Effects of RAD51-stimulatory compound 1 (RS-1) and its vehicle, DMSO, on pig embryo culture.
Pigs have become an important model for agricultural and biomedical purposes. The advent of genomic engineering tools, such as the CRISPR/Cas9 system, has facilitated the production of livestock models with desired modifications. However, precise site-specific modifications in pigs through the homology-directed repair (HDR) pathway remains a challenge. In mammalian embryos, the use of small molecules to inhibit non-homologous end joining (NHEJ) or to improve HDR have been tested, but little is known about their toxicity. The compound RS-1 stimulates the activity of the RAD51 protein, which plays a key role in the HDR mechanism, demonstrating enhancement of HDR events in rabbit and bovine zygotes. Thus, in this study, we evaluated the dosage and temporal effects of RS-1 on porcine embryo development and viability. Additionally, we assessed the effects of its vehicle, DMSO, during embryo in vitro culture. Transient exposure to 7.5 μM of RS-1 did not adversely affect early embryo development and was compatible with subsequent development to term. Additionally, low concentrations of its vehicle, DMSO, did not show any toxicity to in vitro produced embryos. The transient use of RS-1 at 7.5 μM during in vitro culture seems to be the best protocol of choice to reduce the potentially toxic effects of RS-1 while attempting to improve HDR in the pig. Direct injection of the CRISPR/Cas9 system, combined with strategies to increase the frequency of targeted modifications via HDR, have become an important tool to simplify and accelerate the production of genetically modified livestock models.


Gamma tocopherol-enriched supplement reduces sputum eosinophilia and endotoxin-induced sputum neutrophilia in volunteers with asthma.
We and others have shown that the gamma tocopherol (γT) isoform of vitamin E has multiple anti-inflammatory and antioxidant actions and that γT supplementation reduces eosinophilic and endotoxin (LPS)-induced neutrophilic airway inflammation in animal models and healthy human volunteers. We sought to determine whether γT supplementation reduces eosinophilic airway inflammation and acute neutrophilic response to inhaled LPS challenge in volunteers with asthma. Participants with mild asthma were enrolled in a double-blinded, placebo-controlled crossover study to assess the effect of 1200 mg of γT daily for 14 days on sputum eosinophils, mucins, and cytokines. We also assessed the effect on acute inflammatory response to inhaled LPS challenge following γT treatment, focusing on changes in sputum neutrophilia, mucins, and cytokines. Mucociliary clearance was measured using gamma scintigraphy. Fifteen subjects with mild asthma completed both arms of the study. Compared with placebo, γT notably reduced pre-LPS challenge sputum eosinophils and mucins, including mucin 5AC and reduced LPS-induced airway neutrophil recruitment 6 and 24 hours after challenge. Mucociliary clearance was slowed 4 hours postchallenge in the placebo group but not in the γT treatment group. Total sputum mucins (but not mucin 5AC) were reduced at 24 hours postchallenge during γT treatment compared with placebo. When compared with placebo, γT supplementation for 14 days reduced inflammatory features of asthma, including sputum eosinophils and mucins, as well as acute airway response to inhaled LPS challenge. Larger scale clinical trials are needed to assess the efficacy of γT supplements as a complementary or steroid-sparing treatment for asthma.


A transcriptome analysis of two grapevine populations segregating for tendril phyllotaxy.
The shoot structure of cultivated grapevine Vitis vinifera L. typically exhibits a three-node modular repetitive pattern, two sequential leaf-opposed tendrils followed by a tendril-free node. In this study, we investigated the molecular basis of this pattern by characterizing differentially expressed genes in 10 bulk samples of young tendril tissue from two grapevine populations showing segregation of mutant or wild-type shoot/tendril phyllotaxy. One population was the selfed progeny and the other one, an outcrossed progeny of a Vitis hybrid, 'Roger's Red'. We analyzed 13 375 expressed genes and carried out in-depth analyses of 324 of them, which were differentially expressed with a minimum of 1.5-fold changes between the mutant and wild-type bulk samples in both selfed and cross populations. A significant portion of these genes were direct cis-binding targets of 14 transcription factor families that were themselves differentially expressed. Network-based dependency analysis further revealed that most of the significantly rewired connections among the 10 most connected hub genes involved at least one transcription factor. TCP3 and MYB12, which were known important for plant-form development, were among these transcription factors. More importantly, TCP3 and MYB12 were found in this study to be involved in regulating the lignin gene PRX52, which is important to plant-form development. A further support evidence for the roles of TCP3-MYB12-PRX52 in contributing to tendril phyllotaxy was the findings of two other lignin-related genes uniquely expressed in the mutant phyllotaxy background.


Prednisolone inhibits proliferation of cultured pulmonary artery smooth muscle cells of patients with idiopathic pulmonary arterial hypertension.
Idiopathic pulmonary arterial hypertension (IPAH) is associated with proliferation of smooth muscle cells (SMCs) in small pulmonary arteries. There is no therapy that specifically inhibits SMC proliferation. Recent studies reported that prednisolone (PSL) inhibits the postangioplasty proliferation of SMCs in atherosclerotic arteries. In this study, we tested the hypothesis that PSL has antiproliferative effects on pulmonary artery SMCs of patients with IPAH. Pulmonary artery SMCs were harvested from the pulmonary arteries of 6 patients with IPAH who underwent lung transplantation. Control SMCs were obtained from 5 patients with bronchogenic carcinoma who underwent lung lobectomy. After incubation in the presence of platelet-derived growth factor (PDGF), PSL was added at different concentrations and cell proliferation was assessed by 3H-thymidine incorporation. PSL (2x10(-4) and 2x10(-3) mol/L) significantly inhibited PDGF-stimulated proliferation (P<0.05) of SMCs from patients with IPAH but did not affect cell viability of SMCs, as confirmed by trypan blue staining. In cell cycle analysis using a microscope-based multiparameter laser scanning cytometer, PSL inhibited the progression of SMCs from G(0)/G1 to the S phase. This inhibition was associated with increased p27 expression level. PSL (2x10(-4) mol/L) also inhibited PDGF-induced SMC migration. Our results indicate that PSL has an antiproliferative effect on cultured SMCs of pulmonary arteries from patients with IPAH and suggest that PSL may be potentially useful therapeutically in patients with IPAH.


Pear pomace ethanol extract improves insulin resistance through enhancement of insulin signaling pathway without lipid accumulation.
The anti-diabetic activity of pear through inhibition of α-glucosidase has been demonstrated. However, little has been reported about the effect of pear on insulin signaling pathway in obesity. The aims of this study are to establish pear pomace 50% ethanol extract (PPE)-induced improvement of insulin sensitivity and characterize its action mechanism in 3T3-L1 cells and high-fat diet (HFD)-fed C57BL/6 mice. Lipid accumulation, monocyte chemoattractant protein-1 (MCP-1) secretion and glucose uptake were measure in 3T3-L1 cells. Mice were fed HFD (60% kcal from fat) and orally ingested PPE once daily for 8 weeks and body weight, homeostasis model assessment of insulin resistance (HOMA-IR), and serum lipids were measured. The expression of proteins involved in insulin signaling pathway was evaluated by western blot assay in 3T3-L1 cells and adipose tissue of mice. In 3T3-L1 cells, without affecting cell viability and lipid accumulation, PPE inhibited MCP-1 secretion, improved glucose uptake, and increased protein expression of phosphorylated insulin receptor substrate 1 [p-IRS-1, (Tyr632)], p-Akt, and glucose transporter type 4 (GLUT4). Additionally, in HFD-fed mice, PPE reduced body weight, HOMA-IR, and serum lipids including triglyceride and LDL-cholesterol. Furthermore, in adipose tissue, PPE up-regulated GLUT4 expression and expression ratio of p-IRS-1 (Tyr632)/IRS, whereas, down-regulated p-IRS-1 (Ser307)/IRS. Our results collectively show that PPE improves glucose uptake in 3T3-L1 cells and insulin sensitivity in mice fed a HFD through stimulation of the insulin signaling pathway. Furthermore, PPE-induced improvement of insulin sensitivity was not accompanied with lipid accumulation.


Endocytosis, membrane recycling and Fc receptor function.
We have studied the composition and fate of plasma membrane internalized during both fluid-phase and receptor-mediated endocytosis in mouse macrophages. Particular attention has been paid to the macrophage Fc receptor, an intrinsic membrane glycoprotein that we have isolated and characterized biochemically and immunologically. Monoclonal and polyclonal antibodies directed against the receptor and against a series of other unrelated plasma membrane proteins have been used. In addition, we have used radioiodination techniques to label selectively the polypeptides of pinocytic vesicle membrane from within intact cells. Our results indicate that fluid pinocytosis in macrophages involves the internalization of a largely representative sample of plasma membrane polypeptides. Significantly, the Fc receptor seems to be internalized at a rate similar to that of most other membrane proteins. However, selective internalization of the receptor is induced during the endocytosis of certain ligands. The phagocytosis of immunoglobulin G (IgG)-coated erythrocyte ghosts results in the selective and largely irreversible removal of Fc receptors from the macrophage surface. Selectively internalized receptors do not recycle but are rapidly degraded. Fc receptors also appear to be preferentially interiorized during the rapid pinocytosis of IgG-containing soluble immune complexes. Uptake is accompanied by a sharp decrease in the number of surface receptors, which is partially reversed after the removal of ligand.


[Effect of substance P on the ganglion trigeminale in tissue culture (author's transl)].
Explants of the ganglion trigeminale from chick embryos were cultivated in Maximow chambers in the presence of 10-6...10-8 M substance P (SP . 3CH3COOH.4H2O). 1. In SP-treated cultures the index of areas covered by the explants was increased in shorttime tests. 2. The density of cells was related to the type of medio-dorsal (MD) and ventro-lateral (VL) neuroblasts. The density of SP-treated VL cells was not altered. The density of MD cells decreased. 3. The percentage of dark neuroblasts was decreased under the influence of SP. 4. A stimulation of VL neuroblasts did not take place. 5. The diameters of MD pericarya and the areas of MD cell nuclei and the areas of nuclei from nonneuronal cells increased. 6. The possible role of SP as a factor controlling In-vitro-processes is discussed.


