to suppress the CHOP-dependent transactivation. TRB3 is induced by various forms endoplasmic reticulum (ER) stress later than CHOP. Tunicamycin treatment enhanced the TRB3 promoter activity, while dominant-negative forms of CHOP suppressed the tunicamycin-induced activation. In addition, the tunicamycin response region in the TRB3 promoter contains amino-acid response elements overlapping the CHOP-binding site, and CHOP and ATF4 cooperated to activate this promoter activity. Knockdown of endogenous ATF4 or CHOP expression dramatically repressed tunicamycin-induced TRB3 induction. Furthermore, knockdown of TRB3 expression decreased ER stress-dependent cell death. These results indicate that TRB3 is a novel target of CHOP/ATF4 and downregulates its own induction by repression of CHOP/ATF4 functions, and that it is involved in CHOP-dependent cell death during ER stress.


Recombinant human granulocyte colony-stimulating factor accelerates hematopoietic recovery after DLA-identical littermate marrow transplants in dogs.
We studied whether treatment of dogs with recombinant human granulocyte colony-stimulating factor (rhG-CSF), after 920 cGy total body irradiation (TBI) and transplantation of 3.3 +/- 1.0 x 10(8) bone marrow cells per kilogram from a DLA-identical littermate, accelerated hematopoietic recovery and influenced the incidence of subsequent marrow graft failure or graft-versus-host disease (GVHD). Ten animals were treated with 100 micrograms rhG-CSF/kg/d from days 1 through 10 after TBI. Results were compared with those of historical control of 14 dogs not administered rhG-CSF. Neither group of dogs received GVHD prophylaxis. The median time to recovery of 1,000 neutrophils/mm3 was 8 days for dogs administered rhG-CSF compared with 14 days in controls (logrank test: P less than .03). The median time to reach 100 monocytes/mm3 was 17 days in G-CSF-treated dogs compared with 49 days in controls (P less than .002). The median time to attain 500 lymphocytes/mm3 was 15 days versus 31 days, respectively (P less than .01). The median time to reach 20,000 platelets/mm3 was 26 versus 20 days (P = .68). Graft failure occurred in 1 of 10 G-CSF-treated dogs versus 2 of 14 controls (two-tailed Fisher's exact test: P = 1.00). GVHD was seen in 4 of 9 rhG-CSF-treated dogs compared with 1 of 12 controls (P = .12). Two G-CSF-treated dogs died of GVHD versus none of the controls (P = .17). No unusual toxicities were seen in dogs receiving rhG-CSF. In summary, rhG-CSF significantly accelerated recovery of neutrophils, monocytes, and lymphocytes after DLA-identical littermate marrow transplantation without altering platelet recovery. Graft failure was not seen more often than in controls, but there was a trend toward an increased incidence of GVHD.


Honokiol: a novel natural agent for cancer prevention and therapy.
Honokiol (3',5-di-(2-propenyl)-1,1'-biphenyl-2,4'-diol) is a bioactive natural product derived from Magnolia spp. Recent studies have demonstrated anti-inflammatory, anti-angiogenic, anti-oxidative and anticancer properties of honokiol in vitro and in preclinical models. Honokiol targets multiple signaling pathways including nuclear factor kappa B (NF-κB), signal transducers and activator of transcription 3 (STAT3), epidermal growth factor receptor (EGFR) and mammalian target of rapamycin (m-TOR), which have great relevance during cancer initiation and progression. Furthermore, pharmacokinetic profile of honokiol has revealed a desirable spectrum of bioavailability after intravenous administration in animal models, thus making it a suitable agent for clinical trials. In this review, we discuss recent data describing the molecular targets of honokiol and its anti-cancer activities against various malignancies in pre-clinical models. Evaluation of honokiol in clinical trials will be the next step towards its possible human applications.


Wear of crosslinked polyethylene under different tribological conditions.
Ultra high molecular weight polyethylene (UHMWPE) wear debris has been shown to be a major cause of long term failure of total joint replacements. Recently, crosslinking has been extensively introduced to reduce the wear of UHMWPE. In this study the wear of non-crosslinked and crosslinked UHMWPE were compared under a range of conditions. The materials examined were UHMWPE GUR 1050, non-crosslinked, moderately crosslinked--5MRad, and highly crosslinked--10MRad. The wear was examined on a multidirectional pin on plate rig. The effect of counterface roughness on wear under different kinematics was examined. The results from the different counterface conditions showed that highly crosslinked UHMWPE had significantly lower wear against both smooth and scratched counterfaces. However the reduction in wear for crosslinked polyethylene was less for scratched counterfaces. The second part of the study showed that all the UHMWPE's produced lower wear rates under lower multidirectionality because of reduced cross shear frictional forces and work. These findings are relevant to the consideration of the use of crosslinked polyethylene in the knee, where the kinematics have lower levels of cross shear and in the hip and knee against roughened metallic counterfaces.


