A unit's experience with hybrid NICU design: description of care model and implications for patients, families, and professionals.
As the first extra-uterine setting for hospitalized infants, the neonatal intensive care unit (NICU) environment can make a lasting impact on their long-term neurodevelopment. This impact is likely mediated through both specific characteristics of the physical design of the care environment, as well as the experiences that occur within this environment. Recent studies document many established benefits of single-family rooms (SFRs). However, there is concern that infants who spend a prolonged time in SFRs without their parents being intimately involved in their care have reduced opportunities for meaningful experiences, with possible adverse consequences. The purpose of this report is to share an example of an application of the family-centered developmental care model through a hybrid NICU design, inclusive of both SFRs and semi-private bays. In this paper, we empirically describe the physical and operational considerations of a hybrid model, outline the strengths and challenges of this approach, and discuss implications for patients, families, and professionals.


[Exchange of putrescine and potassium between cells and media as a factor in the adaptation of Escherichia coli to hyperosmotic shock].
Putrescine/potassium exchange in response to hyperosmotic stress was studied. The addition of 0.3 M NaCl or 0.44 M sucrose to an exponentially growing E. coli culture induced potassium uptake and putrescine release from the cell. Potassium added to an osmotically stressed potassium-deficient culture was readily absorbed by cells; this was accompanied by the loss of intracellular putrescine, both free and bound. Since DNA is the main binding site of putrescine, the loss of bound putrescine caused a relaxation of DNA supercoiling. The increase in the intracellular content of potassium not only restored but also enhanced DNA supercoiling as compared to the initial level. In vitro experiments showed the degree of plasmid DNA supercoiling to rise drastically at potassium concentrations of 300-500 mM, while different putrescine concentrations affected this parameter differently. Thus, the physiological concentrations of putrescine (below 1 mM) greatly augmented DNA supercoiling, whereas higher concentrations (5-10 mM) exerted a relaxing effect. A change in DNA supercoiling in vivo in response to osmotic stress is the result of competition between biogenic and abiogenic cations for the sites of binding to polyanionic DNA structures. A change in DNA topology serves as the regulatory factor controlling the expression of genes responsible for cell adaptation to osmotic stress.


From birth till death: neurogenesis, cell cycle, and neurodegeneration.
Neurogenesis in the embryo involves many signaling pathways and transcriptional programs and an elaborate orchestration of cell cycle exit in differentiating precursors. However, while the neurons differentiate into a plethora of different subtypes and different identities, they also presume a highly polar structure with a particular morphology of the cytoskeleton, thereby making it almost impossible for any differentiated cell to re-enter the cell cycle. It has been observed that dysregulated or forced cell cycle reentry is closely linked to neurodegeneration and apoptosis in neurons, most likely through changes in the neurocytoskeleton. However, proliferative cells still exist within the nervous system, and adult neural stem cells (NSCs) have been identified in the Central Nervous System (CNS) in the past decade, raising a great stir in the neuroscience community. NSCs present a new therapeutic potential, and much effort has since gone into understanding the molecular mechanisms driving differentiation of specific neuronal lineages, such as dopaminergic neurons, for use in regenerative medicine, either through transplanted NSCs or manipulation of existing ones. Nevertheless, differentiation and proliferation are two sides of the same coin, just like tumorigenesis and degeneration. Tumor formation may be regarded as a de-differentiation of tissues, where cell cycle mechanisms are reactivated in differentiated cell types. It is thus important to understand the molecular mechanisms underlying various brain tumors in this perspective. The recent Cancer Stem Cell (CSC) hypothesis also suggests the presence of Brain Tumor Initiating Cells (BTICs) within a tumor population, although the exact origin of these rare and mostly elusive BTICs are yet to be identified. This review attempts to investigate the correlation of neural stem cells/precursors, mature neurons, BTICs and brain tumors with respect to cell cycle regulation and the impact of cell cycle in neurodegeneration.


The Effectiveness of Caudal Block with Low Doses of Dexmedetomidine and Pethidine in Transrectal Prostate Biopsy: Preliminary Results.
To evaluate the effectiveness of caudal block (CB) using dexmedetomidine and pethidine instead of local anesthesia (LA) for prostate needle biopsy and the effect of CB on urinary retention. A transrectal ultrasound-guided prostate needle biopsy (TRUS-Bx) was performed on 68 patients with a mean age of 65 ± 2.18 years. CB with a combination of dexmedetomidine and pethidine without LA was administered to the patients. The pain levels of the patients were determined using numeric rating scale (NRS) scores to evaluate the effectiveness of CB. Preoperative and postoperative postvoid residual urine volumes (PRUV) were also calculated. The CB success rate was 93.15%. The NRS scores were 0.79 ± 0.19 and 0.89 ± 0.22 during probe entry and manipulation and biopsy, respectively, without any significant differences between them (p = 0.382). The mean PRUVs before and after biopsy did not differ significantly (41 ± 15.6 vs. 71.93 ± 22.3, p = 0.379). The degree of sedation, as assessed using the Ramsay scale, was 2 or 3 in all patients. The combination of dexmedetomidine and pethidine for CB in TRUS-Bx provided quality analgesia for the patient and prevented the development of postoperative urinary retention.


Indoor air pollution from solid fuels and risk of hypopharyngeal/laryngeal and lung cancers: a multicentric case-control study from India.
A recent monograph by the International Agency for Research on Cancer (IARC) has identified indoor air pollution from coal usage as a known human carcinogen, while that from biomass as a probable human carcinogen. Although as much as 74% of the Indian population relies on solid fuels for cooking, very little information is available on cancer risk associated with these fuels in India. Using data from a multicentric case-control study of 799 lung and 1062 hypopharyngeal/laryngeal cancer cases, and 718 controls, we investigated indoor air pollution from various solid fuels as risk factors for these cancers in India. Compared with never users, individuals who always used coal had an increased risk of lung cancer [odds ratio (OR) 3.76, 95% confidence interval (CI) 1.64-8.63]. Long duration of coal usage (>50 years) was a risk factor for hypopharyngeal (OR 3.47, CI 0.95-12.69) and laryngeal (OR 3.65, CI 1.11-11.93) cancers. An increased risk of hypopharyngeal cancer was observed among lifelong users of wood (OR 1.62, CI 1.14-2.32), however this was less apparent among never-smokers. Increasing level of smokiness inside the home was associated with an increasing risk of hypopharyngeal and lung cancer (P(trend) < 0.05). This study showed differential risks associated with indoor air pollution from wood and coal burning, and provides novel evidence on cancer risks associated with solid fuel usage in India. Our findings suggest that reducing indoor air pollution from solid fuels may contribute to prevention of these cancers in India, in addition to tobacco and alcohol control programs.


Adventitial delivery of miR-145 to treat intimal hyperplasia post vascular injuries through injectable and in-situ self-assembling peptide hydrogels.
Intimal hyperplasia is a common lesion that can be observed in diverse vascular diseases. Drug-eluting stents and drug-coated balloons, which can release anti-proliferative agents to inhibit smooth muscle cell (SMC) proliferation, are developed to prevent intimal hyperplasia. However, these intervention devices still cannot achieve satisfactory clinical outcomes. In contrast to endovascular drug delivery, vascular adventitial drug delivery is a new strategy. To develop a vascular adventitial drug delivery system to treat intimal hyperplasia post vascular injuries, we loaded miR-145-5p-agomir (miR-145) into an injectable and in-situ self-assembling RAD peptide hydrogel. In vitro data showed that the miR-145 could be well incorporated into the RAD peptide hydrogels and released in a slow and controlled manner. The released miR-145 could transfect SMCs successfully, and the transfected SMCs exhibited a reduced migration capacity and higher expressions of SMC contractile biomarkers as compared to the non-transfected SMCs. In vivo data showed that the retention of the miR-145 was greatly elongated by the RAD peptide hydrogels. In addition, the application of the miR-145-loaded RAD peptide hydrogels surrounding injured arteries decreased the proliferative SMCs, promoted the regeneration of endothelium, reduced the macrophage infiltration, inhibited the neointimal formation and prevented adverse ECM remodeling via downregulation of KLF4 expression. The RAD peptide hydrogels loaded with miR-145 can successfully inhibit intimal hyperplasia after vascular injuries and thus hold great potential as an innovative extravascular drug delivery approach to treat vascular diseases. STATEMENT OF SIGNIFICANCE: Intimal hyperplasia is a common lesion that can be observed in diverse vascular diseases. Drug-eluting stents and drug-coated balloons, which can release anti-proliferative agents to inhibit smooth muscle cell (SMC) proliferation, are developed to prevent intimal hyperplasia. However, these intervention devices still cannot achieve satisfactory clinical outcomes. In contrast to endovascular drug delivery, vascular adventitial drug delivery is a new strategy. Our work here demonstrates that the RAD peptide hydrogels loaded with miR-145-5p-agomir (miR-145) can successfully reverse intimal hyperplasia after vascular injuries and thus hold great potential as an innovative vascular adventitial drug delivery approach to treat vascular diseases. Our work proposes a possible paradigm shift from endovascular drug delivery to extravascular drug delivery for vascular disorder treatment.


Highly efficient osteogenic differentiation of human mesenchymal stem cells by eradication of STAT3 signaling.
Human bone marrow-derived mesenchymal stem cells (hMSCs) are promising candidates for cellular therapy owing to their multipotency to differentiate into several cell lineages. Elucidating the signaling events involved in the response of hMSCs to diverse stimulants affecting their differentiation may considerably promote their clinical use. In this study, we attempted to illuminate the molecular signaling networks involved in bone morphogenetic protein (BMP)-stimulated hMSC osteogenic differentiation. We demonstrate that eradication of signal transducers and activators of transcription (STAT) signaling considerably enhances BMP-induced osteogenic differentiation of hMSCs. BMP 2 and 4 are shown for the first time to activate the Janus-activated kinase (JAK)-STAT pathway in hMSC. Specifically, we reveal that JAK2 mediates STAT3 tyrosine phosphorylation in response to the two BMPs, whereas BMP2- and BMP4-induced STAT3 serine phosphorylation involves two divergent cascades, namely the mTOR and ERK1/2 cascades, respectively. Furthermore, elimination of the STAT3 signaling pathway by the inhibitors, AG490 or STAT3 siRNA, results in the acceleration and augmentation of BMPs-induced osteogenic differentiation, thus proposing a role for JAK-STAT signaling as a negative regulator of this process in MSCs. We believe that the findings presented in this study may be the basis for the development of a useful strategy to better control stem cell fate through intervention in molecular signaling networks. Hopefully, such a strategy will include the development of more efficient and controllable protocols for hMSC differentiation and facilitate their use in regenerative medicine.