Antibodies raised against bovine beta-lactoglobulin react with beta 2-microglobulin. A possible antigenic region at beta-LG positions 124-140.
beta-Lactoglobulin is a major whey protein in bovine milk. Its presence has been demonstrated in all mammals examined except rodents and humans. However a positive cross reaction was observed for human milk proteins with antibodies raised against bovine beta-lactoglobulin. We isolated and characterized a protein fraction of ca. 12 kDa responsible for the positive cross reaction. N-terminal sequencing and amino-acid analysis indicated that this protein is identical with human beta 2-microglobulin. We observed structural homology between beta-lactoglobulin region 124-140 and beta 2-microglobulin 71-86, which suggested that positions 124-140 could be the antigenic region for beta-lactoglobulin. Six highly conserved amino-acid residues are suggested as candidates for the antigenic site.


Negative/Zero Thermal Quenching of Luminescence via Electronic Structural Transition in Copper-Iodide Cluster-Based Coordination Networks.
Photoluminescence (PL) intensity in organic or metal-organic emitters usually suffers from thermal quenching (TQ), which severely hinders their industrial applications. The development of negative thermal quenching (NTQ) and/or zero thermal quenching (ZTQ) materials depends on a better understanding of the mechanisms underpinning TQ in luminescent solids. In this work, we investigated the temperature dependence of thermally activated delayed fluorescence (TADF) in copper(I)-organic coordination polymers (CP) ligated with an imidazole or triazole derivative over a broad temperature range. The efficient PL emission of CP1 is heavily quenched as the crystalline samples are cooled to 77 K; the PL intensity shows the NTQ effect in the region of 77-238 K followed by a ZTQ effect in the temperature range of 238-318 K. No NTQ or ZTQ effect is observed for reference coordination polymer CP2, where the 1,2,4-triazole group was used instead of the imidazole one. Our work highlights the important role of the ligand's electronic structure in optimizing photophysical properties of coordination polymer emitters and may stimulate new efforts to design luminescent materials exhibiting NTQ and ZTQ effect at higher temperature.


Does uremic environment down-regulate T cell activation via TCR/CD3 antigen receptor complex?
TCR/CD3 receptor complex plays a central role in antigen recognition and T cell activation. Therefore, the present study investigates TCR alpha/beta (TCR-1) and CD3 receptor density (RD, number of receptors per cell) on uremic CD4 T lymphocytes in relation to T cell proliferative response induced by anti-CD3 monoclonal antibodies (mAb). The influence of uremic serum on TCR/CD3 receptor expression of normal and uremic CD4 T lymphocytes was evaluated as well. We found, that: a) percentage of TCR-1 and CD3 positive cells of freshly isolated CD4 T lymphocytes is the same in controls and ESRD-patients, but the TCR/CD3 RD is lower on uremic CD4 T lymphocytes, b) Incubation for 24 h with uremic serum lowers TCR/CD3 RD on normal and uremic CD4 T cells, c) There is positive correlation between TCR/CD3 RD and anti-CD3 induced lymphocyte proliferation. These data might also support the hypothesis that blunted T-cell response to antigen in uremia is due to down-regulation of the TCR/CD3 receptor complex by uremic milieu.


Glial modulation of synaptic transmission in the retina.
Glial modulation of synaptic transmission and neuronal excitability in the mammalian retina is mediated by several mechanisms. Stimulation of glial cells evokes Ca(2+) waves, which propagate through the network of retinal astrocytes and Müller cells and result in the modulation of the activity of neighboring ganglion cells. Light-evoked spiking is enhanced in some ganglion cells and depressed in others. A facilitation or depression of light-evoked excitatory postsynaptic currents is also seen in ganglion cells following glial stimulation. In addition, stimulation of glial cells evokes a sustained hyperpolarizing current in ganglion cells which is mediated by ATP release from Müller cells and activation of neuronal A(1) adenosine receptors. Recent studies reveal that light-evoked activity in retinal neurons results in an increase in the frequency of Ca(2+) transients in Müller cells. Thus, there is two-way communication between neurons and glial cells, suggesting that glia contribute to information processing in the retina.


Super-resolution imaging of photogenerated charges on CdS/g-C3N4 heterojunctions and its correlation with photoactivity.
Construction of heterostructures is an effective way to improve photo-induced charge separation and photocatalytic performance. Among various structures, type II and direct Z-scheme heterojunctions with distinct charge separation mechanisms are the two typical representatives attracting much research attention. Here we prepared type II and Z-scheme CdS/g-C3N4 nanocomposites by thermal treatment and self-assembly chemisorption methods, respectively. High-resolution microscopy techniques including (scanning) transmission electron microscopy (TEM/STEM) and super-resolution fluorescence microscopy (SRM) were used to investigate the charge distribution and flow mechanism. The charge tracking results reveal that the nanocomposite prepared by thermal treatment has a type II heterostructure with charges flowing in the opposite direction, while the self-assembly sample possesses a Z-scheme structure. It was found that the type II system exhibited the lowest charge migration resistance and the best charge separation ability and stability of photoactivity, leading to the highest H2 generation rate of 2410 μmol h-1 g-1. The SRM technique was applied for the first time to map the reactive sites of type II and Z-scheme structures at nanometer resolution. The photoactive species (i.e., e- and h+) were found to be preferentially distributed at the two end segments of CdS nanorods and the edge boundaries of g-C3N4. Therefore, our findings shed more light on the charge distribution and photocatalytic heterogeneity of composite materials at the nanoscale. Such results would provide guidance on optimizing nanocomposite properties and help to design better photocatalysts for efficient solar-to-chemical energy conversion.


Combined treatment with cyclophosphamide and prednisolone can induce remission of nephrotic syndrome in a patient with renal amyloidosis, associated with rheumatoid arthritis.
A 67-year-old woman, who had been diagnosed with classical rheumatoid arthritis (RA), was admitted to our hospital because of massive proteinuria. Biopsy of the kidney revealed deposition of amyloid fibrils in the subepithelial and subendothelial spaces of the glomerular capillary walls. Though the treatment with prednisolone and dipyridamole against nephrotic syndrome and amyloidosis due to RA was not effective, cyclophosphamide, which was added after tapering of prednisolone, was able to induce remission of nephrotic syndrome after two years. The levels of CRP and serum amyloid A protein (SAA) returned to within the normal limits. As the impairment of renal function is thought to be due to deposition of amyloid supplied from the precursors of amyloid fibrils filtered from the general circulation in RA patients, remission of nephrotic syndrome might result from the suppression of production of SAA or removal of amyloid fibrils. Cyclophosphamide, which has the potential both to suppress disease activity in RA and to produce degradation of amyloid fibrils in glomeruli, may be useful against renal or systemic amyloidosis complicated by RA.


Psychological status is associated with the perceived illness stigma in Chinese systemic lupus erythematosus patients.
Systemic lupus erythematosus (SLE) might affect all aspects of life including perceived stigma, but research on perceived stigma is still in its infancy among SLE patients. The objective of this study was to assess the relationships among socioeconomic status, clinical parameters, disease activity, quality of life, depression, and the perceived stigma in Chinese patients with SLE. A total of 133 SLE patients (mean age: 39.36 ± 12.91 years) were included in this cross-sectional study. All data were collected consecutively by face-to-face questionnaires from January 2021 to January 2022. SLE patients completed questionnaires for demographic or clinical variables, the 10-cm Visual Analog Scale for pain, the Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) for disease activity, the patient health questionnaire-9 (PHQ-9) for depression, the Perceived Devaluation Discrimination (PDD) Scale for the perceived stigma, and the Short Form 12 health survey (SF-12) for quality of life. Independent sample t-test, Spearman or Pearson correlations analysis, and the multivariable linear regression model were used to analyze these data. The mean PDD scale score in the SLE patients was 2.79 ± 0.33, which were statistically significant compared with the midpoint (2.50 ± 0.38) of the scale (P < 0.05). The perceived stigma was significantly correlated with income, pain, disease activity, depression, and quality of life. The SF-12 mental composite summaries (MCS) score and depression were the important predictors of the perceived stigma by the multivariable linear regression. This study demonstrates that psychological status is significantly associated with the perceived illness stigma in Chinese SLE patients; dealing with this stigma may be important in promoting optimal coping for these patients.


Neural evidence for a 3-state model of visual short-term memory.
Recent research has suggested that short-term memory (STM) can be partitioned into three distinct states. By this model, a single item is held in the focus of attention making it available for immediate processing (focus of attention), a capacity-limited set of additional items is actively maintained for future processing (direct access region), and other recently presented information is passively active, but can nevertheless influence ongoing cognition (activated portion of long-term memory). While there is both behavioral and neural support for this 3-state model in verbal STM, it is unclear whether the model generalizes to non-verbal STM. Here, we tested a 3-state model of visual STM using fMRI. We found a triple dissociation of regions involved in the access of each hypothesized state. The inferior parietal cortex mediated access to the focus of attention, the medial temporal lobe (MTL) including the hippocampus mediated access to the direct access region, and the left ventrolateral prefrontal cortex (VLPFC) mediated access to the activated portion of long-term memory. Direct comparison with previously collected verbal STM data revealed overlapping neural activations involved in the access of each state across different forms of content suggesting that mechanisms of access are domain general. These data support a 3-state model of STM.


Alveolar pyogenic granuloma: review and report of a case.
A large exophytic bone-resorbing lesion was discovered in the oral cavity of an institutionalized 33-year-old male. An excisional biopsy under general anesthesia was performed. Frozen and permanent histologic sections confirmed a reactive gingival fibroma consistent with a pyogenic granuloma. This lesion is unusual in that it attained a very large size and caused marked remodeling of the alveolar bone of the mandible. Of interest as well, this highly vascular lesion was found to have numerous feeding vessels from the alveolar bone. A retained tooth root was encountered within the lesion, presumably the etiologic factor producing this lesion. A differential diagnosis is presented and discussed. The lesion should be of particular interest to otolaryngologists who deal with intraoral lesions and their treatment, since it illustrates an extreme presentation of a totally benign process.


Investigation of an outbreak of device-related postoperative ventriculitis: a lesson learnt.
Pseudomonas aeruginosa (P aeruginosa) is one of the most common nosocomial pathogens. We report our experience of a device-related outbreak of postoperative ventriculitis caused by P aeruginosa thus initiating investigation of the unusual occurrence. Five neurosurgical patients were affected, postoperatively. The investigations entailed extensive screening of the common sources of contamination for colonization of P aeruginosa. Sterilized instruments used for surgery, including the ultrasonic aspirator (USA) sets and other hollow devices, were randomly sampled and cultured. Conventional culture methods yielded P aeruginosa, with almost similar antibiotic sensitivity pattern in all the patients and the ultrasonic aspirator, clinching the source of contamination. Routine surveillance, identification of unusual patterns, molecular epidemiological typing would be helpful in quick control of outbreaks of postoperative infections.