Evidence for a direct renal stimulating effect of prostaglandin E2 on renin release in patients with congestive heart failure.
The reduced responsiveness of the renin-angiotensin system to hemodynamic changes in patients with congestive heart failure (CHF) could be due to a defect of the juxtaglomerular apparatus. To test this hypothesis, the responses to viprostol, an analog of prostaglandin E2 (PGE2) that is known to stimulate both the macula densa and the juxtaglomerular cells, and to nitroprusside were compared in patients with CHF. An average fall in mean arterial pressure (MAP) of 6 mm Hg with viprostol was associated with a fivefold increase in plasma renin activity (PRA) from 11.4 +/- 6.4 to 47.9 +/- 31.0 ng/ml/hr; in contrast PRA did not change with nitroprusside, despite a significant decrease in preload and an average decrease in MAP of 16 mm Hg. These data demonstrate that the renin-angiotensin system could be activated by PGE2 in patients with CHF, this activation is not related to the global hemodynamic changes induced by PGE2, and the previously reported unresponsiveness of the renin-angiotensin system in patients with CHF cannot be attributed to a defective response of the juxtaglomerular apparatus.


Proteomic approach to identify changes in protein expression modified by 17beta-oestradiol in bovine vascular smooth muscle cells.
The aim of the present study was to use proteomics to analyse modifications in the level of expression of different proteins in BVSMCs (bovine vascular smooth muscle cells) incubated in the absence and presence of 17beta-oestradiol. By using two-dimensional electrophoresis with a pH range of 4-7, we identified several areas on the gels in which the level of expression of proteins were different between control BVSMCs and cells incubated for 24 h with 17beta-oestradiol. Changes in several isoforms of alpha-enolase, HSP60 (heat-shock protein 60), vimentin and PDI (protein disulphide-isomerase) were observed in BVSMCs. The expression of alpha-enolase isoform 1 was enhanced after 17beta-oestradiol treatment. The expression of HSP60 isoform 3, vimentin isoforms 2 and 3 and caldesmon was reduced by 17beta-oestradiol. Finally, the expression of PDI isoforms was reduced by 17beta-oestradiol. In summary, 17beta-oestradiol modified the expression of isoforms of proteins associated with smooth muscle cell proliferation (alpha-enolase, vimentin and HSP-60), cell contraction (vimentin and caldesmon) and cell redox modulation (PDI). These findings confirm that 17beta-oestradiol may modulate a wide range of signalling pathways in vascular smooth muscle cells.


A Bayesian semiparametric survival model with longitudinal markers.
We consider inference for data from a clinical trial of treatments for metastatic prostate cancer. Patients joined the trial with diverse prior treatment histories. The resulting heterogeneous patient population gives rise to challenging statistical inference problems when trying to predict time to progression on different treatment arms. Inference is further complicated by the need to include a longitudinal marker as a covariate. To address these challenges, we develop a semiparametric model for joint inference of longitudinal data and an event time. The proposed approach includes the possibility of cure for some patients. The event time distribution is based on a nonparametric Pólya tree prior. For the longitudinal data we assume a mixed effects model. Incorporating a regression on covariates in a nonparametric event time model in general, and for a Pólya tree model in particular, is a challenging problem. We exploit the fact that the covariate itself is a random variable. We achieve an implementation of the desired regression by factoring the joint model for the event time and the longitudinal outcome into a marginal model for the event time and a regression of the longitudinal outcomes on the event time, i.e., we implicitly model the desired regression by modeling the reverse conditional distribution.


Application of x-ray microanalysis in reproductive physiology.
Sperm, testis, prostate, epididymis and uterus have all beeen examined by X-ray microanalysis in the electron microscope. Specimen preparation has included air drying of whole cells, fixation, histochemical treatment, cryoultramicrotomy and freeze substitution of soft tissues, and micropuncture and pipetting of microdroplets from tissue fluids. Early analyses involved the study of thick samples using the electron probe microanalyser (EPMA) with wavelength dispersive spectrometry (WDS). More recently energy dispersive spectrometers (EDS) have been coupled to EMMA, TEM, SEM and STEM instruments to study these tissues. Although spatial resolution and sensitivity of analysis have greatly improved recently, specimen preparation remains a major limitation to the successful analysis of physiological levels of elements in reproductive tissues. A review of comparative methods of analysis and specimen preparation procedures is given for tissues of male and female species.


