Actinidia arguta (Hardy Kiwi) Root Extract Exerts Anti-cancer Effects via Mcl-1-Mediated Apoptosis in Cholangiocarcinoma.
Cholangiocarcinoma (CCA) is a highly aggressive and chemoresistant liver malignancy. Thus, identification of strategies to overcome insensitivity to apoptosis and growth inhibition is a growing focus of research in this malignancy. This study evaluated the potential anti-cancer effects of an ethanol extract from the Actinidia arguta (Hardy Kiwi) root (RAE) on CCA. Our data demonstrated that RAE decreased cell viability and induced apoptosis by activation of Caspase 3, Caspase 8, and Poly (ADP-ribose) polymerase (PARP) in two CCA cell lines. RAE induced a decrease in Mcl-1 in cultured CCA cells and in xenograft CCA tumors. Administration of RAE every other day led to significant growth inhibition in tumor burden xenograft CCA mice. Western blotting analysis of paired human CCA and normal adjacent tissues from the same patient revealed that CCA tissues exhibited significantly higher Mcl-1 expression than normal tissues. Taken together, our findings demonstrated the anti-cancer effects of RAE on CCA both in vitro and in vivo. These data suggest that RAE may be a promising anti-CCA agent and could be beneficial in the treatment of CCA through the targeting of Mcl-1.


Bilateral endogenous Escherichia coli endophthalmitis.
Escherichia coli endophthalmitis developed in a 62-year-old man following an inadequately treated lower urinary tract infection. Treatment with intravenous and local antibiotics and steroids was successful in eradicating the infection, but blindness was not reversed. The pathogenesis and management of secondary bacterial endophthalmitis are reviewed.


Concurrent versus sequential adjuvant chemo-endocrine therapy in hormone-receptor positive early stage breast cancer patients: a systematic review and meta-analysis.
Although in clinical practice adjuvant chemotherapy (CT) and endocrine therapy (ET) are administered sequentially in patients with hormone-receptor positive breast cancer, the optimal timing, i.e. concurrent or sequential administration, of these treatments has been scarcely investigated. To better clarify this issue we conducted a systematic review and meta-analysis of randomized studies comparing these two modalities of administrations in terms of disease-free survival (DFS) and overall survival (OS). Relevant studies were identified by searching PubMed, Web of Knowledge and the proceedings of the major conferences with no date restriction up to March 2016. The summary risk estimates (pooled hazard ratio [HR] and 95% confidence intervals [CI]) for DFS and OS were calculated using random effect models (DerSimonian and Laird method). A total of three randomized studies were eligible including 2021 breast cancer patients. Overall, 755 DFS events were observed, 365 in the sequential arm and 390 in the concomitant arm, with a pooled HR of 0.95 (95% CI = 0.76 to 1.18, P = 0.643). No association between timing of treatment and OS was observed (HR = 0.95; 95% CI = 0.80 to 1.12, P = 0.529). Our pooled analysis showed no association between the timing of administration of adjuvant CT and ET and DFS and OS in breast cancer patients candidates for both adjuvant treatments. Because of the small number of published trials, the lack of data on the timing with modern adjuvant treatments, i.e. taxane-containing CT and aromatase inhibitors, this topic remain still controversial and requires further studies to be clarified.


Renal function in the noninsulin-dependent diabetic rat: effects of unilateral nephrectomy.
A new model of noninsulin-dependent diabetic (NIDD) is described which exhibits more prominent defects in renal function than does the standard neonatal NIDD model. To produce this model, 2-day-old neonatal male Wistar Kyoto (WKY) rats were injected intraperitoneally with streptozotocin (90 mg/kg; NIDD), while their corresponding nondiabetic controls were administered vehicle (citrate buffer, pH: 4.5; control). At 3 weeks of age, the animals were weaned, and 1 week later, under ether anesthesia, the animals underwent a right nephrectomy or a sham operation. Diabetes was confirmed by intraperitoneal administration of a glucose load (2g/kg), which resulted in significantly higher blood glucose concentration in the NIDD, compared to the nondiabetic rats. Surgical reduction of renal mass had no effect on the glycemic response to a glucose tolerance test in either group. Intravenous administration of an isotonic saline load resulted in a similar pattern of enhanced sodium and fluid excretion in the two-kidney sham-operated nondiabetic and NIDD rats. These responses were significantly higher than those observed in their counterparts with one remaining kidney. Yet, the natriuretic and diuretic responses to the saline load were significantly lower in the nephrectomized NIDD, compared to the nephrectomized nondiabetic rats. The glomerular filtration rate was similar in the sham-operated (two kidneys) NIDD and nondiabetic rats. In contrast, both the basal and saline-stimulated glomerular filtration rate were lower in the nephrectomized NIDD rats compared to the nephrectomized nondiabetic group. Mean arterial pressure was similar between the two nephrectomized groups, thereby ruling out a significant contribution from the pressure-diuresis-natriuresis mechanism to the reduction in sodium and fluid excretion in the nephrectomized NIDD rats. Thus, unilateral nephrectomy is an effective method of accelerating the manifestation of NIDD-related renal alterations. The mild, but progressive, nature of diabetes in this model should facilitate the investigation of temporal changes in renal function in NIDDM.