Occupational Therapy Education in Saudi Arabia: Barriers and Solutions From a Cross-Sectional Survey Study.
Objective Occupational therapy (OT) is an important healthcare profession in Saudi Arabia (SA). Yet, no studies have explored the status of OT education in SA. The current study aims to investigate the status of OT education in SA, as well as the barriers and solutions. Methods A cross-sectional-based survey was conducted. Institutions that offered OT programs were identified and an electronic survey was sent to OT program directors across SA that agreed to participate. The survey included items that focused on the number of students in programs, current faculty members, and their characteristics, as well as barriers and solutions to advancing the OT profession and education in SA. Results Out of 74 institutions, eight offered OT programs and all responded to the survey. Among all programs, one was inactive, seven (87.5%) were governmental institutions, and none were nationally accredited. There was a total of 538 currently enrolled students and 76 full-time faculty members. There are no current OT postgraduate programs. Staff shortages and ineffective communication between institutions (87.5%), financial barriers, and lack of knowledge/awareness of the OT profession (75%) were the most common barriers reported. Conclusion OT education is growing in SA but is still not well-represented throughout the different regions of the country. Initiatives to advance the profession are urgently needed by establishing new OT programs and departments as well as introducing OT to more diverse scopes of practice and in more clinical settings. Further research exploring OT education including curriculum content, teaching methods, and assessment strategies of OT programs. Addressing the barriers identified in the current study and methods to overcome them is needed.


2D Magnetic Janus Semiconductors with Exotic Structural and Quantum-Phase Transitions.
2D magnetic semiconductors are intriguing for their great potential applications in spintronic nanodevices. Despite intensive research for decades, intrinsically 2D magnetic Janus semiconductors are scarce, and their design guidelines remain elusive. Herein we propose new 2D Janus Cr2O2XY (X = Cl, Y = Br/I) ferromagnets with asymmetric out-of-plane structural configurations from ab initio calculations. Abnormally, 2D Janus Cr2O2XY crystals with Pmm2 structures derived from pristine CrOX compounds are dynamically metastable. By introducing novel structural phase transitions, we generated new Pma2 phases with lower total energy and great dynamical stability. These new Janus Cr2O2XY monolayers are intrinsically ferromagnetic semiconductors and could be easily synthesized from experiment. Most interestingly, exotic quantum-phase transitions from the ferromagnetic semiconductor to the antiferromagnetic metal/semiconductor could be achieved in the Cr2O2ClI monolayer by applying compressive strains. Our study provides an alternative strategy to design new Janus Cr2O2XY monolayers and will inspire further investigations on relevant materials for electronic and spintronic applications.


Cdc42 Signaling Pathway Inhibition as a Therapeutic Target in Ras- Related Cancers.
The frequency of pro-oncogenic mutations and development of drug resistance are major challenges for successful Ras-related cancer treatment. Novel targets in the Ras-signaling pathway may address these challenges. Cell division cycle protein 42 (Cdc42) is a classical member of the Rho family of small GTPases in the Ras oncogene superfamily. Enhanced Cdc42-signaling facilitates Ras-mediated cellular transformation, tumorigenesis, and metastasis. Cdc42, Ras, and EGFR are involved in an activation loop that prolongs their signaling. This review evaluates the benefits of targeting Cdc42 signaling as an anti-Ras cancer target. We review the link between Ras and Cdc42 and summarize the roles of Cdc42 and select effectors in cancers. We discuss the discovery/development of Cdc42-signaling modulators and highlight studies that report the inhibition of the Cdc42-signaling pathway in several Ras-related cancer cell lines. Compared to EGFR and Ras, mutations that lead to the prolonged activation of Cdc42 are less common. Activation of upstream signals, changes in regulator expression, and alterations of Cdc42 protein expression play an important role in regulating Cdc42 activity. Eight selected effectors/adaptors of Cdc42 play a role in oncogenic Ras signaling. Of the fourteen natural and synthetic Cdc42 inhibitors discussed, eight small molecule inhibitors of Cdc42 have been used effectively in Ras-related cancer lines derived from breast, colon, lung, and pancreatic cancer. Cdc42 is a putative therapeutic target in Ras-related cancers since Cdc42 functions downstream of EGFR and Ras, Cdc42 promotes/activates EGFR and Ras signaling, and Cdc42 inhibition in Ras-related cancers elicits anticancer effects.


Antithrombotic treatment beyond 1 year after percutaneous coronary intervention in patients with atrial fibrillation.
Beyond 1 year after percutaneous coronary intervention (PCI), guidelines recommend anticoagulant monotherapy in patients with atrial fibrillation (AF) rather than dual therapy with an anticoagulant and an antiplatelet drug. The risks and benefits of this strategy, however, remain uncertain. We examined hospitalization for bleeding and ischaemic risk beyond 1 year after PCI in patients with AF treated with monotherapy vs. dual therapy. Furthermore, among patients treated with monotherapy, we compared direct oral anticoagulant (DOAC) therapy and vitamin K antagonist (VKA) therapy. We included all patients with AF undergoing first-time PCI between 2003 and 2017 from the Western Denmark Heart Registry and followed them for up to 4 years. Follow-up started 15 months after PCI to enable assessment of medical treatment after 12 months. Using a Cox regression model, we computed weighted hazard ratios (HRw) of hospitalization for bleeding and major adverse cardiac events (MACEs). Analyses comparing monotherapy vs. dual therapy included 3331 patients, and analyses comparing DOAC vs. VKA monotherapy included 1275 patients. Risks of hospitalization for bleeding [HRw 0.90, 95% confidence interval (CI) 0.75-1.09] and MACE (HRw 1.04, 95% CI 0.90-1.19) were similar with monotherapy and dual therapy. Similarly, risks of hospitalization for bleeding (HRw 1.27, 95% CI 0.84-1.92) and MACE (HRw 1.15, 95% CI 0.87-1.50) were equal with DOAC and VKA monotherapy. Our results support long-term OAC monotherapy beyond 1 year after PCI in patients with atrial fibrillation and suggest that DOAC monotherapy is as safe and effective as VKA monotherapy.


OKL38 is an oxidative stress response gene stimulated by oxidized phospholipids.
Oxidized 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphorylcholine (OxPAPC) is present in oxidative modified LDL and accumulates in lesions of many chronic inflammatory diseases, such as atherosclerosis. In a microarray study, OxPAPC has been demonstrated to modulate the expression of >700 genes in human aortic endothelial cells. We found that the levels of mRNA for OKL38 [also named Bone marrow Derived Growth Factor (BDGI)], a tumor growth inhibitor, were strongly increased by OxPAPC. Here, we report that OKL38 is regulated by an oxidative signal induced by OxPAPC and its component lipid 1-palmitoyl-2-epoxyisoprostane E2-sn-glycero-3-phosphorylcholine. The stimulation of OKL38 by OxPAPC depends on superoxide production, because the NADPH oxidase (Nox) inhibitor apocynin and the superoxide scavenger N-acetyl cysteine block this stimulation. Oxidative stress by tert-butylhydroquinone treatment also induced the expression of OKL38. The stimulation of OKL38 expression by OxPAPC is mediated via transcription factor nuclear factor E2-related factor (Nrf2), a common factor involved in the regulation of oxidative stress-stimulated genes. Activation of Nrf2 induces the expression of OKL38, whereas small interfering RNA knockdown of Nrf2 blocks the stimulation of OKL38 by OxPAPC. Our results suggest that OKL38 is regulated via the Nox/Nrf2 pathway in response to oxidative stress stimuli.


The natural phenolic compounds as modulators of NADPH oxidases in hypertension.
Hypertension is a major public health problem worldwide. It is an important risk factor for other cardiovascular diseases such as coronary artery disease, stroke, heart failure, atrial fibrillation, peripheral vascular disease, chronic kidney disease, and atherosclerosis. There is strong evidence that excess ROS-derived NADPH oxidase (NOX) is an important agent in hypertension. It augments blood pressure in the presence of other pro-hypertensive factors such as angiotensin II (Ang II), an important and potent regulator of cardiovascular NADPH oxidase, activates NOX via AT1 receptors. NADPH oxidase, a multi-subunit complex enzyme, is considered as a key source of ROS production in the vasculature. The activation of this enzyme is needed for assembling Rac-1, p40phox, p47phox and p67phox subunits. Since, hypertensive patients need to control blood pressure for their entire life and because drugs and other chemicals often induce adverse effects, the use of natural phenolic compounds which are less toxic and potentially beneficial may be good avenues of addition research in our understand of the underlying mechanism involved in hypertension. This review focused on several natural phenolic compounds as berberine, thymoquinone, catechin, celastrol, apocynin, resveratrol, curcumin, hesperidine and G-hesperidine, and quercetin which are NOX inhibitors. In addition, structure activity relationship of these compounds eventually as the most inhibitors was discussed. This comprehensive review is based on pertinent papers by a selective search using relevant keywords that was collected using online search engines and databases such as ScienceDirect, Scopus and PubMed. The literature mainly focusing on natural products with therapeutic efficacies against hypertension via experimental models both in vitro and in vivo was identified. It has been observed that these natural compounds prevent NADPH oxidase expression and ROS production while increasing NO bioavailability. It have been reported that they improve hypertension due to formation of a stable radical with ROS-derived NADPH oxidase and preventing the assembly of NOX subunites. It is clear that natural phenolic compounds have some potential inhibitory effect on NADPH oxidase activity. In comparison to other phenolic plant compounds, the structural variability of the flavonoids should off different impacts on oxidative stress in hypertension including inhibition of nadph oxidase and direct scavenging of free radicals.


Facial approximation: Soft tissue thickness values for Caucasian males using cone beam computer tomography.
The aim of this study was to obtain soft tissue thickness (STTs) of Caucasian males starting from 12 bone landmarks, to allow facial reconstruction and assign an identity to skeletal remains. When a skeleton is found without any circumstantial evidence of identity, through anthropological investigations it is possible to estimate age, sex, and race studying specific characteristics of bones. This first step of identification process helps investigators to narrow down the identity suppositions, but not always forensic analysis guarantees a final positive identification. Moreover, it is possible to rely on facial reconstruction trying to reproduce the likely features of the face from the skull. The obtained images could be used as a support in recognition by relatives who could provide photos and other data to carry out a comparative analysis. Furthermore, identity can be confirmed by conventional identification methods such as DNA profiling, odontological identification, and radiological comparison. Forensic facial reconstruction (FFR) is based on the bone surface that conditions the facial physiognomy. Analyzing cone beam CT (CBCT) scans of 30 Caucasian males, average STTs values were obtained. CBCT, compared with the conventional spiral CT, has much lower radiation doses, lower costs, high spatial resolution and focuses on head and neck. The obtained results were compared with existing literature and databases and were analyzed by descriptive statistics. Two researchers repeated measurements in different times to assess the reliability of the method.