Metabolite Shifts Induced by Marathon Race Competition Differ between Athletes Based on Level of Fitness and Performance: A Substudy of the Enzy-MagIC Study.
This study compared metabolite shifts induced by training for, participation in, and recovery from a marathon race competition among athletes divided into three groups based on fitness (relative maximum oxygen uptake (VO2max)) and performance levels (net running time). Plasma samples from 76 male runners participating in the Munich Marathon were analyzed for metabolite shifts using a targeted metabolomics panel. For the entire cohort of runners, pronounced increases were measured immediately after the race for plasma concentrations of acylcarnitines (AC), the ratio (palmitoylcarnitine + stearoylcarnitine)/free carnitine that is used as a proxy for the activity of the mitochondrial enzyme carnitine palmitoyltransferase, and arginine-related metabolites, with decreases in most amino acids (AA) and phospholipids. Plasma levels of AA and phospholipids were strongly increased 24 and 72 h post-race. Post-race plasma concentrations of AC and arginine-related metabolites were higher in the low compared to top performers, indicating an accumulation of fatty acids and a reliance on protein catabolism to provide energy after the marathon event. This study showed that marathon race competition is associated with an extensive and prolonged perturbation in plasma metabolite concentrations with a strong AC signature that is greater in the slower, less aerobically fit runners. Furthermore, changes in the arginine-related metabolites were observed.


Targeting kidney mesangium by nanoparticles of defined size.
Nanoparticles are being investigated for numerous medical applications and are showing potential as an emerging class of carriers for drug delivery. Investigations on how the physicochemical properties (e.g., size, surface charge, shape, and density of targeting ligands) of nanoparticles enable their ability to overcome biological barriers and reach designated cellular destinations in sufficient amounts to elicit biological efficacy are of interest. Despite proven success in nanoparticle accumulation at cellular locations and occurrence of downstream therapeutic effects (e.g., target gene inhibition) in a selected few organs such as tumor and liver, reports on effective delivery of engineered nanoparticles to other organs still remain scarce. Here, we show that nanoparticles of ~75 ± 25-nm diameters target the mesangium of the kidney. These data show the effects of particle diameter on targeting the mesangium of the kidney. Because many diseases originate from this area of the kidney, our findings establish design criteria for constructing nanoparticle-based therapeutics for targeting diseases that involve the mesangium of the kidney.


Phase II study of radiation therapy combined with weekly nedaplatin in locally advanced uterine cervical carcinoma (LAUCC): Kitasato Gynecologic Radiation Oncology Group (KGROG 0501)--initial analysis.
Locally advanced uterine cervical carcinoma (LAUCC) treated with chemoradiotherapy is considered to be the standard treatment regimen. However, no evidence of its efficacy and safety has been obtained from the Japanese population. Furthermore, the total dose of Japanese radiation therapy protocol is less than that of the USA which indicated that chemoradiotherapy for LAUCC is better than radiation therapy alone by phase III clinical trials. Thus, the current phase II study was designed to evaluate chemoradiotherapy with a lower radiation dose for LAUCC using weekly nedaplatin effectively and safely in the Japanese population. Nedaplatin is a platinum drug and no hydration is required to infuse patients because it is less toxic on renal function. If this phase II trial is successful, chemoradiotherapy for LAUCC in out-patient clinics could be possible. Patients registered in the current study were found to have LAUCC based on the following criteria i) pathologically proven squamous cell carcinoma or adenocarcinoma, ii) FIGO clinical Stage Ib, IIa, IIb with bulky tumor (diameter > 40 mm assessed by pelvic magnetic resonance imaging) or pelvic lymph node swelling (diameter > 10 mm assessed by pelvic computed tomography); iii) FIGO clinical Stage IIIa, IIIb and IVa with no paraaortic lymph node swelling (diameter > 10 mm) observed by abdominal computed tomography; iv) age: 20-75 years; v) performance status: 0-2. The treatment protocol was as follows: Radiation therapy in a combination of external beam radiation therapy (total dose: 50 Gy-52 Gy/25-27 fractions with central shielding after 30-32 Gy) with high-dose rate intracavitary irradiation (24-30 Gy/4-6 fractions to point A). Chemotherapy applied in the current study was weekly nedaplatin infused intravenously (30 mg/mm2/time, once a week, total 150 mg/mm2/5 weeks). Sample size in the current study was 45 LAUCC patients recruited for three years at a single institution. This protocol was permitted by the ethics committee of Kitasato University Hospital. Ten patients were registered in this study between June 2005 and March 2006. The median age was 57.5 years (range 36-73). PS0 was five and PS1 was five. As for clinical stage, nine were IIIb and only one was IIb. Nine patients were proven to have squamous cell carcinoma and one adenocarcinoma. The median maximum tumor diameter was 62.5 mm (range 30-100 mm). As for initial response, eight had CR and two had PR (100% response rate). As for hematological acute morbidity, three were grade 2, six were grade 3, and one was grade 4. This initial analysis of the phase II study confirmed that concurrent chemoradiotherapy using nedaplatin is safe and efficacious, thus we decided to undergo further studies.