Effect of thyroid status on insulin action in rat adipocytes and skeletal muscle.
Isolated adipocytes and soleus muscles prepared from mature rats, rendered hypothyroid by a low iodine diet and propylthiouracil, markedly resisted the ability of insulin to increase glucose utilization. In adipocytes, the sum of basal d-(1-(14)C)-glucose conversion to CO(2), glyceride-glycerol, and fatty acid was unaltered by hypothyroidism, although conversion to fatty acid was decreased. The response of each of these metabolic pathways to insulin at all concentrations tested was greatly diminished in hypothyroid rat adipocytes. 3-O-Methylglucose transport rates in the presence of insulin were not significantly different in adipocytes from hypothyroid as compared with euthyroid rats, although basal transport rates were significantly higher in the hypothyroid state. Lipolysis and cyclic AMP accumulation in adipocytes from hypothyroid rats in response to theophylline were markedly diminished compared with euthyroid controls, but insulin was about as effective in inhibiting lipolysis in these cells as in those derived from euthyroid animals. The binding of (125)I-insulin to adipocytes at several hormone concentrations was also shown to be unaffected by hypothyroidism. In soleus muscle, basal glucose conversion to H(2)O and glycogen was unaltered in the hypothyroid state, whereas insulin action on these pathways was markedly inhibited. The decrease in muscle insulin responsiveness was less marked than that observed in adipocytes. Uptake of either 2-deoxyglucose or l-arabinose in the presence or absence of insulin was similar in soleus muscles derived from euthryoid vs. hypothyroid rats. Similarly, insulin action on the conversion of soleus muscle glycogen synthase D to the I form in the absence of glucose was unaltered by hypothyroidism. We conclude that (a) hypothyroidism in mature rats leads to a marked decrease in the responsiveness of glucose metabolism in adipocytes and skeletal muscle to insulin; (b) no detectable impairment of the membrane insulin effector systems that mediate the regulation of adipocyte hexose transport and glycogen synthase is caused by hypothyroidism in this animal model; and (c) the cellular defect that leads to apparent insulin resistance of adipocyte and soleus muscle glucose utilization resides at the level of one or more intracellular enzymes involved in glucose catabolism.


More species of the Agononida incerta complex revealed by molecules and morphology (Crustacea: Decapoda: Anomura: Munididae).
Squat lobsters from Madagascar, Vanuatu, Papua New Guinea, Fiji, eastern Australia and French Polynesia belonging to the Agononida incerta (Henderson, 1888) species complex are described as four new species: A. madagascerta, A. polycerta, A. tasmancerta and A. vanuacerta. This brings to ten the number of species in this complex. All species are morphologically distinguishable only on the basis of the shape of the anterolateral margin of the telson and setation of the dactyli of pereopods 2-4. The morphological delineation of nine of the species and their taxonomic status are robustly supported by phylogenetic analysis of the partial 16S rDNA gene and the partial mitochondrial cytochrome oxidase subunit 1 genes, and in some cases by colour. A phylogenetic analysis of the nine species for which molecular data are available grouped the species in two clades, one of four species with facial spines on the upper surface of pereopod 4 and the other of five species lacking facial spines.


Effect of electric field direction on neuronal activity: an ex-vivo study.
The effect of electrical stimulation on neurons depends on the spatiotemporal properties of the applied electric field as well as on the biophysical properties of the neural tissue, which includes geometric and electrical characteristics of the cells, and the neural circuit dynamics. In this work, we characterize the effect of electric field direction on neural response in cortical layers. This can, for instance, enable more efficient (e.g., with reduced currents) and/or more selective stimulation. We stimulated mice brain slices using a recently developed brain slice platform to study transcranial currents in an ex-vivo model, where electrodes are separated from the brain slice to inject electric fields at a distance. By rotating the electrode array with respect to the slice, we changed the direction of electric field with respect to the cortical column. Our results demonstrate that in somatosensory cortex, the maximum local field potential (LFP) response is attained when the electric field is oriented parallel to the cortical column. For the same field intensity, when the field is oriented perpendicular to the cortical column, the LFP response is absent. This confirms that electric field direction is an important quantity to determine the effect of neuronal stimulation.


Excitation of confined modes on particle arrays.
We describe both theoretically and experimentally the existence and excitation of confined modes in planar arrays of gold nanodisks. Ordered 2D lattices of monodispersive nanoparticles are manufactured, embedded in a silica matrix, and exposed to evanescent prism-coupling illumination, leading to dark features in the reflectivity, which signal the presence of confined modes guided along the arrays. We find remarkable agreement between theory and experiment in the frequency-momentum dispersion of the resonances. Direct excitation of these modes reveals long propagation distances and deep extinction features. This combined experimental and theoretical characterization of guided modes shows a good understanding of the optical response of metallic particles arrays, which can be beneficial in future designs of optical-signal and distant-sensing applications.


Molecular characterization of type-specific capsular polysaccharide biosynthesis genes of Streptococcus agalactiae type Ia.
The type-specific capsular polysaccharide (CP) of a group B streptococcus, Streptococcus agalactiae type Ia, is a high-molecular-weight polymer consisting of the pentasaccharide repeating unit 4)-[alpha-D-NeupNAc-(2-->3)-beta-D-Galp-(1-->4)-beta-D-GlcpNAc-(1- ->3 )]-beta-D-Galp-(1-->4)-beta-D-Glcp-(1. Here, cloning, sequencing, and transcription of the type Ia-specific capsular polysaccharide synthesis (cps) genes and functional analysis of these gene products are described. A 26-kb DNA fragment containing 18 complete open reading frames (ORFs) was cloned. These ORFs were designated cpsIaA to cpsIaL, neu (neuraminic acid synthesis gene) A to D, orf1 and ung (uracil DNA glycosylase). The cps gene products of S. agalactiae type Ia were homologous to proteins involved in CP synthesis of S. agalactiae type III and S. pneumoniae serotype 14. Unlike the cps gene cluster of S. pneumoniae serotype 14, transcription of this operon may start from cpsIaA, cpsIaE, and orf1 because putative promoter sequences were found in front of these genes. Northern hybridization, reverse transcription-PCR, and primer extension analyses supported this hypothesis. DNA sequence analysis showed that there were two transcriptional terminators in the 3' end of this operon (downstream of orf1 and ung). The functions of CpsIaE, CpsIaG, CpsIaI, and CpsIaJ were examined by glycosyltransferase assay by using the gene products expressed in Escherichia coli JM109 harboring plasmids containing various S. agalactiae type Ia cps gene fragments. Enzyme assays suggested that the gene products of cpsIaE, cpsIaG, cpsIaI, and cpsIaJ are putative glucosyltransferase, beta-1, 4-galactosyltransferase, beta-1,3-N-acetylglucosaminyltransferase, and beta-1,4-galactosyltransferase, respectively.


Primary amyloidosis with high grade transitional cell carcinoma of bladder: a rare case report.
Primary amyloidosis of bladder is a rare disease that closely resembles bladder cancer on clinical presentation with painless gross hematuria. Pathologically this is a totally benign non-neoplastic lesion and its association with urothelial carcinoma of the bladder is rare. We herein report a 64-year-old diabetic male who has been treated for primary amyloidosis of bladder for the last 26 years presented recently with high-grade solid urothelial cancer with osseous metaplasia and sarcomatoid change of bladder with area of amyloid deposition.


Leptin receptor neurons in the mouse hypothalamus are colocalized with the neuropeptide galanin and mediate anorexigenic leptin action.
Leptin acts centrally via leptin receptor (LepRb)-expressing neurons to regulate food intake, energy expenditure, and other physiological functions. LepRb neurons are found throughout the brain, and several distinct populations contribute to energy homeostasis control. However, the function of most LepRb populations remains unknown, and their contribution to regulate energy homeostasis has not been studied. Galanin has been hypothesized to interact with the leptin signaling system, but literature investigating colocalization of LepRb and galanin has been inconsistent, which is likely due to technical difficulties to visualize both. We used reporter mice with green fluorescent protein expression from the galanin locus to recapitulate the colocalization of galanin and leptin-induced p-STAT3 as a marker for LepRb expression. Here, we report the existence of two populations of galanin-expressing LepRb neurons (Gal-LepRb neurons): in the hypothalamus overspanning the perifornical area and adjacent dorsomedial and lateral hypothalamus [collectively named extended perifornical area (exPFA)] and in the brainstem (nucleus of the solitary tract). Surprisingly, despite the known orexigenic galanin action, leptin induces galanin mRNA expression and stimulates LepRb neurons in the exPFA, thus conflicting with the expected anorexigenic leptin action. However, we confirmed that intra-exPFA leptin injections were indeed sufficient to mediate anorexic responses. Interestingly, LepRb and galanin-expressing neurons are distinct from orexin or melanin-concentrating hormone (MCH)-expressing neurons, but exPFA galanin neurons colocalized with the anorexigenic neuropeptides neurotensin and cocaine- and amphetamine-regulated transcript (CART). Based on galanin's known inhibitory function, we speculate that in exPFA Gal-LepRb neurons galanin acts inhibitory rather than orexigenic.


Healing of External Inflammatory Root Resorptions and Periapical Lesions without Surgical Treatment in an Operated Oblique Facial Cleft Case.
This paper describes an operated oblique facial cleft case with external inflammatory root resorption (EIRR) of the permanent maxillary left incisors and canine in a 12-year old patient. Due to the facial oblique cleft, the plastic surgery department operated on the patient five times and placed her on fixed orthodontic therapy. EIRR treatment of the maxillary left incisors and canine was performed using long-term calcium hydroxide therapy. The permanent root canal fillings of the lateral incisor and canine were performed using conventional gutta percha fillings. Because no sufficient apical barrier stop of the central incisor occurred, it was filled with Mineral Trioxide Aggregate (MTA); the canine crown fracture was restored using a carbon-covered fiberglass post and a light-cured composite resin. Examination after 42 months revealed good esthetics and no periapical pathology.