Questionnaire survey and environmental measurements that led to smooth implementation of smoking control measures in workplaces.
In order to promote smoking countermeasures in a manufacturing plant, we conducted a questionnaire survey about smoking control measures in workplaces. Twenty nine point five percent of the subjects responded that they were exposed to passive smoking where they worked and that the most common source of passive smoking in the workplace and rest areas was environmental tobacco smoke (ETS) leaking from smoking areas. For smoking control measures, 27.8% of employees preferred a total ban on smoking in the building while 55.2% preferred measures to prevent ETS leakage from smoking areas. Regardless of whether they were smokers or not, 99.2% of respondents believed that passive smoking countermeasures in the workplace were necessary and 88.9% of smokers responded that banning smoking in the building was unavoidable. Based on these results, a total ban on smoking in the building was implemented in those workplaces where it was feasible to do so, smoking areas in the remaining workplaces were upgraded to prevent ETS infiltration, and the effects were evaluated by real-time monitoring of the concentration of suspended particle matter. The questionnaire survey results showed that 79.9% of smokers were interested in smoking cessation, that awareness of the adverse health effects of smoking on the smoker and surrounding non-smokers and the nuisance it caused was significantly lower among smokers compared to non-smokers (p<0.01), and that 65.5% of non-smokers believed that smoking was beneficial to the mental health of smokers, despite the fact that they had no experience of smoking themselves. Reporting these results to the Safety and Health Committee was found to be useful both in ensuring thorough segregation of smoking areas and in supporting smoking cessation programs in places where no previous action had been taken because smoking was viewed as a matter of personal choice. We also believe that provision of accurate information tailored to actual smoking conditions in the workplace is useful in effectively implementing anti-smoking campaigns on the adverse effects of smoking and smoking cessation programs. The implementation of a questionnaire survey and environmental measurements that lead to countermeasures was shown to be effective in establishing designated smoking areas and educational programs for smoking cessation.


Using a Federated Network of Real-World Data to Optimize Clinical Trials Operations.
Clinical trials, whether industry, cooperative group sponsored, or investigator initiated, have an unacceptable rate of failure as a result of the inability to recruit sufficient numbers of patients. Even those trials that are completed often require time-consuming protocol amendments to achieve accrual goals. These inefficiencies in clinical trial research result in increasing costs and prolong the time needed to bring improved treatments to cancer clinical practice. TriNetX has developed a clinical research collaboration platform-deployed by a federated network of health care organizations (HCOs), pharmaceutical firms (Pharma), and contract research organizations (CROs)-to enable data-driven clinical research study design to reduce accrual failure and protocol amendment. Currently, the network extends to 55 HCOs and covers 84 million patients, mostly within the United States, but with a growing international presence. (Many of the HCOs in United States are Clinical and Translational Science Awardees and/or National Cancer Institute-designated cancer centers.) The TriNetX business model includes Pharma and the CROs as sponsors whose subscriptions financially support the network, including the software and hardware costs of the HCOs. Furthermore, as each HCO network member has their data harmonized with the TriNetX model upon joining, data sharing among them does not require any technical processes to establish connectivity. To date, on the basis of the data on the network, HCOs have been presented approximately 757 studies by Pharma and CROs, and four data-sharing subnetworks have been formed among member HCOs.


Evolution of Neuroplasticity in Response to Physical Activity in Old Age: The Case for Dancing.
From animal research, it is known that combining physical activity with sensory enrichment has stronger and longer-lasting effects on the brain than either treatment alone. For humans dancing has been suggested to be analogous to such combined training. Here we assessed whether a newly designed dance training program that stresses the constant learning of new movement patterns is superior in terms of neuroplasticity to conventional fitness activities with repetitive exercises and whether extending the training duration has additional benefits. Twenty-two healthy seniors (63-80 years) who had been randomly assigned to either a dance or a sport group completed the entire 18-month study. MRI, BDNF and neuropsychological tests were performed at baseline and after 6 and 18 months of intervention. After 6 months, we found a significant increase in gray matter volume in the left precentral gyrus in the dancers compared to controls. This neuroplasticity effect may have been mediated by the increased BDNF plasma levels observed in the dancers. Regarding cognitive measures, both groups showed significant improvements in attention after 6 months and in verbal memory after 18 months. In addition, volume increases in the parahippocampal region were observed in the dancers after 18 months. The results of our study suggest that participating in a long-term dance program that requires constant cognitive and motor learning is superior to engaging in repetitive physical exercises in inducing neuroplasticity in the brains of seniors. Therefore, dance is highly promising in its potential to counteract age-related gray matter decline.


The Microbiome and p-Inulin in Hemodialysis: A Feasibility Study.
The intestinal microbiome is an appealing target for interventions in ESKD because of its likely contribution to uremic toxicity. Before conducting clinical trials of microbiome-altering treatments, it is necessary to understand the within-person and between-person variability in the composition and function of the gut microbiome in patients with ESKD. We conducted a multicenter, nonrandomized, crossover feasibility study of patients on maintenance hemodialysis consisting of three phases: pretreatment (8 weeks); treatment, during which the prebiotic, p-inulin, was administered at a dosage of 8 g twice daily (12 weeks); and post-treatment (8 weeks). Stool samples were collected 1-2 times per week and blood was collected weekly for 28 weeks. The gut microbiome was characterized using 16S ribosomal-RNA sequencing and metabolomic profiling. A total of 11 of the 13 participants completed the 28-week study. Interparticipant variability was greater than intraparticipant variability for microbiome composition (P<0.001 by UniFrac distances) and metabolomic composition (P<0.001 by Euclidean distances). p-Inulin was well tolerated by 12 of 13 participants. Adherence to the frequent sample collection and self-aliquoting of stool samples were both 96%. A change in the microbiome composition from pretreatment to post-treatment was evident by the overall shifts in weighted UniFrac distances (P=0.004) and a progressive decrease in prevalence of high intraclass correlations, indicating an increase in intraparticipant microbiome diversity during and after p-inulin treatment. An effect of p-inulin on the metabolomic profile was not evident. The intraparticipant stability of the gut microbiome under no-treatment conditions, the tolerability of p-inulin, the signals of increased diversity of the microbiome with p-inulin treatment, and the willingness of participants to provide stool samples all support the feasibility of a larger trial to investigate interventions targeting the gut microbiome in patients with ESKD. Whether or not p-inulin has sufficient efficacy as an intervention requires evaluation in larger studies. Gut Microbiome and p-Inulin in Hemodialysis, NCT02572882.


Association of Skin Intrinsic Fluorescence with Retinal Microvascular Complications of Long Term Type 1 Diabetes in the Wisconsin Epidemiologic Study of Diabetic Retinopathy.
To determine the association between skin intrinsic fluorescence (SIF), a noninvasive measure of advanced glycation endproducts and oxidative stress in skin, and retinal microvascular complications of long duration type 1 diabetes, proliferative diabetic retinopathy (PDR) and macular edema. A cross-sectional cohort study of persons with type 1 diabetes in the Wisconsin Epidemiologic Study of Diabetic Retinopathy (WESDR) who participated in a 32-year follow-up examination in 2012-2014. Subjects underwent a physical examination, answered a health questionnaire, and had fundus photographs taken. SIF was measured on the underside of the left forearm near the elbow with the SCOUT DS® skin fluorescence spectrometer. Two representative SIF measures were used for these analyses: SIF01 excited by an LED centered at 375 nm with correction factors Kx = 0.6 and Km = 0.2 and SIF15 excited by an LED centered at 456 nm with correction factors Kx = 0.4 and Km = 0.9. The 414 participants had mean diabetes duration of 42.2 years (standard deviation 6.8 years, range 32.9-67.9 years). PDR was statistically significantly associated (p < 0.05) with both SIF measures in multivariate models including other relevant factors (odds ratio [OR] = 1.17 for SIF01 and 1.20 for SIF15). Skin intrinsic fluorescence measures are independently associated with PDR in the WESDR. Incidence information is needed to evaluate whether there is a causal relationship.


Aberrant resting state in microRNA-30e rat model of cognitive impairment.
Increasing evidence suggests that microRNA (miRNA)-30e is implicated in the cognitive symptoms of many neuropsychiatric diseases. Our previous studies showed that miRNA-30e is associated with cognitive impairment in schizophrenia and depression. Neuroimaging studies have suggested that cognitive impairment is best characterized as abnormal local activity or a disconnection syndrome. Therefore, we constructed a cognitively impaired overexpressing miRNA-30e rat model for study using functional MRI (fMRI). The model was developed by transfected lentiviral particles carrying the miRNA-30e into the hippocampal dentate gyrus. The Morris water maze and open-field test were used to evaluate cognitive ability. We used the regional homogeneity approach to analyze resting-state fMRI data to explore the changes in regional synchronization. We then used Granger causality analysis to explore connectivity between the hippocampus, striatum, and thalamus. The model group showed higher regional homogeneity in the right hippocampus and striatum. One-way Granger causality connections were observed from the thalamus to the hippocampus in the model group, whereas connections from the thalamus to the striatum were observed in normal rats. After fluoxetine treatment, we found indirect connections between the thalamus and the striatum; we also found connections from the hippocampus to the striatum after Shuganjieyu capsule treatment. Our results support the hypothesis that cognitive impairment is related to disrupted local functionality or aberrant brain connectivity, with antidepressant drugs partially reversing cognitive impairment. The characteristics of resting-state fMRI in miRNA-30e overexpressing rats can provide further evidence for investigating the neural mechanisms of cognitive impairment in mental disorders. Video abstract; Supplemental digital content 1, http://links.lww.com/WNR/A385.