[Spatial contrast sensitivity in the differential diagnosis of optic neuritis].
Contrast sensitivity was examined in patients with optic neurites of different etiology. Achromatic and chromatic (red-black, green-black, and blue-black) sinusoidal patterns were presented in succession against the black background at a frequency of 1-22 cycles/degree on the monitor of an IBM computer. Contrast sensitivity was found altered during exacerbation of optic neuritis on both involved and intact eyes, this indicating a possible involvement of the chiasmal region. The authors discuss a new approach to investigation of the mechanisms of impairment of the optic nerve in optic neuritis in the presence of disseminated sclerosis and neuritis of obscure etiology.


Sleep patterns according to genetically determined ethnicity in the population of São Paulo, Brazil.
Sleep is a behavior expressed differently for each individual. However, studies have shown that some ethnic groups express common sleep patterns, which can be observed in different ethnic groups. Previous studies have shown the existence of sleep disparities in populations of different ethnicities. Most of these studies have considered self-reported ethnicity and assessed sleep subjectively. Therefore, the aim of this study was to evaluate sleep disparities in different ethnic groups based on an analysis of genetic ancestry and the use of objective sleep evaluation. To do this, we used data from the São Paulo Epidemiologic Sleep Study (EPISONO), which was undertaken in Brazil, a country that is known for its ethnic/racial diversity. All individuals completed a series of questionnaires, underwent full polysomnography and had their blood collected for DNA extraction. After genotyping and identifying samples with high-quality DNA suitable for genetic analysis, 31 ancestry-informative markers (AIMs) were selected. These markers exhibited substantial allelic frequency differences, enabling the characterization of the three primary founding populations of modern Brazil - Europeans, West-Africans, and Native Americans. Through this analysis, the genetic contribution of each of these ancestral groups was identified in respect of each participant. Based on this, a latent class cluster analysis (LCCA) was performed to define the three clusters that best classified the sample according to ethnic group: African (n = 255), Caucasian (n = 668) and Native American (n = 83). Applying the adjusted model for the confounding variables (age, socio-economic class and sex), statistically significant differences in sleep variables between ethnicities were found. Africans had higher sleep latency compared to the other groups (β = 4.46, CI = 1.18 to 7.74 and β = 7.83, CI = 3.50 to 12.15), while Caucasians had longer total sleep time (β = -16.47, CI = -29.94 to -2.99) and better sleep efficiency (β = -2.19, CI = -4.35 to -0.02) compared to Africans. Regarding the respiratory arousals index (β = -1.11, IC = -2.07 to -0.16) and periodic leg movements index (β = -7.48, CI = -12.08 to -2.88), both were higher among Caucasians compared to Africans. We were able to conclude that genetic ancestry might modulate sleep structure and the occurrence of sleep disorders.


microRNA profiling in the Weddell seal suggests novel regulatory mechanisms contributing to diving adaptation.
The Weddell Seal (Leptonychotes weddelli) represents a remarkable example of adaptation to diving among marine mammals. This species is capable of diving > 900 m deep and remaining underwater for more than 60 min. A number of key physiological specializations have been identified, including the low levels of aerobic, lipid-based metabolism under hypoxia, significant increase in oxygen storage in blood and muscle; high blood volume and extreme cardiovascular control. These adaptations have been linked to increased abundance of key proteins, suggesting an important, yet still understudied role for gene reprogramming. In this study, we investigate the possibility that post-transcriptional gene regulation by microRNAs (miRNAs) has contributed to the adaptive evolution of diving capacities in the Weddell Seal. Using small RNA data across 4 tissues (brain, heart, muscle and plasma), in 3 biological replicates, we generate the first miRNA annotation in this species, consisting of 559 high confidence, manually curated miRNA loci. Evolutionary analyses of miRNA gain and loss highlight a high number of Weddell seal specific miRNAs. Four hundred sixteen miRNAs were differentially expressed (DE) among tissues, whereas 80 miRNAs were differentially expressed (DE) across all tissues between pups and adults and age differences for specific tissues were detected in 188 miRNAs. mRNA targets of these altered miRNAs identify possible protective mechanisms in individual tissues, particularly relevant to hypoxia tolerance, anti-apoptotic pathways, and nitric oxide signal transduction. Novel, lineage-specific miRNAs associated with developmental changes target genes with roles in angiogenesis and vasoregulatory signaling. Altogether, we provide an overview of miRNA composition and evolution in the Weddell seal, and the first insights into their possible role in the specialization to diving.