[Role of carotid chemoreceptors in formation of adaptive reactions in animals].
After surgical denervation of sinocarotid reflexogenic zones and bilateral glomectomy in white laboratory rats oxygen consumption, rectal temperature, rate of cardial contractions and thermoregulatory activity of skeletal muscles display authentic increase. Glomectomy results in decreasing calorigecic effect of noradrenaline. Compensatory increase of thermoregulatory activity of sceletal muscles in response to beta-adrenogenic blocade with inderal in post-glomectomic animals is authentically less, than before inactivation of carotid receptors. In animals after carotid glomectomy resistance to acute hypoxia is clearly reduced. True reduction of number of erythrocytes, of hemoglobin concentration, of hematocrite parameter in post glomectic animals was found, which indicates anemisation phenomena. It was found that glomectomy after adaptation of animals in the mountains of Tien Shan at the height of 3200 m during 30 days didn't substantively change resistance to acute hypoxia. Resistance to acute hypoxia of animals living on mountains (susliks, marmots) is higher than of animals living on plains. Glomectomy performed on animals living on mountain resulted in an insignificant decrease in resistance to acute hypoxia. Resistance to acute hypoxia in postglomectic animals was found to be directly linked with absolute amount of hemoglobin concentration and erythrocyte number. In that way denervation of sinocarotid reflexogenic zones and bilateral glomectomy is an adequate method of comparative research of functions regulation mechanism during formation of adaptive responses in animals in dependence of various factors of external environment in norm, as well, as in pathology.


[Novel approaches for transurethral en-bloc resection of large bladder tumors].
to develop optimal techniques of en-bloc resection of large non-muscle invasive bladder tumors, determine the proper method of specimen extraction and assess the quality of specimens obtained by different techniques. A total of 12 patients with primary cT1 bladder cancer underwent transurethral en-bloc resection between January 2018 and March 2019 were enrolled into the study. Tumor size ranged from 3.5 cm to 6.2 cm. For removal and extraction of large bladder tumors using thulium fiber en-bloc laser three different techniques were developed: "swiss cheese technique", "crown and root technique" and "three steps technique" technique". The main pathologic criteria used for assessment of removal technique were tumor grade (G), depth of invasion (T), presence of carcinoma in situ (CIS), variant histology (VH), lymphovascular invasion (LVI), presence of detrusor muscle. Additional criteria were horizontal and vertical resection margin, subclassification of T1-stage and presence of focal necrosis in tumor. Among the techniques developed and tested, the best quality of specimens for morphological evaluation was obtained using the combined "crown and root technique". First step is electroresection of the exophytic part of the tumor into pieces, and the next step is en-bloc laser resection (using thulium fiber or holmium laser) of the tumor base. Overall, the quality of all specimens obtained using three techniques met the current requirements of pathologic study. En-bloc resection techniques of large bladder tumors allow obtaining specimen suitable for proper morphological evaluation and correct tumor staging. Further studies are required to evaluate the impact of these techniques on long-term results of treatment options.


Active disturbance rejection control of temperature for ultrastable optical cavities.
This paper describes the application of a novel active disturbance rejection control (ADRC) to the stabilization of the temperature of two ultra-stable Fabry-Perot cavities. The cavities are 10 cm long and entirely made of ultralow- expansion glass. The control is based on a linear extended state observer that estimates and compensates the disturbance in the system in real time. The resulting control is inherently robust and easy to tune. A digital implementation of ADRC gives a temperature instability of 200 μK at one day of integration time.


Processes in arithmetic strategy selection: a fMRI study.
This neuroimaging (functional magnetic resonance imaging) study investigated neural correlates of strategy selection. Young adults performed an arithmetic task in two different conditions. In both conditions, participants had to provide estimates of two-digit multiplication problems like 54 × 78. In the choice condition, participants had to select the better of two available rounding strategies, rounding-up (RU) strategy (i.e., doing 60 × 80 = 4,800) or rounding-down (RD) strategy (i.e., doing 50 × 70 = 3,500 to estimate product of 54 × 78). In the no-choice condition, participants did not have to select strategy on each problem but were told which strategy to use; they executed RU and RD strategies each on a series of problems. Participants also had a control task (i.e., providing correct products of multiplication problems like 40 × 50). Brain activations and performance were analyzed as a function of these conditions. Participants were able to frequently choose the better strategy in the choice condition; they were also slower when they executed the difficult RU than the easier RD. Neuroimaging data showed greater brain activations in right anterior cingulate cortex (ACC), dorso-lateral prefrontal cortex (DLPFC), and angular gyrus (ANG), when selecting (relative to executing) the better strategy on each problem. Moreover, RU was associated with more parietal cortex activation than RD. These results suggest an important role of fronto-parietal network in strategy selection and have important implications for our further understanding and modeling cognitive processes underlying strategy selection.


[Role of peritoneovenous shunt therapy in end-of-life care of refractory malignant ascites cases].
The short- and long-term outcomes of 34 patients with refractory malignant ascites who underwent peritoneovenous shunt (PVS) therapy were retrospectively reviewed. The primary disease was gastrointestinal cancer in 31 patients and gynecologic cancer in 3 patients. Regarding performance status, 21 patients had Eastern Cooperative Oncology Group Performance Status (PS) 2 and 13 patients were PS 3;thus, many were in a poor general condition. After treatment, abdominal distention disappeared in 79.4% of patients, and appetite improved in 60.9%. The median postoperative survival time was 38 days (range, 1-294 days), and 18 patients (52.9%) were discharged. Disseminated intravascular coagulation with clinical symptoms was observed in 3 patients (8.8%), and heart failure was observed in 7 patients (20.6%). PVS therapy was useful in improving the subjective symptoms of patients with refractory malignant ascites and in enabling them to receive care at home. However, serious postoperative complications are a concern, and appropriate preoperative evaluation is necessary.


Education in Australia.
School-based adoption of Multimedia: An Australian Perspective. This paper will look first at the work of Young Media Australia--a national community-based, information, research, training and advocacy organization working in the field of children, young people and mass media. The adoption rate of multi-media, including information technologies, in school systems across Australia will then be examined. Issues relating to the use of school-based multimedia, including the internet, will also be identified.


Cytokinesis in higher plants.
Cytokinesis partitions the cytoplasm between two or more nuclei. In higher plants, cytokinesis is initiated by cytoskeleton-assisted targeted delivery of membrane vesicles to the plane of cell division, followed by local membrane fusion to generate tubulo-vesicular networks. This initial phase of cytokinesis is essentially the same in diverse modes of plant cytokinesis whereas the subsequent transformation of the tubulo-vesicular networks into the partitioning membrane may be different between systems. This review focuses on membrane and cytoskeleton dynamics in cell plate formation and expansion during somatic cytokinesis.


Vascular endothelial function is improved after active mattress use.
Active mattresses are used to prevent, treat and relieve pressure ulcers (PU) by intermittent contact pressure/relief. However, no studies have directly assessed the vascular endothelial response to long-term active mattress use. This study investigated the hypothesis that eight weeks use of an active mattress would lead to improvements in vascular endothelial function in healthy participants. Physiological parameters of baseline skin temperature (BskT), resting blood flow (RBF) and endothelial function as measured using post-occlusive reactive hyperaemia (PORH), were assessed at baseline (week 0); following eight weeks of sleeping on an active mattress, and after an eight week washout period (at week 16). We recruited 10 healthy participants (four male, age 52.7±8.5 years, six female age 51.8±17.5 years). Following active mattress use RBF, PORH and BskT at the hallux pulp increased by 336%, 197% and 3.5ºC, respectively. Mean values increased from 24.3±38.3 perfusion units to 106.0±100.3 perfusion units (p=0.021) and from 13,456±10,225 to 40,252±23,995 perfusion units x seconds (p=0.003) and from 22.9±2.5ºC to 26.4±1.9ºC (p<0.001), respectively. Active mattress use for eight weeks leads to significant improvements in RBF, PORH, and BskT. These results suggest that active mattress use can improve endothelial function. Future research is required to explore the potential of active mattress use in the treatment and management of diseases and conditions that would benefit from an improved endothelial function.


Telotristat Ethyl: First Global Approval.
Telotristat ethyl (Xermelo™) is a peripheral tryptophan hydroxylase (TPH) inhibitor that was developed by Lexicon Pharmaceuticals, Inc. for the treatment of carcinoid syndrome. Many neuroendocrine tumours secrete serotonin (5-HT) into the blood stream, resulting in a number of symptoms, notably diarrhoea. Telotristat ethyl inhibits TPH, thereby reducing the production of 5-HT. In February 2017, telotristat ethyl was approved in the USA for the treatment of carcinoid syndrome diarrhoea in combination with somatostatin analog (SSA) therapy in adults inadequately controlled by SSA therapy. This article summarizes the milestones in the development of telotristat ethyl leading to this first global approval.


Syntheses, photophysical properties, and application of through-bond energy-transfer cassettes for biotechnology.
We have designed fluorescent "through-bond energy-transfer cassettes" that can harvest energy of a relatively short wavelength (e.g., 490 nm), and emit it at appreciably longer wavelengths without significant loss of intensity. Probes of this type could be particularly useful in biotechnology for multiplexing experiments in which several different outputs are to be observed from a single excitation source. Cassettes 1-4 were designed, prepared, and studied as model systems to achieve this end. They were synthesized through convergent routes that feature coupling of specially prepared fluorescein- and rhodamine-derived fragments. The four cassettes were shown to emit strongly, with highly efficient energy transfer. Their emission maxima cover a broad range of wavelengths (broader than the four dye cassettes currently used for most high-throughput DNA sequencing), and they exhibit faster energy-transfer rates than a similar through-space energy-transfer cassette. Specifically, energy-transfer rates in these cassettes is around 6-7 ps, in contrast to a similar through-space energy-transfer system shown to have a decay time of around 35 ps. Moreover, the cassettes are considerably more stable to photobleaching than fluorescein, even though they each contain fluorescein-derived donors. This was confirmed by bulk fluorescent measurements, and in single-molecule-detection studies. Modification of a commercial automated DNA-sequencing apparatus to detect the emissions of these four energy-transfer cassettes enabled single-color dye-primer sequencing.


Energy disclosure, market behavior, and the building data ecosystem.
Energy disclosure laws represent one of the most promising public policy tools to accelerate market transformation around building energy efficiency. For this type of information to have an impact on market behavior, it must be collected, analyzed, and disseminated to support the decision-making processes of each end user and influence both the producers and consumers of building performance data. This paper explores the significance of energy disclosure requirements and outlines a framework for utilizing these new sources of transparent, publicly available information. It presents the mechanisms by which information can alter market behavior in the commercial real estate sector and develops a wiring diagram for the flows of information through the building data ecosystem. It concludes with a discussion of the motivations, metrics, and constraints faced by the various stakeholders in the ecosystem and how these factors influence investment decision models.