Seasonal plankton succession is in accordance with phycotoxin occurrence in Disko Bay, West Greenland.
Harmful algal blooms (HABs) are occurring more frequently in the world's oceans, probably as a consequence of climate change. HABs have not been considered a serious concern in the Arctic, even though the Arctic warms faster than any other region. While phycotoxins and toxin-producing phytoplankton have been found in Arctic waters on several occasions, there is a lack of information on seasonal succession of species and whether the occurrence of harmful species correlates with the presence of their respective phycotoxins. Hence, there is no baseline to assess future changes of HABs in this area. Here, we investigated two periods, from winter to spring and from the spring bloom until summer, in Disko Bay, West Greenland and followed the succession of toxins and their producers using metabarcoding, as well as analyses of particulate and dissolved toxins. We observed a typical seasonal succession with a spring bloom dominated by diatoms, followed by dinoflagellates in summer, with the two most important potentially toxic taxa found being Pseudo-nitzschia spp. and Alexandrium ostenfeldii. The Pseudo-nitzschia spp. peak correlated with a clear increase in particulate domoic acid, reaching 0.05 pg/L. Presence of Alexandrium ostenfeldii could be linked to an increase in spirolides, up to 56.4 pg/L in the particulate phase. Generally, the majority of detected dissolved toxins followed the succession pattern of the particulate toxins with a delay in time. Our results further show that Arctic waters are a suitable habitat for various toxin producers and that the strong seasonality of this environment is reflected by changing abundances of different toxins that pose a potential threat to the ecosystem and its beneficiaries.


Rh(0) or D, -D- and the blocking patterns. A genetic (template) explanation.
By the use of the gene template it will be shown that D appears at two different sites on the Rh locus, and that the locus cannot simply be DCE - or a similar one. Further, -D- does not appear to be a super Rh(0) as described by Wiener. Finally, a simple explanation is offered for the action of incomplete (blocking) and agglutinating antibodies.


Single-molecule kinetic analysis of HP1-chromatin binding reveals a dynamic network of histone modification and DNA interactions.
Chromatin recruitment of effector proteins involved in gene regulation depends on multivalent interaction with histone post-translational modifications (PTMs) and structural features of the chromatin fiber. Due to the complex interactions involved, it is currently not understood how effectors dynamically sample the chromatin landscape. Here, we dissect the dynamic chromatin interactions of a family of multivalent effectors, heterochromatin protein 1 (HP1) proteins, using single-molecule fluorescence imaging and computational modeling. We show that the three human HP1 isoforms are recruited and retained on chromatin by a dynamic exchange between histone PTM and DNA bound states. These interactions depend on local chromatin structure, the HP1 isoforms as well as on PTMs on HP1 itself. Of the HP1 isoforms, HP1α exhibits the longest residence times and fastest binding rates due to DNA interactions in addition to PTM binding. HP1α phosphorylation further increases chromatin retention through strengthening of multivalency while reducing DNA binding. As DNA binding in combination with specific PTM recognition is found in many chromatin effectors, we propose a general dynamic capture mechanism for effector recruitment. Multiple weak protein and DNA interactions result in a multivalent interaction network that targets effectors to a specific chromatin modification state, where their activity is required.


Ultrastructure of human cataract in retinitis pigmentosa.
A second ultrastructural study of retinitis pigmentosa cataract showed differences from the previous case with respect to sex, age of cataract onset, age at time of cataract extraction, and mode of inheritance of retinitis pigmentosa. Furthermore, the cataract in the present study was limited clinically and preponderantly ultrastructurally to the posterior subcapsular area, which is typical of the location of cataracts associated with retinitis pigmentosa. The cataract was characterized by severe lens fiber disorganization, resulting in intricately distorted membrane configurations and varying cytoplasmic densities; however, "figure eight" configurations as noted in the other report were not observed. Aberrantly migrated epithelial cells were distributed unevenly in the posterior subcapsular zone. New capsular basement membrane, not mentioned in the other report, was conspicuous in our case. Thus, retinitis pigmentosa cataract may have diverse ultrastructural alterations.