Two new neurophysiological indices of cocaine craving: evoked brain potentials and cue modulated startle reflex.
Craving for cocaine is one of the hallmarks of cocaine dependence. One of the problems with craving is its measurement. Traditional psychophysiological indices such as skin conductance and heart rate have yielded contradictory results. These measures of craving were found to correlate only moderately with self-reported craving. In the present study, event-related brain potentials (ERPs) and the cue modulated startle response (CMSR) are evaluated as indices for cocaine craving. Twenty-one abstinent cocaine-dependent subjects were divided into high and low cravers group based on the median split of self-reported craving scores. ERPs and CMSR were measured when subjects watched neutral, pleasant, unpleasant and cocaine-related pictures. Overall, it was found that cocaine-dependent subjects showed augmented slow-positive waves (SPWs) of the ERP on the cocaine pictures compared to neutral pictures. Only high cravers showed larger SPWs on the cocaine cues, suggesting an association between cue-elicited SPWs and self-reported cocaine craving. By contrast to the ERP measures, CMSR did not differentiate between cocaine pictures and neutral pictures. In addition, no differences between the low- and high cravers on the CMSR measure were found. The present results show that the evoked-potentials paradigm provides promising results to index cue-elicited craving. The use of startle modulation deserves further investigation.


Lyophilization stabilizes clinical-stage core-crosslinked polymeric micelles to overcome cold chain supply challenges.
CriPec technology enables the generation of drug-entrapped biodegradable core-crosslinked polymeric micelles (CCPM) with high drug loading capacity, tailorable size, and drug release kinetics. Docetaxel (DTX)-entrapped CCPM, also referred to as CPC634, have demonstrated favorable pharmacokinetics, tolerability, and enhanced tumor uptake in patients. Clinical efficacy evaluation is ongoing. CPC634 is currently stored (shelf life > 5 years) and shipped as a frozen aqueous dispersion at temperatures below -60°C, in order to prevent premature release of DTX and hydrolysis of the core-crosslinks. Consequently, like other aqueous nanomedicine formulations, CPC634 relies on cold chain supply, which is unfavorable for commercialization. Lyophilization can help to bypass this issue. Freeze-drying methodology for CCPM was developed by employing CPC634 as a model formulation, and sucrose and trehalose as cryoprotectants. We studied the residual moisture content and reconstitution behavior of the CPC634 freeze-dried cake, as well as the size, polydispersity index, morphology, drug retention, and release kinetics of reconstituted CPC634. Subsequently, the freeze-drying methodology was validated in an industrial setting, yielding a CPC634 freeze-dried cake with a moisture content of less than 0.1 wt%. It was found that trehalose-cryoprotected CPC634 could be rapidly reconstituted in less than 5 min at room temperature. Critical quality attributes such as size, morphology, drug retention, and release kinetics of trehalose-cryoprotected freeze-dried CPC634 upon reconstitution were identical to those of non-freeze-dried CPC634. Our findings provide proof-of-concept for the lyophilization of drug-containing CCPM and our methodology is readily translatable to large-scale manufacturing for future commercialization.


Cloning and expression analysis of a new member of the cytochrome P450, CYP2A15 from the Chinese hamster, encoding testosterone 7alpha-hydroxylase.
We cloned a new cytochrome P450 cDNA encoding testosterone 7alpha-hydroxylase in the Chinese hamster, designated CYP2A15 which shares significant amino acid sequence homology with members of the CYP2A subfamily. The CYP2A15 cDNA was isolated by screening a liver cDNA library and the sequence contains an open reading frame of 1482 nucleotides encoding a polypeptide of 493 amino acids with a calculated molecular mass of 56,295 Da. This is flanked by a 5'-untranslated region of 2 bp and a 3' untranslated region of 191 bp including the poly(A) tail. We determined the catalytic activity of CYP2A15 using microsomes obtained by transient expression of its cDNA in transfected COS-7 cells. The heterologously expressed CYP2A15 was found to hydroxylate testosterone at position 7alpha in a reconstituted system. RT-PCR experiments revealed that the mRNA of CYP2A15 was expressed in liver, but not detected in kidney, lung, or small intestine. The expression of CYP2A15 mRNA was slightly induced by treatment with either rifampicin or 3-methylcholanthrene.