Risk of intracranial haemorrhage in antidepressant users with concurrent use of non-steroidal anti-inflammatory drugs: nationwide propensity score matched study.
To define the risk of intracranial haemorrhage among patients treated with antidepressants and non-steroid anti-inflammatory drugs (NSAIDs), compared with the risk among those treated with antidepressants without NSAIDs. Retrospective nationwide propensity score matched cohort study. Korean nationwide health insurance database between 1 January 2009 and 31 December 2013. Patients who began receiving antidepressants for the first time (index date) without a history of having received a prescription for antidepressants during the preceding year. Patients who had been diagnosed as having cerebrovascular diseases within a year before the index date were excluded. Time to first hospital admission with intracranial haemorrhage within 30 days after drug use. Matched Cox regression models were used to compare the risk of intracranial haemorrhage among patients who were treated with antidepressants with and without NSAIDs, after propensity score matching with a 1:1 ratio. After propensity score estimation and matching in a 1:1 ratio, the cohort used in the analysis included 4,145,226 people. The 30 day risk of intracranial haemorrhage during the entire study period was higher for combined use of antidepressants and NSAIDs than for use of antidepressants without NSAIDs (hazard ratio 1.6, 95% confidence interval 1.32 to 1.85). No statistically meaningful differences were found in risk of intracranial haemorrhage between the antidepressant drug classes. Combined use of antidepressants and NSAIDs was associated with an increased risk of intracranial haemorrhage within 30 days of initial combination.


Optic disc abnormalities - diagnosis, evolution and influence on visual acuity.
Congenital abnormalities of the optic disc are not so rare. The etiology for the most of them is unknown. Visual acuity of affected eye may be minimally or severely affected, depending on the extent of lesion. All of these conditions can be unilateral or bilateral. Children who have unilateral optic disc abnormalities generally present during the preschool years with sensory esotropia. Visual acuity may be unaffected like in optic disc pit, optic disc drusen, fibre medullares, ect. However, during the evolution they may cause a decrease in visual acuity like serous retinal detachment in optic disc pit, atrophy or subretinal neovascularisation in optic disc drusen. Some of them like fibre medullares needs only a good diagnose and they do not have any evolution. Fluorescein angiography and ultrasonography may be crucial diagnostic procedures to discover some of them, like optic disc drusen. Optic disc abnormalities may be associated with other congenital disorders of the eye and often central nervous system malformations. Secondary they may be associated retinal detachment, retinochisis, macular edema, choroid neovascularisation and lipid exudation. Some of these conditions may be found on routine ophthalmologic exam such as optic disc drusen and fibre medullares and often are diagnostically problem. The aim of our study was to present some of our cases with different optic disc abnormalities such as fibre medullares, optic disc coloboma, hypoplasio disc, optic disc drusen and optic disc pit.


The Relationship Between the Big Five Personality Factors, Anger-hostility, and Alcohol and Violence in Men and Women: A Nationally Representative Cohort of 15,701 Young Adults.
Alcohol consumption is known to have a disinhibiting effect and is associated with a higher likelihood of aggressive behavior, especially among men. People with certain personality traits maybe more likely to behave aggressively when intoxicated, and there may also be variation by gender. We aimed to investigate whether the reason why men and women with certain personality traits are more likely to engage in violence may be because of their alcohol use.The Big Five personality traits and anger-hostility, alcohol consumption, and violence were measured by questionnaire in 15,701 nationally representative participants in the United States. We tested the extent to which alcohol mediates the relationship between personality factors and violence in men and women.We found that agreeableness was inversely associated with violence in both genders. Alcohol mediated approximately 11% of the effect in males, but there was no evidence of an effect in females. Anger-hostility was associated with violence in both sexes, but alcohol mediated the effect only in males. We also found that Extraversion was associated with violence and alcohol use in males and females. Alcohol accounted for 15% of the effect of extraversion on violence in males and 29% in females.The mechanism by which personality traits relate to violence may be different in men and women. Agreeableness and anger-hostility underpin the relationship between alcohol and violence in men, but not in women. Reducing alcohol consumption in men with disagreeable and angry/hostile traits would have a small but significant effect in reducing violence, whereas in women, reducing alcohol consumption among the extraverted, would have a greater effect.


Mycoplasma gallisepticum: a devastating organism for the poultry industry in Egypt.
Mycoplasma gallisepticum (MG) is a worldwide ruined bacteria affecting different avian species, causing severe economic losses. Consequently, the current research sought to detect the incidence of MG among different commercial broiler, layer chickens and turkey farms, and environmental litter samples in different Egyptian governorates (Damietta, Giza, El-Qalyobia, El-Sharqia, and El-Behera) from January 2019 to December 2020. Four hundred samples (infraorbital sinus aspirates, tracheal swabs, serum from diseased birds, and organ samples; lung tissues, air sacs and tracheal bifurcation from freshly dead birds), and environmental samples (litter) were collected for MG isolation. Samples were subjected to phenotypic and molecular identification. Positive bacteriological samples were subjected for molecular identification using polymerase chain reaction (PCR) test to detect MG, then sequencing for PCR amplicon of mgc2 gene. Out of 332 samples subjected for bacteriological examination, 206 were bacteriologically positive for MG with an incidence of 62%. The highest incidence of MG was detected in turkey farms at a rate of 83%, followed by broiler chicken farms, layer chicken farms and litter samples at a percentage of 70, 40, and 40, respectively. The highest prevalence of MG in chickens and turkey was recorded during the winter and autumn seasons. Molecular identification of MG isolates revealed that 85% of isolates were positive for mgc2 gene using PCR. The Four sequenced strains in this study are closely related and placed in one group with the vaccine strain 6/85 and ts11 strain.


Model for the intrusion of batholiths associated with the eruption of large-volume ash-flow tuffs.
Pyroclastic eruption and the intrusion of batholiths associated with large-volume ash-flow tuffs may be driven by a decrease in reservoir pressure caused by the low density of the magma column due to vesiculation. Batholithic intrusion would then be accomplished by the subsidence and settling of kilometer-sized crustal blocks through the magma chamber, resulting in eventual collapse to form large caldera structures at the surface. Such a model does not require the formation of a large, laterally extensive, shallow magma chamber before the onset of large-volume ash-flow eruptions. Eruption could commence directly from a deeper reservoir, with only a small channelway being opened to the surface before the onset of catastrophic ash-flow eruptions of the scale of Yellowstone or Long Valley. Such a model has wide-ranging implications, and explains many of the problems inherent in the simple collapse model involving shallow magna chambers as well as the process and timing of batholith intrusion in such cases.


Discriminant analysis of mandibular measurements for the estimation of sex in a modern Brazilian sample.
The present study aimed to evaluate the accuracy of mandibular measurements for sex determination in a Brazilian population. The sample was composed of 100 mandibles, of which 53 were female and 47 were male, and the average age was 57.03 years. The mandible measurement protocol was composed of 15 measurements, of which six were bilateral and nine were unique. Mandibles were directly measured using a digital caliper and a protractor. The descriptive analysis of the present study revealed higher mean values for male mandibles compared to those for female mandibles with the exception of the left mandibular angle. Among the 21 measures analyzed in this group, 15 were statistically significant (p < 0.05). Univariate discriminant analyses produced a mean percentage of correct predictions that varied between 49 and 79%. The association of variables increased the percentage of correct prediction of sex to vary from 76 to 86%. The receiver operator characteristic (ROC) curve analysis indicated that the best variable for estimating sex was bigonial breadth (BGB; area under the ROC curve (AUC) = 0.764) followed by the right maximum ramus height (MRHr; AUC = 0.763). A reference table for estimating sex in a Brazilian population using mandible measurements was developed based on the ROC curve analysis. Mandibular measures provide a simple and reliable method for sex discrimination in Brazilian adults due to the sexual dimorphism revealed by analysis of the metric variables and the satisfactory results demonstrated by discriminant formulas, ROC curve analysis, and the reference table.


The Absence of Tryptase Mcpt6 Causes Elevated Cellular Stress in Response to Modulation of the Histone Acetylation Status in Mast Cells.
Mast cells contain large amounts of proteases stored within their secretory granules. Previously we showed that one of these proteases, tryptase, in addition to its location within granules, can also be found within the mast cell nucleus, where it has the capacity to affect the acetylation profile of nucleosomal core histones in aging cells. Based on this notion, and on the known sensitivity of mast cells to modulation of histone acetylation, we here asked whether tryptase could impact on the responses against cellular stress caused by disturbed histone acetylation status. To address this, wild-type and tryptase-deficient (Mcpt6-/-) mast cells were subjected to cell stress caused by trichostatin A (TSA), a histone deacetylase inhibitor. Wild-type and Mcpt6-/- mast cells were equally sensitive to TSA at an early stage of culture (~8 weeks). However, in aging mast cells (>50 weeks), tryptase-deficiency led to increased sensitivity to cell death. To address the underlying mechanism, we assessed effects of tryptase deficiency on the expression of markers for proliferation and cell stress. These analyses revealed aberrant regulation of thioredoxin, thioredoxin reductase, glutaredoxin, and glutathione reductase, as well as blunted upregulation of ribonucleotide reductase subunit R2 in response to TSA in aging cells. Moreover, the absence of tryptase led to increased expression of Psme4/PA200, a proteasome variant involved in the processing of acetylated core histones. Altogether, this study identifies a novel role for tryptase in regulating the manifestations of cell stress in aging mast cells.


A Randomised Controlled Trial of Efficacy of Cognitive Rehabilitation in Multiple Sclerosis: A Cognitive, Behavioural, and MRI Study.
Aim. To explore the efficacy of home-based, computerised, cognitive rehabilitation in patients with multiple sclerosis using neuropsychological assessment and advanced structural and functional magnetic resonance imaging (fMRI). Methods. 38 patients with MS and cognitive impairment on the Brief International Cognitive Assessment for MS (BICAMS) were enrolled. Patients were randomised to undergo 45 minutes of computerised cognitive rehabilitation using RehaCom software (n = 19) three times weekly for six weeks or to a control condition (n = 19). Neuropsychological and MRI data were obtained at baseline (time 1), following the 6-week intervention (time 2), and after a further twelve weeks (time 3). Cortical activations were explored using fMRI and microstructural changes were explored using quantitative magnetisation transfer (QMT) imaging. Results. The treatment group showed a greater improvement in SDMT gain scores between baseline and time 2 compared to the control group (p = 0.005). The treatment group exhibited increased activation in the bilateral prefrontal cortex and right temporoparietal regions relative to control group at time 3 (p < 0.05FWE corrected). No significant changes were observed on QMT. Conclusion. This study supports the hypothesis that home-based, computerised, cognitive rehabilitation may be effective in improving cognitive performance in patients with MS. Clinical trials registration is ISRCTN54901925.