Synthesis and electrochemical characterization of hexanuclear platinum bis-pseudohalides.
The hexanuclear phosphido-bridged dication [Pt6(μ-PBu(t)2)4(CO)6](2+), (1)(2+), reacts under mild conditions with pseudo-halide anions (CN(-), NCO(-), NCS(-)) to afford the corresponding neutral bis-substituted clusters Pt6(μ-PBu(t)2)4(CO)4X2 (2, X = CN; 3, X = SCN; 4, X = NCO). The reaction with sodium azide affords 4, which may arise from the formation of the intermediate bis-azido derivative Pt6(μ-PBu(t)2)4(CO)4(N3)2, 5, and CO. These react rapidly with each other affording 4 and N2. Cluster 5 was alternatively prepared as a stable compound by reacting with NaN3 the neutral cluster Pt6(μ-PBu(t)2)4(CO)4(OTf)2, 14, which contains two weakly bonded triflate anions. As expected, 5 reacts with carbon monoxide (1 atm) affording cluster 4 instantaneously and quantitatively. The new pseudo-halide clusters 2-5, which are interesting potential precursors of cluster-containing molecular frameworks, have been characterized by IR and multinuclear NMR spectroscopy. The solid state structures of clusters 2-4 have also been studied by single-crystal X-ray diffractometry. The main features of the molecular structures remain similar to those of many related congeners described previously; in addition, an interesting reversible phase transition was observed in the crystal structure of cluster 3. As their known congeners, the clusters undergo two reversible one-electron reductions and an irreversible oxidation. An excellent linear correlation was found between the redox potentials of the cathodic processes and Lever's ligand parameter E(L).


Organic micropollutant removal from wastewater effluent-impacted drinking water sources during bank filtration and artificial recharge.
Natural treatment systems such as bank filtration (BF) and artificial recharge (via an infiltration basin) are a robust barrier for many organic micropollutants (OMPs) and may represent a low-cost alternative compared to advanced drinking water treatment systems. This study analyzes a comprehensive database of OMPs at BF and artificial recharge (AR) sites located near Lake Tegel in Berlin (Germany). The focus of the study was on the derivation of correlations between the removal efficiencies of OMPs and key factors influencing the performance of BF and AR. At the BF site, shallow monitoring wells located close to the Lake Tegel source exhibited oxic conditions followed by prolonged anoxic conditions in deep monitoring wells and a production well. At the AR site, oxic conditions prevailed from the recharge pond along monitoring wells to the production well. Long residence times of up to 4.5 months at the BF site reduced the temperature variation during soil passage between summer and winter. The temperature variations were greater at the AR site as a consequence of shorter residence times. Deep monitoring wells and the production well located at the BF site were under the influence of ambient groundwater and old bank filtrate (up to several years of age). Thus, it is important to account for mixing with native groundwater and other sources (e.g., old bank filtrate) when estimating the performance of BF with respect to removal of OMPs. Principal component analysis (PCA) was used to investigate correlations between OMP removals and hydrogeochemical conditions with spatial and temporal parameters (e.g., well distance, residence time and depth) from both sites. Principal component-1 (PC1) embodied redox conditions (oxidation-reduction potential and dissolved oxygen), and principal component-2 (PC2) embodied degradation potential (e.g., total organic carbon and dissolved organic carbon) with the calcium carbonate dissolution potential (Ca(2+) and HCO(3)(-)) for the BF site. These two PCs explained a total variance of 55% at the BF site. At the AR site, PCA revealed redox conditions (PC1) and degradation potential with temperature (PC2) as principal components, which explained a total variance of 56%.


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O. Brehant, D. Fuks, C. Sabbagh, A. Wouters, C. Mention, F. Dumont, JM. Regimbeau When surgery is indicated for bleeding duodenal ulcer, the traditional standard of care has been "radical surgical treatment is preferable to conservative therapy since the risk of rebleeding is reduced without an augmentation in morbidity and mortality". This principle is based on two prospective studies published before 1995. Radical surgery at that time consisted of antrectomy, while conservative therapy included oversewing of the bleeding vessel in the ulcer bed and ligation of the gastroduodenal artery (Weinberg procedure). This strategy must be re-evaluated in 2008 in view of our better understanding of the role of Helicopacter pylori in the causation of duodenal ulceration and the decreased risk of post-operative re-bleeding with the use of proton pump inhibitors. The role of surgery has changed. Its aim is no longer to cure the ulcer diathesis but rather to urgently control bleeding in anticipation of ulcer cure with medical therapy.