Situating the Continuum of Overdose Risk in the Social Determinants of Health: A New Conceptual Framework.
Policy Points This article reconceptualizes our understanding of the opioid epidemic and proposes six strategies that address the epidemic's social roots. In order to successfully reduce drug-related mortality over the long term, policymakers and public health leaders should develop partnerships with people who use drugs, incorporate harm reduction interventions, and reverse decades of drug criminalization policies. Drug overdose is the leading cause of injury-related death in the United States. Synthetic opioids, predominantly illicit fentanyl and its analogs, surpassed prescription opioids and heroin in associated mortality rates in 2016. Unfortunately, interventions fail to fully address the current wave of the opioid epidemic and often omit the voices of people with lived experiences regarding drug use. Every overdose death is a culmination of a long series of policy failures and lost opportunities for harm reduction. In this article, we conducted a scoping review of the opioid literature to propose a novel framework designed to foreground social determinants more directly into our understanding of this national emergency. The "continuum of overdose risk" framework is our synthesis of the global evidence base and is grounded in contemporary theories, models, and policies that have been successfully applied both domestically and internationally. De-escalating overdose risk in the long term will require scaling up innovative and comprehensive solutions that have been designed through partnerships with people who use drugs and are rooted in harm reduction. Without recognizing the full drug-use continuum and the role of social determinants, the current responses to drug overdose will continue to aggravate the problem they are trying to solve.


Modulation of chewing behavior and reticular pH in nonlactating cows challenged with concentrate-rich diets supplemented with phytogenic compounds and autolyzed yeast.
Feeding of concentrate-rich diets impairs chewing behavior and leads to rumen acidosis in cattle. Because of their modulatory effects on ruminal fermentation, phytogenic compounds (PHY) and autolyzed yeast derivatives (AY) may alleviate the negative consequences of high-concentrate diets. Therefore, this research investigated if chewing behavior and the reticular pH dynamics are modulated by AY and PHY supplementation during repeated concentrate-rich challenges used to simulate intermittent rumen acidotic insults. Eight rumen-cannulated, dry, and nonpregnant Holstein cows were assigned to an incomplete double 4 × 3 Latin square design with 3 treatments and 4 experimental runs (n = 8/treatment). Cows were fed concentrates either not supplemented (CON) or supplemented with PHY or AY. Initially, cows were fed a pure forage diet (FD) and switched to a 65% concentrate diet on DM basis for 1 (CONC 1) and 2 (CONC 2) wk. Between CONC 1 and CONC 2, the cows were fed the FD for 1 wk. Chewing activity was measured using noseband sensors and reticular pH by wireless pH sensors. Data showed that cows spent less time ruminating in CONC 1 than in CONC 2. In agreement, reticular pH drop was more pronounced during CONC 1 than during CONC 2. Cows fed with PHY spent 4 h less with reticular pH <6.0 during CONC 1 and 3 h less with pH <6.0 h in CONC 2 as compared with CON cows. Similarly, PHY supplementation extended rumination time with 88 min/d compared with CON cows during CONC 1. The AY supplementation increased DMI by 20% resulting in a longer eating time compared with CON diet during CONC 1. Enhancement of ruminating by PHY and eating time by AY supplementation resulted in longer total chewing time for PHY (474 min/d) and AY (466 min/d) as compared with CON (356 min/d) in CONC 1. In conclusion, cows experiencing 2 intermittent concentrate-rich challenges increased their ruminating behavior during the second challenge, and this effect was associated with higher reticular pH readings. The PHY supplementation enhanced rumination as well as reticular pH during CONC 1. However, the enhanced pH of cows fed with PHY during CONC 2 was not related to greater rumination, suggesting that influencing factors beyond rumination seemed to play a role in modulating reticular pH in PHY cows during CONC 2. The AY supplementation increased DMI without depressing rumination or reticular pH. Effects of both feed additives were more pronounced during CONC 1 challenge when reticular pH was lower.