Identification of connective tissue components in healing rat gingiva.
The aim of the study was to examine connective tissue fiber organization during healing of an incisional wound in rat molar gingiva. Forty rats 50 days old were divided into 10 experimental groups each comprising four animals. Following interdental incisions, healing periods of 11-20 days, and then 3H-proline injection, the animals were sacrificed and specimens prepared for light microscopy, autoradiography, and transmission electron microscopy. Isotope labeling with 3H-proline occurred over newly formed collagen in the path of incision, while preexisting tissue was unlabeled. Ultrastructurally, preexisting and new tissue were identified by measurement of collagen fibril thickness. The spatial relationship between new and remaining fibrous tissue in the transitional zone suggests that reunion is established by side-by-side alignment of new and severed fibrils.


Attention and Executive Disorders in Neurofibromatosis 1: Comparison Between NF1 With ADHD Symptomatology (NF1 + ADHD) and ADHD Per Se.
Objective: To compare children with Neurofibromatosis type 1 and associated ADHD symptomatology (NF1 + ADHD) with children having received a diagnosis of ADHD without NF1. The idea was that performance differences in tasks of attention between these two groups would be attributable not to the ADHD symptomatology, but to NF1 alone. Method: One group of children with NF1 + ADHD (N = 32), one group of children with ADHD (N = 31), and one group of healthy controls (N = 40) participated in a set of computerized tasks assessing intensive, selective, and executive aspects of attention. Results: Differences were found between the two groups of patients in respect of several aspects of attention. Children with NF1 + ADHD did not always perform worse than children with ADHD. Several double dissociations can be established between the two groups of patients. Conclusion: ADHD symptomatology in NF1 does not contribute to all attention deficits, and ADHD cannot account for all attention impairments in NF1.


Impact of aging-related consumption trend on carbon emission efficiency in China: mediation effect model based on industrial structure adjustment.
With the deepening of China's aging process, changes in the age structure of the population affect the industrial structure and consumption structure in different ways and have a knock-on effect on the whole economic system. Therefore, aging is one of the objective factors affecting future carbon emissions in China. This study analyzes the impact mechanism of aging-related consumption trend on carbon emission efficiency (CEE) based on panel data of 30 Chinese provinces from 2000 to 2019. The results show that the aging-related consumption trend is conducive to the improvement of regional CEE, and the mediation transmission mechanism of industrial structure adjustment is obvious, with a coefficient of 0.1496. The core industry closely linked to the demand for aging-related consumption is consumer services. The promotion of the consumption demand of the aging in the eastern region on the CEE and the transmission stimulation of the industrial structure adjustment are the most obvious. The mediation effect in the central and western regions is relatively weak, and the aging-related consumption demand has not formed a positive interaction with the aging industry. Therefore, improving the market construction of products and services for the aging is beneficial to achieve a virtuous cycle of aging-related consumption upgrading and carbon emission efficiency. This research can provide insights for China to promote industrial structure transformation within the aging trend and also help China meet its carbon neutrality target on schedule.


Imaging appearances of lateral ankle ligament reconstruction.
Six patients were retrospectively identified as having undergone lateral ligament reconstruction surgery. The surgical procedures were categorized into four groups: direct lateral ligament repair, peroneus brevis tendon rerouting, peroneus brevis tendon loop, and peroneus brevis tendon split and rerouting. At radiography and magnetic resonance (MR) imaging, the presence of one or more suture anchors in the region of the anterior talofibular ligament indicates direct ligament repair, whereas a fibular tunnel indicates peroneus brevis tendon rerouting or loop. Both ultrasonography (US) and MR imaging demonstrate rerouted tendons as part of lateral ankle reconstruction; however, MR imaging can also depict the rerouted tendon within an osseous tunnel if present, especially if T1-weighted sequences are used. Artifact from suture material may obscure the tendon at MR imaging but not at US. With both modalities, the integrity of the rerouted peroneus brevis tendon is best evaluated by following the tendon proximally from its distal attachment site, which typically remains unchanged. The rerouted tendon or portion of the tendon can then be traced proximally to its reattachment site. Familiarity with the surgical procedures most commonly used for lateral ankle ligament reconstruction, and with the imaging features of these procedures, is essential for avoiding diagnostic pitfalls and ensuring accurate assessment of the ligament reconstruction.


Tin Oxide Nanorod Array-Based Photonic Memristors with Multilevel Resistance States Driven by Optoelectronic Stimuli.
One-dimensional (1D) metal oxide-based photonic memristors, combining information storage and optical response, have shown great potential for the design and development of high-density and high-efficient computing systems beyond the era of von-Neumann architecture and Moore's law. Here, the functional memristive devices based on SnOx slanted nanorod arrays are demonstrated; wherein both the optical and electrical stimuli have been used to modulate the switching characteristics to achieve multilevel cell operations. The switching characteristics of Al/SnOx/FTO devices include low operating voltages (0.7 V/-0.6 V), moderate ON/OFF ratio (>10), and longer endurance (>102 cycles) and retention (>103 s) with a self-compliance effect in the dark. Under illumination, ranging from ultraviolet (254 and 365 nm) to visible light (405 and 533 nm), an unusual negative photo response with an enlarged ON/OFF ratio of >107 and a faster response time of <8 ms is observed. Additionally, multiple low and high resistance states have been achieved by modulating the programming current and the optical stimulus, respectively. The optoelectronic resistive memory behavior is attributed to the electric field-induced formation and light-stimulated dissolution of oxygen vacancies. Comprehensively, the results suggest that the optical illumination reduces the oxygen ion migration barrier, leading to the dissolution of conductive filaments and thereby locally increasing the OFF state resistance. The fabricated photonic memristors demonstrate the potential applications of metal oxide-based 1D nanostructures for artificial visual memory and optoelectronic applications.


Cell surface dynamics: the balance between diffusion, aggregation and endocytosis.
The cell membrane lies at the interface between an extracellular set of signals and the appropriate intracellular response. Specifically, lymphocyte activity is determined by the spatial and structural response to antigens, as mediated by cell surface receptors. In order to correlate experimentally observed cellular activities, such as secretion, anergy, death, survival and division to external stimuli, it is necessary to monitor cell surface dynamics. B-lymphocyte activation results from the stimulation by large immune complexes comprising antigens, B-cell receptors (BcRs) and co-receptors. Compartmentalisation of the interacting molecular components is required in order to assure the rapid initiation of specialised and sustained signalling cascades. In this study, a Monte Carlo simulation of the cell membrane dynamics was developed to clarify the receptor dynamics, aggregation mechanisms and their combined effect on cellular functions. This simulation is based on experimentally measured parameters and represents a feasible, advanced and reliable framework to investigate the cell surface. The current study focussed on B-cell surface dynamics. A model demonstrating the basic properties of BcR dynamics and how BcR kinetics is affected by lipid rafts is developed. The authors studied BcR interactions with multivalent ligands and the influence of lipid rafts on this interaction. Finally, the dynamics of the initial steps of BcR-mediated cell activation is estimated and the effect of the association of signalling molecules with lipid rafts is demonstrated. These results are used to suggest some novel hypotheses on BcR-mediated B-cell activation.


[The analysis of protein-protein interaction with special reference to PRIP-1].
Analysis of protein-protein interaction is one of the powerful methods for elucidating the new functions of functionally unknown proteins. Using this approach, we isolated two proteins interacting with PRIP-1, which was isolated as a new Ins(1,4,5) P3 binding protein from brain. One was protein phosphatase 1 catalytic subunit (PP1c) and the other was GABARAP (GABAA-receptor-associated protein). The region of PRIP-1 responsible for their interaction was the site preceding to the pleckstrin homology domain of PRIP-1 for PP1c and the EF-hand motifs of PRIP-1 for GABARAP, which were determined by beta-galactosidase assay of yeast two-hybrid system. The association between PRIP-1 and PP1c was confirmed in vitro by a pull-down assay, a far-western assay, an immunoprecipitation analysis and a surface plasmon resonance analysis. The interaction of PRIP-1 with PP1c resulted in inhibition of the catalytic activity of PP1c in a PRIP-1 concentration-dependent manner. The association between PRIP-1 and GABARAP was also confirmed by a pull-down assay, and we found that PRIP-1 competitively inhibited the binding of the gamma 2 subunit of the GABAA receptor to GABARAP in vitro. Our electrophysiological and behavioral analysis of PRIP-1 knockout mice revealed that PRIP-1 is essential for the function of GABAA receptors, especially in response to the agents acting on the gamma 2 subunit.


[GENDER VARIABILITY OF MORPHOFUNCTIONAL INDICES IN ADOLESCENTS OF MOUNTAIN ALTAI].
Gender differences in the functioning of the organism of teenagers in extreme climatic conditions of the environment are not been well understood. We estimated the variability of morphofunctional indices in adolescents aged of 11-16 years residing in lowlands and midlands of Mountain Altai in dependence on area of residence, age, and gender The variability of morphological and functional indices of male and female body in a critical period of ontogenesis was found to be dependent in varying degrees on the climatic conditions of the Mountainous Altai. Revealed significant differences in morphofunctional indices depending on the area in boys are more signifcant than in girls. In male adolescents, residing in middleland unlike peers of lowland there was noted functional exertion of the cardiovascular system, as well as delay in physical and sexual development. It testifies about the gender variability of adaptation of an organism depending on factors of environment and higher sensitivity of a male organism during the period of puberty to external negative influences.


A Spinning Umbrella: Carbon Monoxide and Dinitrogen Bound MB12- Clusters (M = Co, Rh, Ir).
Strong binding of carbon monoxide (CO) and dinitrogen (N2) by MB12- (M = Co, Rh, Ir) clusters results in a spinning umbrella-like structure. For OCMB12- and NNMB12- complexes, the bond dissociation energy values range within 50.3-67.7 kcal/mol and 25.9-35.7 kcal/mol, respectively, with the maximum value obtained in Ir followed by that in Co and Rh analogues. COMB12- complex is significantly less stable than the corresponding C-side bonded isomer. The associated dissociation processes for OCMB12- and NNMB12- into CO or N2 and MB12- are highly endergonic in nature at 298 K, implying their high thermochemical stability with respect to dissociation. In OCMB12- and NNMB12- complexes, the C-O and N-N bonds are found to be elongated by 0.022-0.035 Å along with a large red-shift in the corresponding stretching frequencies, highlighting the occurrence of bond activation therein toward further reactivity due to complexation. The obtained red-shift is explained by the dominance of L←M π-back-donation (L = CO, OC, NN) over L→M σ-donation. The binding of L enhances the energy barrier for the rotation of the inner B3 unit within the outer B9 ring by 0.4-1.8 kcal/mol, which can be explained by a reduction in the distance of the longest bond between inner B3 and outer B9 rings upon complexation. A good correlation is found between the change in rotational barrier relative to that in MB12- and the energy associated with the L→M σ-donation. Born-Oppenheimer molecular dynamics simulations further support that the M-L bonds in the studied systems are kinetically stable enough to retain the original forms during the internal rotation of inner B3 unit.