Novel phages of healthy skin metaviromes from South Africa.
Recent skin metagenomic studies have investigated the harbored viral diversity and its possible influence on healthy skin microbial populations, and tried to establish global patterns of skin-phage evolution. However, the detail associated with the phages that potentially play a role in skin health has not been investigated. While skin metagenome and -metavirome studies have indicated that the skin virome is highly site specific and shows marked interpersonal variation, they have not assessed the presence/absence of individual phages. Here, we took a semi-culture independent approach (metaviromic) to better understand the composition of phage communities on skin from South African study participants. Our data set adds over 130 new phage species of the skin to existing databases. We demonstrated that identical phages were present on different individuals and in different body sites, and we conducted a detailed analysis of the structural organization of these phages. We further found that a bacteriophage related to the Staphylococcus capitis phage Stb20 may be a common skin commensal virus potentially regulating its host and its activities on the skin.


Methodologic factors influencing plasma binding of alpha-1-acid glycoprotein-bound and albumin-bound drugs.
Plasma binding of imipramine and lidocaine, two drugs that bind predominantly to alpha-1 acid glycoprotein (AAG), and of diazepam and phenytoin, albumin-bound drugs, were studied in fresh human plasma. Binding was determined by equilibrium dialysis with 0.1 M pH 7.4 phosphate buffer at 37 degrees C. AAG was determined by immunodiffusion. Lidocaine free fraction (FF) (30-35%) was time-dependent, reaching equilibrium by five hours. However, dialysis time exceeding 8 hours greatly increased lidocaine FF (60%) accompanied by a decrease in AAG concentration. Lidocaine binding and AAG-concentration were not affected by plasma freezing, and were independent of lidocaine concentrations from 0.5-10 micrograms/ml. Imipramine behaved comparably, with FF increasing from 15% at 5 hours of dialysis to 30% at 24 h, concurrent with a drop in AAG concentration. Imipramine binding and AAG concentration were also independent of plasma freezing and drug concentration from 0.25 to 10.0 micrograms/ml. Binding of diazepam (FF = 1.2%) and phenytoin (FF = 17%) were stable at 24 hours, not affected by sample freezing or drug concentration, and were independent of AAG concentration. Therefore, changes in AAG concentration alter plasma protein binding of AAG-bound drugs lidocaine and imipramine. Extended dialysis results in decreased concentrations of immunoreactive AAG and increased FF. In contrast, the binding of albumin-bound drugs diazepam and phenytoin are not affected by these variables.


Computed Tomography Screening for Early Lung Cancer, COPD and Cardiovascular Disease in Shanghai: Rationale and Design of a Population-based Comparative Study.
To describe the rational and design of a population-based comparative study. The objective of the study is to assess the screening performance of volume-based management of CT-detected lung nodule in comparison to diameter-based management, and to improve the effectiveness of CT screening for chronic obstructive pulmonary disease (COPD) and cardiovascular disease (CVD), in addition to lung cancer, based on quantitative measurement of CT imaging biomarkers in a Chinese screening setting. A population-based comparative study is being performed, including 10,000 asymptomatic participants between 40 and 74 years old from Shanghai urban population. Participants in the intervention group undergo a low-dose chest and cardiac CT scan at baseline and 1 year later, and are managed according to NELCIN-B3 protocol. Participants in the control group undergo a low-dose chest CT scan according to the routine CT protocol and are managed according to the clinical practice. Epidemiological data are collected through questionnaires. In the fourth year from baseline, the diagnosis of the three diseases will be collected. The unnecessary referral rate will be compared between NELCIN-B3 and standard protocol for managing early-detected lung nodules. The effectiveness of quantitative measurement of CT imaging biomarkers for early detection of lung cancer, COPD and CVD will be evaluated. We expect that the quantitative assessment of the CT imaging biomarkers will reduce the number of unnecessary referrals for early detected lung nodules, and will improve the early detection of COPD and CVD in a Chinese urban population. ClinicalTrials.gov, NCT03988322. Registered on 14 June 2019.


Sequencing of Pax6 loci from the elephant shark reveals a family of Pax6 genes in vertebrate genomes, forged by ancient duplications and divergences.
Pax6 is a developmental control gene essential for eye development throughout the animal kingdom. In addition, Pax6 plays key roles in other parts of the CNS, olfactory system, and pancreas. In mammals a single Pax6 gene encoding multiple isoforms delivers these pleiotropic functions. Here we provide evidence that the genomes of many other vertebrate species contain multiple Pax6 loci. We sequenced Pax6-containing BACs from the cartilaginous elephant shark (Callorhinchus milii) and found two distinct Pax6 loci. Pax6.1 is highly similar to mammalian Pax6, while Pax6.2 encodes a paired-less Pax6. Using synteny relationships, we identify homologs of this novel paired-less Pax6.2 gene in lizard and in frog, as well as in zebrafish and in other teleosts. In zebrafish two full-length Pax6 duplicates were known previously, originating from the fish-specific genome duplication (FSGD) and expressed in divergent patterns due to paralog-specific loss of cis-elements. We show that teleosts other than zebrafish also maintain duplicate full-length Pax6 loci, but differences in gene and regulatory domain structure suggest that these Pax6 paralogs originate from a more ancient duplication event and are hence renamed as Pax6.3. Sequence comparisons between mammalian and elephant shark Pax6.1 loci highlight the presence of short- and long-range conserved noncoding elements (CNEs). Functional analysis demonstrates the ancient role of long-range enhancers for Pax6 transcription. We show that the paired-less Pax6.2 ortholog in zebrafish is expressed specifically in the developing retina. Transgenic analysis of elephant shark and zebrafish Pax6.2 CNEs with homology to the mouse NRE/Pα internal promoter revealed highly specific retinal expression. Finally, morpholino depletion of zebrafish Pax6.2 resulted in a "small eye" phenotype, supporting a role in retinal development. In summary, our study reveals that the pleiotropic functions of Pax6 in vertebrates are served by a divergent family of Pax6 genes, forged by ancient duplication events and by independent, lineage-specific gene losses.


Olanzapine plus fluoxetine treatment increases Nt-3 protein levels in the rat prefrontal cortex.
Evidence is emerging for a role for neurotrophins in the treatment of mood disorders. In this study, we evaluated the effects of chronic administration of fluoxetine, olanzapine and the combination of fluoxetine/olanzapine on the brain-derived-neurotrophic factor (BDNF), nerve growth factor (NGF), and neurotrophin-3 (NT-3) in the rat brain. Wistar rats received daily injections of olanzapine (3 or 6 mg/kg) and/or fluoxetine (12.5 or 25mg/kg) for 28 days, and we evaluated for BDNF, NGF and NT-3 protein levels in the prefrontal cortex, hippocampus and amygdala. Our results showed that treatment with fluoxetine and olanzapine alone or in combination did not alter BDNF in the prefrontal cortex (p=0.37), hippocampus (p=0.98) and amygdala (p=0.57) or NGF protein levels in the prefrontal cortex (p=0.72), hippocampus (p=0.23) and amygdala (p=0.64), but NT-3 protein levels were increased by olanzapine 6 mg/kg/fluoxetine 25mg/kg combination in the prefrontal cortex (p=0.03), in the hippocampus (p=0.83) and amygdala (p=0.88) NT-3 protein levels did not alter. Finally, these findings further support the hypothesis that NT-3 could be involved in the effect of treatment with antipsychotic and antidepressant combination in mood disorders.


Violence, discrimination, and sexual health practices among adolescent men who have sex with men, transgender women and travestis in three cities in Brazil.
The HIV epidemic has a disproportionate impact on adolescent and young men who have sex with men (AMSM) and transgender women and travestis (ATGW), with an increased HIV prevalence over the last 10 years. Violence affects the lives of these populations, undermining their ability to self-care and making them more vulnerable to HIV infection. In this study, we aimed to examine the association between different types of victimization by violence and discrimination and sexual health practices of these adolescent populations in steady and casual relationships. We conducted a cross-sectional study using baseline data from the cohort of PrEP1519 project. We used the mean score of sexual health practices as our outcome and the cumulative score of discrimination (within family, community, education, religious, online and public spaces) and violence (physical, sexual and intimate partner) as our exposure variable. We performed linear regression analyses to estimate the association between exposure and outcome. We found that 90% of AMSM and 95% of ATGW experienced at least one form of violence in the three months prior to this study and about 45% of ATGW suffered sexual violence during the same period. Experiencing discrimination within healthcare settings (from facilities or providers) was negatively associated with sexual health practices. Discrimination and violence negatively affect sexual health practices. HIV prevention and care of AMSM and ATGW people should involve listening to their experiences and addressing discrimination and violence in this population.


Fluorescent light exposure incites acute and prolonged immune responses in zebrafish (Danio rerio) skin.
Artificial light produces an emission spectrum that is considerably different than the solar spectrum. Artificial light has been shown to affect various behavior and physiological processes in vertebrates. However, there exists a paucity of data regarding the molecular genetic effects of artificial light exposure. Previous studies showed that one of the commonly used fluorescent light source (FL; 4100K or "cool white") can affect signaling pathways related to maintenance of circadian rhythm, cell cycle progression, chromosome segregation, and DNA repair/recombination in the skin of male Xiphophorus maculatus. These observations raise questions concerning the kinetics of the FL induced gene expression response, and which biological functions become modulated at various times after light exposure. To address these questions, we exposed zebrafish to 4100K FL and utilized RNA-Seq to assess gene expression changes in skin at various times (1 to 12h) after FL exposure. We found 4100K FL incites a robust early (1-2h) transcriptional response, followed by a more protracted late response (i.e., 4-12h). The early transcriptional response involves genes associated with cell migration/infiltration and cell proliferation as part of an overall increase in immune function and inflammation. The protracted late transcriptional response occurs within gene sets predicted to maintain and perpetuate the inflammatory response, as well as suppression of lipid, xenobiotic, and melatonin metabolism.


Low-dose CT reconstruction via edge-preserving total variation regularization.
High radiation dose in computed tomography (CT) scans increases the lifetime risk of cancer and has become a major clinical concern. Recently, iterative reconstruction algorithms with total variation (TV) regularization have been developed to reconstruct CT images from highly undersampled data acquired at low mAs levels in order to reduce the imaging dose. Nonetheless, the low-contrast structures tend to be smoothed out by the TV regularization, posing a great challenge for the TV method. To solve this problem, in this work we develop an iterative CT reconstruction algorithm with edge-preserving TV (EPTV) regularization to reconstruct CT images from highly undersampled data obtained at low mAs levels. The CT image is reconstructed by minimizing energy consisting of an EPTV norm and a data fidelity term posed by the x-ray projections. The EPTV term is proposed to preferentially perform smoothing only on the non-edge part of the image in order to better preserve the edges, which is realized by introducing a penalty weight to the original TV norm. During the reconstruction process, the pixels at the edges would be gradually identified and given low penalty weight. Our iterative algorithm is implemented on graphics processing unit to improve its speed. We test our reconstruction algorithm on a digital NURBS-based cardiac-troso phantom, a physical chest phantom and a Catphan phantom. Reconstruction results from a conventional filtered backprojection (FBP) algorithm and a TV regularization method without edge-preserving penalty are also presented for comparison purposes. The experimental results illustrate that both the TV-based algorithm and our EPTV algorithm outperform the conventional FBP algorithm in suppressing the streaking artifacts and image noise under a low-dose context. Our edge-preserving algorithm is superior to the TV-based algorithm in that it can preserve more information of low-contrast structures and therefore maintain acceptable spatial resolution.


Roles for transforming growth factor beta superfamily proteins in early folliculogenesis.
Primordial follicle formation and the subsequent transition of follicles to the primary and secondary stages encompass the early events during folliculogenesis in mammals. These processes establish the ovarian follicle pool and prime follicles for entry into subsequent growth phases during the reproductive cycle. Perturbations during follicle formation can affect the size of the primordial follicle pool significantly, and alterations in follicle transition can cause follicles to arrest at immature stages or result in premature depletion of the follicle reserve. Determining the molecular events that regulate primordial follicle formation and early follicle growth may lead to the development of new fertility treatments. Over the last decade, many of the growth factors and signaling proteins that mediate the early stages of folliculogenesis have been identified using mouse genetic models, in vivo injection studies, and ex vivo organ culture approaches. These studies reveal important roles for the transforming growth factor beta (TGF-beta) superfamily of proteins in the ovary. This article reviews these roles for TGF-beta family proteins and focuses in particular on work from our laboratories on the functions of activin in early folliculogenesis.


Interaction of the simple carbene c-C3H2 with H2: potential energy surface and low-energy scattering.
Cyclopropenylidene, c-C3H2, is a simple hydrocarbon, ubiquitous in astrophysical gases, and possessing a permanent electric dipole moment. Its readily observed rotational transitions make it an excellent probe for the physics and history of interstellar matter. The collisional properties of c-C3H2 with the main background gas, H2, are computed here. We present a full 5-D Potential Energy Surface in the rigid molecule approach, and fit it to relevant functionals for subsequent scattering. We perform low-energy quantum scattering at energies less than 50 cm-1. We use both ortho and para H2 as projectiles. We determine the quality of the various approximations to exact coupled channel scattering and examine paths to go towards higher energy scattering relevant for astrophysics. We compare the results obtained here with earlier ones for scattering with helium.


Minimally-invasive Right Hepatectomy for Perihilar Cholangiocarcinoma.
The magnification of images provided by minimally-invasive surgery (MIS) allows a very sharp and precise dissection of the hepatic hilum, allowing to overcome the technical complexity of surgery of perihilar cholangiocarcinoma (PHC). Recently, the feasibility and reproducibility of MIS for PHC are reported: within centers with adequate expertise and respecting the cornerstones of oncological adequacy, it provides short term advantages in a selected population of patients. The video reports the case of a patient with PHC involving the right biliary duct and requiring right hepatectomy with biliary confluence and segment 1 resection, with associated lymphadenectomy. Current evidences, together with feasibility and reproducibility of the technique shown in this video, appear promising and constitute a good prerequisite for the further implementation of this approach to improve patients outcome while following the principles of surgical oncology in hilar cholangiocarcinoma.


[The role of genetic factors in the manifestation of delirium tremens].
Among 27,692 patients suffering from alcoholism, delirium tremens occurs only in 8.1% of the cases. From 2417 patients with this psychosis repeated delirium tremens was noted in 12.9%. In the studied group (n = 2417) delirium tremens was observed in men (84.2%) 5.3 times more often than in women (15.8%). The mean age of the onset of the delirium was 43.2 years in women and was older than in the group of men (42.0 years). Age distribution of the disease onset in men and women follows a curve of normal distribution. In 125 patients with schizophrenia combined with delirium tremens there was a high rate of repeated alcoholic delirium (22.4%), epileptic seizures (21.6%), diabetes mellitus of type II (10.4%). These facts confirm the role of hereditary predisposition to development of delirium tremens and allow to relate alcoholic delirium to multifactorial diseases.


Variation in accessible cell surface immunoglobulin among antibody-firming cells.
Spleen cells from CBA mice that had been primarily or secondarily immunized with sheep red blood cells were reacted at 0 degrees C with a (125)I-labeled polyvalent rabbit anti-mouse globulin reagent. After suitable washing, the cells were placed in a plaque-revealing monolayer and warmed to 37 degrees C. Plaques appeared within 10-20 min. Single plaque-forming cells (PFC) were taken from the middle of plaques, were washed by micromanipulation, and were singly dried on glass slides. The amount of attached antireceptor was assessed by quantitative radioautography. Great variation in "receptor density" was encountered among the 258 single cells studied. However, early, immature PFC in both primary and secondary responses had statistically significantly more receptors than late, mature PFC. On any given day point, no difference was found between IgM- and IgG-forming cells. The results were consistent with the view that cells still able to be driven to further proliferation by antigen retain receptors, and conversely that cells, as they mature, lose both receptors and ability to be influenced by antigen.


Synthetic Biology of Small RNAs and Riboswitches.
In bacteria and archaea, small RNAs (sRNAs) regulate complex networks through antisense interactions with target mRNAs in trans, and riboswitches regulate gene expression in cis based on the ability to bind small-molecule ligands. Although our understanding and characterization of these two important regulatory RNA classes is far from complete, these RNA-based mechanisms have proven useful for a wide variety of synthetic biology applications. Besides classic and contemporary applications in the realm of metabolic engineering and orthogonal gene control, this review also covers newer applications of regulatory RNAs as biosensors, logic gates, and tools to determine RNA-RNA interactions. A separate section focuses on critical insights gained and challenges posed by fundamental studies of sRNAs and riboswitches that should aid future development of synthetic regulatory RNAs.


Cranial biomechanics underpins high sauropod diversity in resource-poor environments.
High megaherbivore species richness is documented in both fossil and contemporary ecosystems despite their high individual energy requirements. An extreme example of this is the Late Jurassic Morrison Formation, which was dominated by sauropod dinosaurs, the largest known terrestrial vertebrates. High sauropod diversity within the resource-limited Morrison is paradoxical, but might be explicable through sophisticated resource partitioning. This hypothesis was tested through finite-element analysis of the crania of the Morrison taxa Camarasaurus and Diplodocus. Results demonstrate divergent specialization, with Camarasaurus capable of exerting and accommodating greater bite forces than Diplodocus, permitting consumption of harder food items. Analysis of craniodental biomechanical characters taken from 35 sauropod taxa demonstrates a functional dichotomy in terms of bite force, cranial robustness and occlusal relationships yielding two polyphyletic functional 'grades'. Morrison taxa are widely distributed within and between these two morphotypes, reflecting distinctive foraging specializations that formed a biomechanical basis for niche partitioning between them. This partitioning, coupled with benefits associated with large body size, would have enabled the high sauropod diversities present in the Morrison Formation. Further, this provides insight into the mechanisms responsible for supporting the high diversities of large megaherbivores observed in other Mesozoic and Cenozoic communities, particularly those occurring in resource-limited environments.


Negative regulation of a protein tyrosine phosphatase by tyrosine phosphorylation.
The low molecular weight protein tyrosine phosphatase (LMW-PTP) is a ubiquitously expressed enzyme with several proposed roles in cell signaling. Previously, two tyrosine phosphorylation modifications of LMW-PTP at sites Tyr-131 and Tyr-132 in response to growth factor stimulation have been mapped and suggested to stimulate LMW-PTP phosphatase activity. Biochemical analysis of tyrosine phosphorylation of a tyrosine phosphatase is challenging because of the intrinsic instability of these modifications. Here we used expressed protein ligation to site-specifically incorporate a phosphotyrosine mimic (phosphonomethylenephenylalanine, Pmp) at the Tyr-131 and Tyr-132 positions and measured the catalytic activity of these semisynthetic LMW-PTPs. The phosphonate-modified LMW-PTPs were 10- to 23-fold less active in dephosphorylating phosphotyrosine peptides derived from the PDGF receptor and p190RhoGap, two putative cellular substrates. These findings suggest the first example of a tyrosine phosphatase that is inhibited by tyrosine phosphorylation and provide a new model for the regulation of LMW-PTP and its role in cell adhesion.


Induction of apoptosis by isoflavonoids from the leaves of Millettia taiwaniana in human leukemia HL-60 cells.
We have isolated two new isoflavonoids, millewanin-F (1) and furowanin-A (2), together with five known isoflavonoids from the leaves of Millettia taiwaniana Hayata (Leguminosae) and examined their effects on the growth of human leukemia HL-60 cells. Among the isolated isoflavonoids, furowanin-A (2), warangalone (3), isoerysenegalensein-E (4), and euchrenone b10 (6) showed significant cytotoxicity against HL-60 cells. After treatment with three of the cytotoxic isoflavonoids, furowanin-A (2), warangalone (3), and isoerysenegalensein-E (4), fluorescence microscopy with Hoechst 33,342 staining revealed that the percentage of apoptotic cells with fragmented nuclei and condensed chromatin increased in a time-dependent manner. In addition, the activities of caspase-9 and caspase-3 were also enhanced in a time-dependent manner upon treatment with the isoflavonoids 2, 3, and 4. Caspase-9 and caspase-3 inhibitors suppressed apoptosis induced by isoflavonoids 2, 3, and 4. These results suggest that the isoflavonoids induced apoptosis in HL-60 cells through activation of the caspase-9/caspase-3 pathway, which is triggered by mitochondrial dysfunction.