A differing bidirectional impact on the recognition accuracy of facial expression.
This study explored a bidirectional impact on the recognition accuracy of various facial expressions deriving from both the observer and sender in a sample of Chinese participants. A facial manipulation task was used to examine the ability of an observer's facial feedback to modulate the recognition of various facial expressions. Furthermore, the effect of a sender's facial expression with an open or closed mouth on recognition accuracy was investigated. The results showed that only recognition accuracy of a sad facial expression was influenced simultaneously by bidirectional sources from a sender and observer. Moreover, the impact of the unidirectional cue of a sender's facial feature (i.e., mouth openness) on happy and neutral faces was found to influence the recognition accuracy of these faces, but not the observer's bodily state. These findings indicate that the bidirectional impact derived from an observer and sender on facial expression recognition accuracy differs for emotional and neutral expressions.


Autologous Doping with Cryopreserved Red Blood Cells - Effects on Physical Performance and Detection by Multivariate Statistics.
The discovery of erythropoietin (EPO) simplified blood doping in sports, but improved detection methods, for EPO has forced cheating athletes to return to blood transfusion. Autologous blood transfusion with cryopreserved red blood cells (RBCs) is the method of choice, because no valid method exists to accurately detect such event. In endurance sports, it can be estimated that elite athletes improve performance by up to 3% with blood doping, regardless of method. Valid detection methods for autologous blood doping is important to maintain credibility of athletic performances. Recreational male (N = 27) and female (N = 11) athletes served as Transfusion (N = 28) and Control (N = 10) subjects in two different transfusion settings. Hematological variables and physical performance were measured before donation of 450 or 900 mL whole blood, and until four weeks after re-infusion of the cryopreserved RBC fraction. Blood was analyzed for transferrin, iron, Hb, EVF, MCV, MCHC, reticulocytes, leucocytes and EPO. Repeated measures multivariate analysis of variance (MANOVA) and pattern recognition using Principal Component Analysis (PCA) and Orthogonal Projections of Latent Structures (OPLS) discriminant analysis (DA) investigated differences between Control and Transfusion groups over time. Significant increase in performance (15 ± 8%) and VO2max (17 ± 10%) (mean ± SD) could be measured 48 h after RBC re-infusion, and remained increased for up to four weeks in some subjects. In total, 533 blood samples were included in the study (Clean = 220, Transfused = 313). In response to blood transfusion, the largest change in hematological variables occurred 48 h after blood donation, when Control and Transfused groups could be separated with OPLS-DA (R2 = 0.76/Q2 = 0.59). RBC re-infusion resulted in the best model (R2 = 0.40/Q2 = 0.10) at the first sampling point (48 h), predicting one false positive and one false negative. Over all, a 25% and 86% false positives ratio was achieved in two separate trials. In conclusions, autologous re-infusion of RBCs increased VO2max and performance as hypothesized, but hematological profiling by multivariate statistics could not reach the WADA stipulated false positive ratio of <0.001% at any time point investigated. A majority of samples remained within limits of normal individual variation at all times.


Increased muscle regeneration after repair of divided motor nerve with neuronotrophic factors containing glue.
Neuronotrophic factors (NTFs) directed to spinal cord motor neurons were collected in rats within silicone nerve regeneration chambers according to LONGO et al. (1983b). Unilateral addition of NTFs to the fibrin glue used for the repair of divided sciatic nerves improved locally nerve regeneration without affecting the controlateral side. Nerve regeneration was assessed by weight gain of the reinnervated muscles and by radioactive labelling of the acid-soluble phosphate fractions of both nerve Schwann cells and reinnervated muscle cells. Fast gastrocnemius and slow soleus muscles, the motor nerve of which had been repaired with added NTFs, were significantly heavier (21 and 28%) than their controlateral controls, and the metabolic dedifferentiation attendant on post-division nerve repair was less marked. It is suggested that this experimental nerve regeneration model is suitable to test potential nerve-active agents in vivo, under conditions close to the usual clinical setting, with, as ultimate goal, the improvement of the end-results of microsurgical repair of peripheral nerve in man.


SOX9 specifies the pyloric sphincter epithelium through mesenchymal-epithelial signals.
Gastrointestinal (GI) development is highly conserved across vertebrates. Although several transcription factors and morphogenic proteins are involved in the molecular controls of GI development, the interplay between these factors is not fully understood. We report herein the expression pattern of Sox9 during GI development, and provide evidence that it functions, in part, to define the pyloric sphincter epithelium. SOX9 is expressed in the endoderm of the GI tract (with the exclusion of the gizzard) and its derivate organs, the lung and pancreas. Moreover, SOX9 is also expressed at the mesoderm of the pyloric sphincter, a structure that demarcates the gizzard from the duodenum. Using retroviral misexpression technique, we show that Sox9 expression in the pyloric sphincter is under the control of the BMP signaling pathway, known to play a key role in the development of this structure. By misexpressing SOX9 in the mesoderm of the gizzard, we show that SOX9 is able to transdifferentiate the adjacent gizzard epithelium into pyloric sphincter-like epithelium through the control of mesodermal-epithelial signals mediated in part by Gremlin (a modulator of the BMP pathway). Our results suggest that SOX9 is necessary and sufficient to specify the pyloric sphincter epithelial properties.


Prevention of Orchialgia After Left-Sided Laparoscopic Donor Nephrectomy-A Prospective Study.
Etiology of orchialgia or testicular pain after laparoscopic donor nephrectomy (LDN) has been found to be related to injury of the spermatic plexus during gonadal (testicular) vein (GV) or ureteral ligation. This study aimed to evaluate and validate the impact of the level of ligation of GV and ureter in relation to the crossing of iliac vessels (CIV) on incidence of orchialgia. A prospective study was conducted on 70 males who underwent left LDN from January 2008 to December 2010 (group A) to determine the correlation between orchialgia and level of ligation of the GV and ureter with respect to CIV; this revealed that the ligation of the GV and/or ureter above the level of the CIV (level 1, n=40) is less likely to cause orchialgia than ligating them at or below (level 2, n=30). Subsequently, in 45 male patients (group B) for left LDN from January 2011 to June 2013, we ensured that clipping of the ureter and GV be performed above the CIV to validate the above findings. Patients with a history of scrotal pathology or surgical procedure were excluded. One-sided Z-test with pooled variance was used to calculate the sample size. In group A, orchialgia was seen in 10 (14.3%) patients. The clipping of the ureter and GV at level 2 (orchialgia, n=9) was associated with a significantly higher incidence of orchialgia than clipping them at level 1 (orchialgia, n=1) (P=0.001,95% confidence interval=0.0707 to 0.2471). In group B, 43 patients were finally analyzed, and none had orchialgia. The level of ligation of the GV and ureter has significant impact on the incidence of orchialgia. Ipsilateral testicular pain in patients with left-sided LDN is preventable, if the ureter and GV are ligated or clipped above the level of iliac vessels bifurcation.


Reversible Posterior Leukoencephalopathy Syndrome (RPLS) in a Psoriasis Patient Treated With Ustekinumab.
The use of monoclonal antibodies against interleukin (IL)-12 and -23, such as ustekinumab, has considerably reduced the disease burden in many patients with moderate to severe psoriasis. Reversible posterior leukoencephalopathy syndrome (RPLS) is a neurologic disorder that has been documented with increased frequency with the use of systemic and biologic agents. We report a case of a 58-year-old man with psoriasis who presented with confusion and memory difficulties after being on treatment with ustekinumab for over six years. Imaging with CT and MRI revealed mild parenchymal edema with the typical appearance and distribution of RPLS, confirming the diagnosis of this condition. This case reports the second case of RPLS associated with ustekinumab treatment, with the only other known case reported during clinical trials. With the increasing use of biologics in patients with moderate to severe psoriasis, it is critical that clinicians are cognizant of this potential associated adverse event.
J Drugs Dermatol. 2017;16(2):177-179.
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[Uridine transport and phosphorylation in 3T3 and CHO cells with induced cell proliferation].
In the serum-deficient medium, the cultured Swiss 3T3 and CHO-K1 cells transit to the resting state. The rates of uridine phosphorylation and RNA synthesis in these cells are lowered. After the addition of fresh medium containing 10% serum, cell proliferation is induced. At the early stage of cell entrance into the cell cycle uridine transport through the cell plasma membrane remains unchanged in both cultures. During the 1st hour after serum addition the rate of uridine phosphorylation increases in 3T3 cells to remain practically unchanged in CHO-K1 cells. At this time, RNA synthesis in cells increases almost twofold in both cultures. A correlation has been revealed between the initial level of uridine phosphorylation in 3T3 cells and the percentage of its maximal elevation after serum addition. No such a correlation was observed for CHO-K1 cells. The rate of uridine phosphorylation in arrested CHO-K1 cells is higher than that in 3T3 cells. It has been included that the initial increase of uridine phosphorylation during serum stimulation may be not obligatory for all cell types, but depends on the level of uridine kinase activity before serum addition to the cells.


Central neuraxial blockade promotes external cephalic version success after a failed attempt.
External cephalic version (ECV) has been successfully used to decrease the fetal and maternal morbidity and costs of cesarean delivery. As there are limited data regarding the use of central neuraxial blockade in the setting of previously failed ECV attempts, we sought to evaluate the efficacy and safety of spinal and epidural anesthesia in this setting. A retrospective review of all ECV attempts performed by a single experienced obstetrician between 1995 and 1999 was conducted. Standardized tocolytic and anesthetic regimens were used. A total of 77 patients underwent ECV attempts; of these, 37 (48%) were unsuccessful, 15 of which consented to further attempts with anesthesia. Neuraxial anesthesia was associated with frequent ECV success in both multiparous 4/4 (100%) and nulliparous 9/11 (82%) parturients. Overall 5/6 (83%) and 8/9 (89%) (P = NS) ECV attempts were successful with spinal and epidural anesthesia, respectively, with 2/5 (40%) and 6/8 (75%) (P = NS) resulting in vaginal deliveries. One successful ECV in the epidural group had an urgent cesarean delivery for persistent fetal bradycardia with good neonatal and maternal outcomes. We conclude central neuraxial anesthesia promotes successful ECV after previously failed ECV attempts. Our retrospective analysis of central neuraxial techniques, both epidural and spinal anesthesia, noted a significant success rate in the setting of previously failed external cephalic version attempts.