Emerging strategies to treat rare and intractable subtypes of melanoma.
Melanoma is the deadliest form of skin cancer, possessing a diverse landscape of subtypes with distinct molecular signatures and levels of aggressiveness. Although immense progress has been achieved therapeutically for patients with the most common forms of this disease, little is known of how to effectively treat patients with rarer subtypes of melanoma. These subtypes include acral lentiginous (the rarest form of cutaneous melanoma; AL), uveal, and mucosal melanomas, which display variations in distribution across (a) the world, (b) patient age-groups, and (c) anatomic sites. Unfortunately, patients with these relatively rare subtypes of melanoma typically respond worse to therapies approved for the more common, non-AL cutaneous melanoma and do not have effective alternatives, and thus consequently have worse overall survival rates. Achieving durable therapeutic responses in these high-risk melanoma subtypes represents one of the greatest challenges of the field. This review aims to collate and highlight effective preclinical and/or clinical strategies against these rare forms of melanoma.


An optimized electrochemistry-liquid chromatography-mass spectrometry method for studying guanosine oxidation.
Oxidative stress can disrupt the integrity of genetic material. Due to its importance in the pathogenesis of different kinds of disease, including neurodegenerative disease, cardiovascular disease and cancer, major efforts are put into the elucidation of mechanisms involved. Herein, the combination of electrochemistry/liquid chromatography/mass spectrometry (EC/LC/MS) is presented as convenient, fast and simple method to study nucleic acids oxidation. Guanosine was selected as test compound. 8-Hydroxyguanosine and (guanosine-H)(2) were identified as primary oxidation products. Oxidation was accomplished in an electrochemical thin-layer cell integrated in the flow path of the autosampler of the chromatographic system. The reaction mixture was separated and mass analyzed by LC/MS. The use of LC was found to be particularly beneficial to resolve isobaric oxidation products. Another advantage of the setup used was the ability to decouple the electrochemical cell and the electrospray ionization source from each other eliminating any kind of cell potential interaction. Separation of EC from LC/MS, furthermore, facilitates method optimization. Experimental parameters were optimized for both techniques independently. Highest yields and best detectability of oxidation products were obtained with 10 mM ammonium formate at physiological pH delivered at a flow rate of 2.5-5 μL/min through the electrochemical cell.


Thoracic splenosis. Report of a case and review of the diagnostic workup.
Splenosis is the autoimplantation of splenic tissue to ectopic sites after spleen injury. Although splenosis most commonly occurs in the abdomen, it may occur in the thorax in case of diaphragm rupture. Thoracic splenosis (TS) is often asymptomatic and is diagnosed incidentally in the course of chest examination. We describe the case of a man, with a history of thoracoabdominal trauma, undergoing routine chest radiography with the evidence of radio-opaque images close to the inferior left curvature of the cardiac shadow, which resulted to be nodules of TS at the contrast enhanced CT scan. CT scan or MRI and an accurate anamnesis are usually sufficient to diagnose TS, otherwise scintigraphy with 99mTc is needed. Imaging-guided biopsy and thoracoscopy should be performed if scintigraphy is unavailable or results are inconclusive. It is not usually necessary to remove the TS because the splenic tissue is slow growing, non-invasive and benign. Rarely surgery may be required for symptomatic TS (hemoptysis, cough or pleuritic chest pain). TS may be difficult to diagnose, especially if features suggesting TS are not recognized and the anamnesis in not known. This may lead to an extensive work-up and unnecessary invasive diagnostic procedures (including biopsy, thoracoscopy, up to thoracotomy). In the workup of thoracic nodules TS should be considered in patients with a history of trauma and spleen injury. Thoracic splenosis, Spleen, Mediastinal nodules, Thoracoabdominal trauma.


Collagen scaffolds modified with collagen-binding bFGF promotes the neural regeneration in a rat hemisected spinal cord injury model.
Nerve conduit is one of strategies for spine cord injury (SCI) treatment. Recently, studies showed that biomaterials could guide the neurite growth and promote axon regeneration at the injury site. However, the scaffold by itself was difficult to meet the need of SCI functional recovery. The basic fibroblast growth factor (bFGF) administration significantly promotes functional recovery after organ injuries. Here, using a rat model of T9 hemisected SCI, we aimed at assessing the repair capacity of implantation of collagen scaffold (CS) modified by collagen binding bFGF (CBD-bFGF). The results showed that CS combined with CBD-bFGF treatment improved survival rates after the lateral hemisection SCI. The CS/CBD-bFGF group showed more significant improvements in motor than the simply CS-implanted and untreated control group, when evaluated by the 21-point Basso-Beattie-Bresnahan (BBB) score and footprint analysis. Both hematoxylin and eosin (H&E) and immunohistochemical staining of neurofilament (NF) and glial fibrillary acidic protein (GFAP) demonstrated that fibers were guided to grow through the implants. These findings indicated that administration of CS modified with CBD-bFGF could promote spinal cord regeneration and functional recovery.


Molecular identifications of HLA-DR4, MT3, and TB21 antigens on HLA-DR4 homozygous B cell lines.
The HLA-DR locus in the human major histocompatibility complex determines a series of polymorphic cell surface antigens; these antigens are composed of two noncovalently associated glycoproteins of 34,000 daltons and 29,000 daltons and are predominantly expressed on B cells, monocytes, and activated T cells (1). To date, 10 HLA-DR specificities have been well characterized by using alloantisera obtained from multiparous women (2). In addition to these DR antigens, two other B cell alloantigen systems (MT and MB) were proposed on the basis of the serologic data (3,4); the MB1 or MT1 specificities are found in association with DR1, DR2, and DRw6, whereas MT2 is associated with DR3, DR5, DRw6, and DRw8; MT3 is associated with DR4, DR7, and DRw9, and MB3 or MT4 is associated with DR4, DR5, and DRw8, respectively (3, 4). We have also described that the TB21 antigen is expressed in association with DR4, DR5, and DRw9 (5). The HLA-DR, MB, MT, or TB antigens are collectively referred to as class II antigens. The number of human class II antigens has been of primary concern because of their similarity to murine Ia antigens and especially because of their close relationship to certain diseases. With the aid of immunochemical means and alloantisera, it has been demonstrated that at least two loci control human class II molecules (6-10). The data presented in this report show the existence of three class II molecules carrying well-known allospecificities, DR4, MT3, and TB21, on HLA-DR4 homozygous cell lines.


DNA damage in children with asthma bronchiale and its association with oxidative and antioxidative measurements.
Increased production of reactive oxygen species leading to an imbalance between the oxidative forces and the antioxidant defense systems favoring an oxidative injury has been implicated in the pathogenesis of asthma. The aim of the study was to investigate the peripheral DNA damage, and its association with oxidative and antioxidative measurements in children with asthma bronchiale. The study population contained 42 children with asthma bronchiale and 32 healthy controls. DNA damage was assessed by alkaline comet assay in peripheral lymphocytes. Plasma levels of total antioxidant status (TAS), total peroxide concentration (LOOHs), and total oxidant status (TOS) were determined. In asthma bronchiale patients, DNA damage was significantly higher than in controls (17.9 +/- 11.8 AU vs. 1.2 +/- 2.0 AU, p < 0.001). Plasma TOS and LOOHs were higher in patients than in healthy controls (13.4 +/- 7.0 vs. 9.0 +/- 3.5, p = 0.002; 9.9 +/- 3.4 vs. 4.4 +/- 1.5, p < 0.001, respectively). Plasma TAS level in patients was higher than in healthy controls (5.5 +/- 2.5 vs. 1.0 +/- 0.6, p < 0.001). DNA damage was correlated with TOS (r = 0,616, p < 0.001). The findings indicated that lymphocyte DNA damage level increases in children with asthma bronchiale. Elevated DNA damage may be related to increased oxidative stress. However, the mechanism of this association, and whether it is direct or indirect, remains to be explored.


The in vitro response of turkey lymphocytes to steroid hormones.
The in vitro mitogen response of whole blood turkey lymphocytes to various concentrations of steroid hormones was evaluated. Corticosterone (COS) at concentrations between 1 and 80 ng/ml significantly suppressed the proliferative response (3H-thymidine incorporation) to phytohemagglutinin (PHA) and concanavalin A (ConA). Non-mitogen-stimulated (NMS) cells were suppressed at concentrations of COS above 5 ng/ml. Progesterone significantly suppressed NMS cells at concentrations of 80 ng/ml, PHA-stimulated cells at concentrations of 500 ng/ml, and ConA-stimulated cells at concentrations of 1000 ng/ml. beta-Estradiol enhanced the response of NMS cells at concentrations of 500 ng/ml, had no effect on PHA-stimulated cells, and suppressed the response of ConA-stimulated cells at concentrations greater than 500 ng/ml. Testosterone affected only the ConA response, causing suppression at concentrations above 2000 ng/ml. Corticosterone and progesterone caused 80 and 95% suppression, respectively, of the proliferative response to ConA when compared with non-hormone-treated cells. The possible implications of steroid hormone-induced immunosuppression in the pathogenesis of aspergillosis is discussed.


Natural Cytotoxic Diterpenoids, a Potential Source of Drug Leads for Melanoma Therapy.
Diterpenes present complex structure and due to their unique carbon skeleton and interesting biological activities, have been the focus of continuous studies for the development of new anticancer agents. Phorbol esters have been known for their activity against skin malignancies since ancient times. Taxol was first studied in melanoma cells, and recently, ingenol mebutate has been approved for the chemoprevention of melanoma in actinic keratosis patients. Therefore, there is a scope for research on this class of compounds. We here aim to review the relevant original research reporting on isolated diterpenes with cytotoxic and/or antitumoral activities upon melanoma cells. By collating and discussing the implications of past and current developments on diterpenes, we hope to steer further interest on this field and facilitate the drug discovery activities of the scientific community towards finding potential alternatives to current melanoma chemotherapy.


Disorder of G2-M Checkpoint Control in Aniline-Induced Cell Proliferation in Rat Spleen.
Aniline, a toxic aromatic amine, is known to cause hemopoietic toxicity both in humans and animals. Aniline exposure also leads to toxic response in spleen which is characterized by splenomegaly, hyperplasia, fibrosis and the eventual formation of tumors on chronic in vivo exposure. Previously, we have shown that aniline exposure leads to iron overload, oxidative DNA damage, and increased cell proliferation, which could eventually contribute to a tumorigenic response in the spleen. Despite our demonstration that cell proliferation was associated with deregulation of G1 phase cyclins and increased expression of G1 phase cyclin-dependent kinases (CDKs), molecular mechanisms, especially the regulation of G2 phase and contribution of epigenetic mechanisms in aniline-induced splenic cellular proliferation remain largely unclear. This study therefore, mainly focused on the regulation of G2 phase in an animal model preceding a tumorigenic response. Male Sprague-Dawley rats were given aniline (0.5 mmol/kg/day) in drinking water or drinking water only (controls) for 30 days, and expression of G2 phase cyclins, CDK1, CDK inhibitors and miRNAs were measured in the spleen. Aniline treatment resulted in significant increases in cell cycle regulatory proteins, including cyclins A, B and CDK1, particularly phosphor-CDK1, and decreases in CDK inhibitors p21 and p27, which could promote the splenocytes to go through G2/M transition. Our data also showed upregulation of tumor markers Trx-1 and Ref-1 in rats treated with aniline. More importantly, we observed lower expression of miRNAs including Let-7a, miR-15b, miR24, miR-100 and miR-125, and greater expression of CDK inhibitor regulatory miRNAs such as miR-181a, miR-221 and miR-222 in the spleens of aniline-treated animals. Our findings suggest that significant increases in the expression of cyclins, CDK1 and aberrant regulation of miRNAs could lead to an accelerated G2/M transition of the splenocytes, and potentially to a tumorigenic response on chronic aniline exposure.