Evaluation of the Remler M2000 blood pressure recorder. Comparison with intraarterial blood pressure recordings both at hospital and at home.
The Remler M2000 is a semiautomated device that has been used to collect epidemiological data and assess blood pressure variability. It has been subjected to limited evaluation in operation, however, and no studies of its accuracy away from the hospital or office environment have been undertaken. We recruited a group of 28 patients with essential hypertension who were undergoing intraarterial ambulatory blood pressure monitoring and compared the intraarterial recordings with those made with the Remler instrument both at home and in the hospital. The Remler recordings were also compared with simultaneous indirect blood pressure measurements made with the random zero sphygmomanometer. The mean difference between the Remler and intraarterial blood pressure recordings was -3/7 in the hospital and 7/0 at home. All standard deviations were greater than 10 mm Hg, indicating large between-subject variability. Overall, the relationship of the Remler M2000 readings to intraarterial pressures was as close if not closer than standard indirect sphygmomanometry and thus might provide useful data for epidemiological surveys or drug trials. It would appear that for accurate measurement of short-term blood pressure variation and 24-hour recording, intraarterial recording is the method of choice.


Dynamic photocontrol of the coffee-ring effect with optically tunable particle stickiness.
When a colloidal drop dries on a surface, most of the particles accumulate at the drop periphery, yielding a characteristic ring-shaped pattern. This so-called coffee-ring effect (CRE) is observed in any pinned evaporating drop containing non-volatile solutes. Here, the CRE is dynamically controlled for the first time by using light, and an unprecedented reconfigurability of the deposit profile is demonstrated. This is achieved through a new mechanism where particle stickiness is optically tuned on demand, thus offering reliable modulation of the deposition pattern. The system consists of anionic nanoparticles and photosensitive cationic surfactants dispersed in water. It is shown that light-dependent modulation of surfactant-particle interactions dictates particle attraction and trapping at the liquid-gas interface, which allows us to direct particle deposition into a wide range of patterns from rings to homogeneous disks. Patterning from single drops is photoreversible upon changing the wavelength whereas spatial control in multiple drop arrays is achieved using a photomask.


Health on the Net Foundation: assessing the quality of health web pages all over the world.
The Internet provides a great amount of information and has become one of the communication media which is most widely used [1]. However, the problem is no longer finding information but assessing the credibility of the publishers as well as the relevance and accuracy of the documents retrieved from the web. This problem is particularly relevant in the medical area which has a direct impact on the well-being of citizens. In this paper, we assume that the quality of web pages can be controlled, even when a huge amount of documents has to be reviewed. But this must be supported by both specific automatic tools and human expertise. In this context, we present various initiatives of the Health on the Net Foundation informing the citizens about the reliability of the medical content on the web.


Preventive effects of selenium-enriched spiruline (SESP) on radiation pneumonitis.
We studied the early effects of selenium-enriched spiruline (SESP) on radiation-induced pulmonary fibrosis using histopathology, cDNA-mRNA dot-blot hybridization, and a biochemical technique for quantifying the hydroxyproline content. We found marked lung injury in the irradiated group, whereas only slight hyperemia, hemorrhage, exudation, and thickness of the interalveolar wall in the lung in the selenium-treated group. The hydroxyproline (hyp) content in the lungs and the synthesis of type III collagen mRNA decreased in the SESP-treated group. Selenium-enriched spiruline may have a protective effect on the development of radiation pneumonitis.


How to keep V(D)J recombination under control.
Breaking apart chromosomes is not a matter to be taken lightly. The possible negative outcomes are obvious: loss of information, unstable chromosomes, chromosomal translocations, tumorigenesis, or cell death. Utilizing DNA rearrangement to generate the desired diversity in the antigen receptor loci is a risky business, and it must be carefully controlled. In general, the regulation is so precise that the negative consequences are minimal or not apparent. They are visible only when the process of V(D)J recombination goes awry, as for example in some chromosomal translocations associated with lymphoid tumors. Regulation is imposed not only to prevent the generation of random breaks in the DNA, but also to direct rearrangement to the appropriate locus or subregion of a locus in the appropriate cell at the appropriate time. Antigen receptor rearrangement is regulated essentially at four different levels: expression of the RAG1/2 recombinase, intrinsic biochemical properties of the recombinase and the cleavage reaction, the post-cleavage /DNA repair stage of the process, and accessibility of the substrate to the recombinase. Within each of these broad categories, multiple mechanisms are used to achieve the desired aims. The major focus of this review is on accessibility control and the role of chromatin and nuclear architecture in achieving this regulation, although other issues are touched upon.


Development and Mechanistic Studies of Iron-Catalyzed Construction of Csp2-B Bonds via C-O Bond Activation.
Herein we describe an iron-catalyzed borylation of alkenyl and aryl carbamates through the activation of a C-O bond. This protocol exhibits high efficiency, a broad substrate scope, and the late-stage borylation of biorelevant compounds, thus providing potential applications in medicinal chemistry. Moreover, this method enables orthogonal transformations of phenol derivatives and also offers good opportunities for the synthesis of multisubstituted arenes. Preliminary mechanistic studies suggest that a FeII/FeIII catalytic cycle via a radical pathway might be involved in the reaction.


[Non-allelic interaction of mutant genes of tomato].
The results on studying of mutant genes with a non-allelic interaction in tomato are presented. It is determined that the mutant c and e genes of the leaf form interact by type of recessive epistasis with predominance of the homozygote cc over ee and the manifestation of the genotype ee can be influenced by genes-suppressors. It is defined that mutants ful, l-2, au, lg interact by type of dominant complementarity in F1 and by type of recessive complementarity in F2.


Highly Permeable Graphene Oxide/Polyelectrolytes Hybrid Thin Films for Enhanced CO2/N2 Separation Performance.
Separation of CO2 from other gasses offers environmental benefits since CO2 gas is the main contributor to global warming. Recently, graphene oxide (GO) based gas separation membranes are of interest due to their selective barrier properties. However, maintaining selectivity without sacrificing permeance is still challenging. Herein, we described the preparation and characterization of nanoscale GO membranes for CO2 separation with both high selectivity and permeance. The internal structure and thickness of the GO membranes were controlled by layer-by-layer (LbL) self-assembly. Polyelectrolyte layers are used as the supporting matrix and for facilitating CO2 transport. Enhanced gas separation was achieved by adjusting pH of the GO solutions and by varying the number of GO layers to provide a pathway for CO2 molecules. Separation performance strongly depends on the number of GO bilayers. The surfaces of the multilayered GO and polyelectrolyte films are characterized by atomic force microscopy and scanning electron microscopy. The (poly (diallyldimethylammonium chloride) (PDAC)/polystyrene sulfonate (PSS)) (GO/GO) multilayer membranes show a maximum CO2/N2 selectivity of 15.3 and a CO2 permeance of 1175.0 GPU. LbL-assembled GO membranes are shown to be effective candidates for CO2 separation based on their excellent CO2/N2 separation performance.


A rare presentation of myxofibrosarcoma as a Pancoast tumor: a case report.
Myxofibrosarcoma is an aggressive soft tissue neoplasm, classified as a variant of malignant fibrous histiocytoma. Most often, it occurs in middle to late adult life peaking in the seventh decade and involving the lower extremities (77%), trunk (12%), and retroperitoneum or mediastinum (8%). We report the first case of thoracic myxofibrosarcoma presenting as a Pancoast tumor. A 48-year-old non-tobacco smoking African-American man presented with a slow-growing mass in his neck along with 11 kg weight loss over 9 months. A review of his systems was positive for hoarseness and lowgrade intermittent fever without any shortness of breath or cough. A physical examination revealed a mass on the left side of his neck superior to his sternoclavicular joint measuring 3 × 3 × 1 cm. He had ptosis and miosis of his left eye. His breath sounds were decreased and coarse at the left apex. A neurological examination revealed 3/5 strength in his left upper arm. The remainder of the physical examination was unremarkable. Ultrasound of his neck showed an ill-defined heterogeneous mass lateral to his left thyroid lobe. A computed tomography scan of his chest showed a large multiloculated pleural-based mass in his left lung surrounding the adjacent neurovascular structures. A percutaneous biopsy was non-diagnostic. Subsequently, he underwent a left thoracotomy with biopsy. The mass extended from his anterior mediastinum medially at the level of the pulmonary trunk, superiorly into the superior sulcus and posteriorly into his chest wall. Surgical pathology confirmed the diagnosis of myxofibrosarcoma. Here we present a case of Pancoast tumor with myxofibrosarcoma as the underlying etiology. Pancoast syndrome generally entails an infiltrating lesion in the superior sulcus presenting with upper extremity pain, atrophy of the hand muscles, and Horner's syndrome. The differential diagnosis of Pancoast syndrome includes inflammatory and infectious etiologies, as well as neoplasms of benign and malignant nature. Of the neoplasms implicated, the most common are non-small cell lung carcinomas; myxofibrosarcoma presenting as a Pancoast tumor has not been reported in the literature.


Epidemiology of Hepatitis B and Hepatitis C Infections and Benefits of Programs for Hepatitis Prevention in Northeastern China: A Cross-Sectional Study.
To investigate the epidemiology of hepatitis B and C infections and the benefits of programs aimed at hepatitis prevention and control in Northeastern China. Individuals receiving health examinations were recruited to complete a questionnaire and undergo laboratory tests for hepatitis infection. Data on demographic characteristics, results of hepatitis B virus (HBV) and hepatitis C virus (HCV) serological tests, for HBV and HCV infection were analyzed. Among 227 808 study participants, the hepatitis B surface antigen (HBsAg) and anti-HCV-positive rates were 6.1% and 3.0%, respectively. Among HBsAg-positive participants, 63.8% tested positive for HBV DNA, 20.2% had an abnormal alanine aminotransferase (ALT) level, and 10.7% had cirrhosis. Among anti-HCV-positive participants, 57.2% tested positive for HCV RNA, 29.6% had an abnormal ALT level, and 8.4% had cirrhosis. Among HBsAg- or anti-HCV-positive participants, 47.1% and 32.0%, respectively, were aware of their infection. Among participants infected with HBV or HCV and suitable for antivirus treatment, 23.5% and 16.1%, respectively, had received antivirus treatment. The HBV plus HCV coinfection rate was 0.08%. The HBsAg-positive rate decreased significantly after implementation of recently introduced HBV control programs in China. However, the anti-HCV-positive rate showed only a slight decrease, indicating that programs for the prevention and control of hepatitis viruses require continued strengthening. ChiCTR-ECS-13004009.