Mechanisms of deep brain stimulation and future technical developments.
Possible mechanisms underlying the therapeutic effect of deep brain stimulation (DBS) are reviewed, particularly the notion that DBS is inhibitory. Computer simulations are described that model the effect of different frequencies and regularity of neuronal activity (target neuron), either spontaneous or stimulated, on information transfer between two other neurons. Most simulations resulted in a loss of information. These were the least with high frequency and regular activity or stimulation of the target neuron with regularity having the least deleterious effect on information transfer. The simulations suggest that irregular activity in neurons converging with other neurons can result in a loss of information transfer. This may explain why increased irregularity in globus pallidus activity associated with Parkinson's disease, dystonia and hemiballismus may result in symptoms. Further, the therapeutic effect of DBS may be due to driving neurons at higher and perhaps more importantly, regular frequencies. There were simulations in which information transfer was augmented suggesting the presence of stochastic resonance. This most often occurred with low frequency activity in the target neuron. It is hypothesized that low frequency activity, either spontaneous or stimulated, could account for involuntary movements, including tremor. Future directions and challenges to DBS are also discussed.


Chromothripsis: breakage-fusion-bridge over and over again.
The acquisition of massive but localized chromosome translocations, a phenomenon termed chromothripsis, has received widespread attention since its discovery over a year ago. Until recently, chromothripsis was believed to originate from a single catastrophic event, but the molecular mechanisms leading to this event are yet to be uncovered. Because a thorough interpretation of the data are missing, the phenomenon itself has wrongly acquired the status of a mechanism used to justify many kinds of complex rearrangements. Although the assumption that all translocations in chromothripsis originate from a single event has met with criticism, satisfactory explanations for the intense but localized nature of this phenomenon are still missing. Here, we show why the data used to describe massive catastrophic rearrangements are incompatible with a model comprising a single event only and propose a molecular mechanism in which a combination of known cellular pathways accounts for chromothripsis. Instead of a single traumatic event, the protection of undamaged chromosomes by telomeres can limit repetitive breakage-fusion-bridge events to a single chromosome arm. Ultimately, common properties of chromosomal instability, such as aneuploidy and centromere fission, might establish the complex genetic pattern observed in this genomic state.


Cardiovascular impact of near complete estrogen deprivation in premenopausal women with breast cancer: The CROWN study.
Survival with operable breast cancer has improved markedly in recent decades, however, treatment-related cardiovascular toxicities threaten to offset these gains. Ovarian function suppression paired with aromatase inhibition, for premenopausal women with hormone receptor (HR)-positive breast cancer, is a newer widely adopted therapy with the potential for significant long-term cardiovascular toxicity. Abrupt estrogen deprivation for non-cancer reasons is associated with accelerated coronary artery disease. Women with breast cancer treated with aromatase inhibition in addition to ovarian function suppression experience a dual hit with regards to estrogen exposure. The CaRdiac Outcomes With Near-complete estrogen deprivation (CROWN) study seeks to understand the early, subclinical natural history of cardiovascular compromise in young women undergoing near-complete estrogen deprivation (NCED) therapy. It is critical to understand the early subclinical development of cardiovascular disease to identify a window for therapeutic intervention before overt cardiovascular events occur. This three-site regional study (Atrium Health Wake Forest, Duke, and Virginia Commonwealth University) uses serial stress cardiac magnetic resonance (CMR) imaging and cardiac computed tomography angiography (CCTA) obtained during the initial two years of NCED therapy to study myocardial prefusion reserve (MPR), large cardiovascular vessel changes, left ventricular function, and other cardiovascular parameters. The CROWN cohort will consist of 90 premenopausal women with breast cancer, 67 with HR-positive disease receiving NCED and 23 comparators with HR-negative disease. Participants will undergo three annual CMR scans and 2 CCTA scans during the 2-year study period. After initial activation hurdles, accrual has been brisk, and the study is expected to complete accrual in December 2024. Efforts are in place to encourage participant retention with the study primary outcome, change in MPR between the two groups, to be reported in 2026 to 2027. The results of this study will enable premenopausal women with breast cancer to balance the health burdens of cancer at a young age and treatment-related cardiovascular morbidity. Finally, the tools developed here can be utilized to study cardiovascular risk across a range of cancer types and cancer therapies with the ultimate goals of both developing generalizable risk stratification tools as well as validating interventions which prevent overt cardiovascular compromise.


Zebrafish cardiac repolarization does not functionally depend on the expression of the hERG1b-like transcript.
Zebrafish provide a translational model of human cardiac function. Their similar cardiac electrophysiology enables screening of human cardiac repolarization disorders, drug arrhythmogenicity, and novel antiarrhythmic therapeutics. However, while zebrafish cardiac repolarization is driven by delayed rectifier potassium channel current (IKr), the relative role of alternate channel transcripts is uncertain. While human ether-a-go-go-related-gene-1a (hERG1a) is the dominant transcript in humans, expression of the functionally distinct alternate transcript, hERG1b, modifies the electrophysiological and pharmacologic IKr phenotype. Studies of zebrafish IKr are frequently translated without consideration for the presence and impact of hERG1b in humans. Here, we performed phylogenetic analyses of all available KCNH genes from Actinopterygii (ray-finned fishes). Our findings confirmed zebrafish cardiac zkcnh6a as the paralog of human hERG1a (hKCNH2a), but also revealed evidence of a hERG1b (hKCNH2b)-like N-terminally truncated gene, zkcnh6b, in zebrafish. zkcnh6b is a teleost-specific variant that resulted from the 3R genome duplication. qRT-PCR showed dominant expression of zkcnh6a in zebrafish atrial and ventricular tissue, with low levels of zkcnh6b. Functional evaluation of zkcnh6b in a heterologous system showed no discernable function under the conditions tested, and no influence on zkcnh6a function during the zebrafish ventricular action potential. Our findings provide the first descriptions of the zkcnh6b gene, and show that, unlike in humans, zebrafish cardiac repolarization does not rely upon co-assembly of zERG1a/zERG1b. Given that hERG1b modifies IKr function and drug binding in humans, our findings highlight the need for consideration when translating hERG variant effects and toxicological screens in zebrafish, which lack a functional hERG1b-equivalent gene.


[The PTSD Checklist for DSM-5 (PCL-5): comparing responsivity with the Outcome Questionnaire (OQ-45) and practical utility].
The PTSD Checklist for the DSM-5 (PCL-5) may be a suitable addition for routine outcome monitoring (ROM) for patients with PTSD.
 AIM: To determine whether the PCL-5 is worth the extra effort that administration requires from the patient.
 METHOD: Pretest and retest measurement results of the PCL-5 and the OQ-45 were compared head-to-head in 464 patients from the Sinai Center of Arkin.
 RESULTS: The correlations between scores on the instruments were high and analysis of variance for repeated measurements revealed no difference in responsiveness. Comparison of Cohen's d (0.49 vs. 0.43) and Delta T (5.0 vs. 4.4), indicated a slightly better responsiveness of the PCL-5 and also the proportion of recovered patients was greater according to the PCL-5 compared to the OQ-SD.
 CONCLUSION: At first glance, the PCL-5 and the OQ-SD were equally sensitive to detect change during treatment. However, the PCL-5 provided more detailed information about the nature and severity of symptomatology in an individual patient and with the PCL-5 we were slightly better able to demonstrate clinical significant change than with the OQ-SD. We recommend to add the PCL-5 to ROM for patients with PTSD.


[Cryosurgery in rectal carcinoma--report of 41 cases].
Fourty-one patients with rectal carcinoma treated by cryosurgery in our hospital from 1973 to 1982 are presented. The 5, 4, 3, 2, and 1-year survival rates were 34.1%, 41%, 56%, 66% and 90%, respectively Eighteen patients who underwent radical cryosurgery gave a 5-year survival rate of 66%. The results showed that cryosurgery inhibited the multiplication of cancer cells and improved immune response through observing the changes of DNA content, ultrastructures, anti-bodies (IgG, A, M), T-cell subpopulations (OKT3, OKT4, OKT8) and so on. Cryosurgery could avert colostomy when used for rectal carcinoma.


Oxygen Vacancy-Tailored Schottky Heterojunction Activates Interface Dipole Amplification and Carrier Inversion for High-Performance Potassium-Ion Batteries.
An oxygen vacancy-tailored Schottky heterostructure composed of polyvinylpyrrolidone-assisted Bi2 Sn2 O7 (PVPBSO) nanocrystals and moderate work function graphene (mWFG, WF = 4.36 eV) is designed, which in turn intensifies the built-in voltage and interface dipole across the space charge region (SCR), leading to the inversion of majority carriers for facilitating K+ transport/diffusion behaviors. Thorough band-alignment experiments and interface simulations reveal the dynamics between deficient BSO and mWFG, and how charge redistribution within the SCR leads to carrier inversion, demonstrating the impact of different defect engineering degrees on the amplification of Schottky junctions. The ordered transport of bipolar carriers can boost electrons and K ions easily passing through the inner and outer surfaces of the heterostructure. With high activity and low resistance in electrochemical reactions, the PVPBSO/mWFG exhibits an attractive capacity of 430 mA h g-1 and a rate capability exceeding 2000 mA g-1 , accompanied by minimal polarization and efficient utilization of conversion-alloying reactions. The substantial cell capacity and high-redox plateau of PVPBSO/mWFG//PB contribute to the practical feasibility of high-energy full batteries, offering long-cycle retention and high-voltage output. This study emphasizes the direct importance of interface and junction engineering in improving the efficiency of diverse electrochemical kinetic and diffusion processes for potassium-ion batteries.