Body size among Holocene foragers of the Cape Ecozone, southern Africa.
Temporal and geographic variability in adult body size can be a useful indicator of a population's adaptation. The southern African Cape supported foraging populations exclusively until some pastoralism is seen, ca. 2000 BP. This paper describes and interprets body-size patterns among foragers, as deduced from maximum femoral lengths and femoral head diameters, using 127 individually dated adult skeletons from the western (70) and southern (57) regions of the Cape (64 male, 60 female, 3 sex undetermined). Estimated statures are comparable to historic Khoesan samples, but show lower values and greater variance during the fifth/fourth millennium before the present among both sexes and both biomes. Variation in femoral length does not correlate with diet protein, as reflected in stable isotope (delta(13)C and delta(15)N) values. Positive correlations between femoral head diameter and isotopic indicators suggest greater body mass with more reliance on marine protein. A decline in femoral length begins at around 4000 BP, a time when archaeologists suggest that population growth led to the incorporation of lower-ranked food resources, and to reduced mobility. A clearly identifiable linear recovery, beginning at around 3000 BP, greatly predates the earliest evidence of pastoralism on the Cape. Apparent problems of food sufficiency were addressed and solved, within a hunting and gathering economy.


Evidence that children born at early term (37-38 6/7 weeks) are at increased risk for diabetes and obesity-related disorders.
Prematurity is known to be associated with high rates of endocrine and metabolic complications in the offspring. Offspring born early term (37-38 6/7 weeks' gestation) were also shown to exhibit long-term morbidity resembling that of late preterm, in several health categories. We aimed to determine whether early term delivery impacts on the long-term endocrine and metabolic health of the offspring. A population-based cohort analysis was performed, including all term singleton deliveries occurring from 1991 through 2013 at a single regional tertiary medical center. Congenital malformations and multiple pregnancies were excluded. Gestational age upon delivery was subdivided into early term deliveries and deliveries occurring at full term and later (≥39 weeks' gestation, comparison group). Endocrine and metabolic morbidity (including diabetes, obesity, hypoglycemia, hyperlipidemia, and hypothyroidism) of the offspring, up to the age of 18 years, was evaluated according to hospitalization files. Kaplan-Meier survival curves were used to compare cumulative morbidity incidence. A Weibull parametric survival model was used to control for time to event, siblings, and other confounders. During the study period 225,260 term deliveries met the inclusion criteria. Of them, 24% (n = 54,073) occurred at early term. Endocrine and metabolic morbidity was significantly more common in the early term group (0.51% vs 0.41%, P = .003). Specifically, overweight and obesity were more common among the early term group (P = .002). Differences were more prominent among children >5 years, who exhibited higher rates of type 1 diabetes mellitus, as well as obesity, when born at early term (P < .05). The survival curves demonstrated higher cumulative incidence of total endocrine and metabolic morbidity in the early term group. Using the Weibull parametric survival model, while controlling for siblings, maternal diabetes, hypertension, labor induction, and Apgar score, early term delivery exhibited an independent association with long-term childhood endocrine and metabolic morbidity of the offspring (adjusted hazard ratio, 1.17; 95% confidence interval, 1.01-1.34) and more so for age >5 years (adjusted hazard ratio, 1.30; 95% confidence interval, 1.08-1.56). Deliveries occurring at early term are associated with higher rates of long-term pediatric endocrine and metabolic morbidity of the offspring as compared with deliveries occurring at a later gestational age. This association may be due to absence of full maturity of the hormonal axis in early term neonates or, alternatively, suggest an underlying fetal endocrine dysfunction as the initial mechanism responsible for spontaneous early term delivery.


Nonoperative management of malignant biliary obstruction: a radiologic alternative.
Twelve patients with advanced malignant biliary obstruction were managed with a combination of sonography, percutaneous fine-needle aspiration biopsy, transhepatic cholangiography, and percutaneous biliary drainage. Excellent palliation of biliary obstruction was obtained in nine patients, four of whom are still living. Surgery was avoided in all cases, and a single episode of sepsis was the only complication. The literature indicates that surgical bypass procedures for malignant bile duct obstruction incur an average 20% operative mortality and provide only a 6 month mean survival. A combined radiologic approach offers an alternative to standard operative management of malignant biliary obstruction. When the cost-benefit ratios of operative vs. nonoperative management are considered, perhaps more patients should undergo radiologic management.


Peritumor to tumor apparent diffusion coefficient ratio is associated with biologically more aggressive breast cancer features and correlates with the prognostication tools.
The apparent diffusion coefficient (ADC) is increasingly used to characterize breast cancer. The peritumor/tumor ADC ratio is suggested to be a reliable and generally applicable index. However, its overall prognostication value remains unclear. We aimed to evaluate the associations between the peritumor/tumor ADC ratio and histopathological biomarkers and published prognostic tools in patients with invasive breast cancer. This prospective study included 88 lesions (five bilateral) in 83 patients with primary invasive breast cancer who underwent preoperative 3.0-T magnetic resonance imaging. The lowest intratumoral mean ADC value on the slice with the largest tumor cross-sectional area was designated the tumor ADC, and the highest mean ADC value on the peritumoral breast parenchymal tissue adjacent to the tumor border was designated the peritumor ADC. The peritumor/tumor ADC ratio was then calculated. The tumor and peritumor ADC values and peritumor/tumor ADC ratios were compared with histopathological parameters using an unpaired t test, and their correlations with published prognostic tools were evaluated with Pearson's correlation coefficient. The peritumor/tumor ADC ratio was significantly associated with tumor size (p<0.001), histological grade (p = 0.005), Ki-67 index (p = 0.006), axillary-lymph-node metastasis (p = 0.001), and lymphovascular invasion (p = 0.006), but was not associated with estrogen receptor status (p = 0.931), progesterone receptor status (p = 0.160), or human epidermal growth factor receptor 2 status (p = 0.259). The peritumor/tumor ADC ratio showed moderate positive correlations with the Nottingham Prognostic Index (r = 0.498, p<0.001) and mortality predicted using PREDICT (r = 0.436, p<0.001). The peritumor/tumor ADC ratio was correlated with histopathological biomarkers in patients with invasive breast cancer, showed significant correlations with published prognostic indexes, and may provide an easily applicable imaging index for the preoperative prognostic evaluation of breast cancer.


Cholinesterase inhibitors in the clinical management of Alzheimer's disease: importance of early and persistent treatment.
Alzheimer's disease is a neurodegenerative disease that greatly affects the quality of life of patients and their caregivers and places a heavy cost burden on the healthcare system. The cholinesterase inhibitors (ChEIs) donepezil, rivastigmine and galantamine have a central role in the treatment of Alzheimer's disease in the mild to moderate stages. Clinical trials with ChEIs have demonstrated therapeutic benefits for symptoms of cognition, function and behaviour across the disease course. These agents are most effective when started early in the disease course and used persistently, without treatment gaps. Early recognition of Alzheimer's disease and a global evaluation of treatment effectiveness are therefore essential. This article identifies barriers to early recognition and effective care of patients with Alzheimer's disease and discusses practical strategies to overcome them.


Optimal prevention of seizures induced by high-dose busulfan.
High-dose busulfan is frequently used in a variety of conditioning regimens for hematopoietic cell transplantation. In this setting, busulfan has marked neurotoxicity, specifically causing seizures that generally are tonic-clonic in character. Phenytoin has been the preferred drug to treat busulfan-induced seizures, but this practice should be reexamined in light of newer antiepileptic drugs being preferentially used by neurologists. Characteristics of ideal seizure prophylaxis include lack of overlapping toxicity with the conditioning regimen, lack of interference with engraftment of donor cells, and minimal potential for pharmacokinetic drug interactions. Based on these criteria, phenytoin is suboptimal due to possible toxicities and is especially ill suited because of its ability to induce busulfan metabolism. It is postulated that this induction adversely affects efforts to update methods for targeting busulfan doses to individual patients, based on recent developments in the understanding of the pharmacogenomics of busulfan metabolism. The existing clinical data support the use of benzodiazepines, most notably clonazepam and lorazepam, to prevent busulfan-induced seizures. The second-generation antiepileptic drug levetiracetam possesses the characteristics of optimal prophylaxis for busulfan-induced seizures, and early data of its efficacy are promising, although further study is needed.


The ATP hydrolysis-dependent reaction cycle of the Escherichia coli Hsp70 system DnaK, DnaJ, and GrpE.
Molecular chaperones of the Hsp70 class bind unfolded polypeptide chains and are thought to be involved in the cellular folding pathway of many proteins. DnaK, the Hsp70 protein of Escherichia coli, is regulated by the chaperone protein DnaJ and the cofactor GrpE. To gain a biologically relevant understanding of the mechanism of Hsp70 action, we have analyzed a model reaction in which DnaK, DnaJ, and GrpE mediate the folding of denatured firefly luciferase. The binding and release of substrate protein for folding involves the following ATP hydrolysis-dependent cycle: (i) unfolded luciferase binds initially to DnaJ; (ii) upon interaction with luciferase-DnaJ, DnaK hydrolyzes its bound ATP, resulting in the formation of a stable luciferase-DnaK-DnaJ complex; (iii) GrpE releases ADP from DnaK; and (iv) ATP binding to DnaK triggers the release of substrate protein, thus completing the reaction cycle. A single cycle of binding and release leads to folding of only a fraction of luciferase molecules. Several rounds of ATP-dependent interaction with DnaK and DnaJ are required for fully efficient folding.


A proposal for detecting and managing gestational diabetes by coordinating existing services.
A significant improvement in the quality of births by low-income women can be achieved by implementing a low-cost screening procedure and by coordinating private and public sector services that these women may already be receiving. This proposal outlines a screening program for gestational diabetes, coupled with multidisciplinary team management of this disorder through cooperative efforts of private sector medical practitioners and the public sector nutrition program for Women, Infants, and Children (WIC). The investment in this proposal is catalytic: the long-term intent is to persuade those in the medical community in the targeted geographic area to adopt the screening procedure and coordination with the WIC Program as a standard part of their prenatal care. If this proposed program is successful, it could be replicated in other parts of the country.