Three-dimensional characterization of the anterior cruciate ligament's femoral footprint.
There is increasing use of three-dimensional (3D) computed tomography (CT) for researching anterior cruciate ligament (ACL) reconstructions and tunnel placement. However, there is limited 3D CT data on the ACL footprint. The purpose of this study is to define the native ACL femoral footprint using 3D surface reconstructions of computed tomography (CT) imaging of cadaveric knees. The femoral insertion of the ACL was meticulously dissected and marked with drill holes in seven cadaveric knees. CT scans were performed on each specimen, and 3D computer models were created. Distance from the condyle edges to the margins of the footprint were referenced to the total condylar size. This was performed both parallel and perpendicular to the femoral axis as well as the intercondylar notch. The mean condylar depth (c/C) ratios along the axis of the femur were 0.45 ± 0.06 for the anterior border, 0.44 ± 0.08 for the posterior border, 0.26 ± 0.07 for the proximal border, and 0.63 ± 0.08 for the distal border. The mean notch (n/N) ratios for the four margins were 0.37 ± 0.04 for the anterior border, 0.67 ± 0.08 for the posterior border, 0.49 ± 0.07 for the proximal margin, and 0.50 ± 0.06 for the distal border. The mean c/C ratios parallel the intercondylar notch measured 0.23 ± 0.03 for the anterior border, 0.27 ± 0.04 for the posterior border, 0.37 ± 0.04 for the proximal border, and 0.12 ± 0.02 for the distal border. The mean n/N ratios perpendicular to the intercondylar notch measured 0.11 ± 0.06 for the anterior border, 0.52 ± 0.09 the posterior border, 0.29 ± 0.06 for the proximal border, and 0.30 ± 0.06 for the distal border. This study provides reference measures of the femoral footprint of the ACL using 3D CT. It will assist future studies that use advanced imaging to evaluate accuracy of ACL reconstruction.


Multiple steps of HLA-G in ovarian carcinoma metastasis: alter NK cytotoxicity and induce matrix metalloproteinase-15 (MMP-15) expression.
Previous study showed that aberrant HLA-G expression in cancer cells plays important roles in disease progression and it was associated with tumor metastasis and with poor survival in an animal model with ovarian cancer; however, the mechanisms remain to be explored. In this study, we found that HLA-G expression could dramatically decreased the NK cytotoxicity against the ovarian carcinoma cell line (HO-8910) engineered to express HLA-G (HO-8910-G), and matrix metalloproteinase-15 (MMP-15) expression was up-regulated in HO-8910-G cells. Consistent with this, a strong correlation between HLA-G and MMP-15 expression were observed in a cohort of ovarian cancer samples. Knockdown the HLA-G induced MMP-15 expression by small interfere RNA (siRNA) significantly decreased the HO-8910-G cell migration potential and tumor metastasis. Collectively, our study indicated that HLA-G involved in tumor invasiveness or metastasis may rely on the NK cytotoxicity inhibition and induction of MMP-15 expression in ovarian cancer.


Rethinking antipsychotic formulary policy.
In this commentary, we review recent research suggesting that (a) second-generation antipsychotics (SGAs) may be no more effective than first-generation antipsychotics (FGAs), (b) the reduced risk of EPS and tardive dyskinesia with SGAs is more weakly supported by the research literature than has been appreciated, and (c) benefits may be offset by greater metabolic risks of some SGAs and their substantially greater cost. Bearing in mind, as well, that risperidone, currently the least expensive SGA, will soon be available as an even less expensive generic drug, we propose a new algorithm for maintenance antipsychotic therapy. We further outline a cautious implementation procedure that relies on standardized documentation and feedback, without a restrictive formulary that would limit physician choice. The algorithm outlined here and the process for its implementation are intended as a stimulus for discussion of potential policy responses, not as a finalized proposition.


Electromyographic Comparison of Five Lower-Limb Muscles between Single- and Multi-Joint Exercises among Trained Men.
Resistance-training exercises can be classified as either single- or multi-joint exercises and differences in surface electromyography (EMG) amplitude between the two training methods may identify which muscles can benefit from either training modality. This study aimed to compare the surface EMG amplitude of five hip- and knee extensors during one multi-joint (leg press) and two single-joint exercises (knee extension and kickback). Fifteen resistance-trained men completed one familiarization session to determine their unilateral six repetitions maximum (6RM) in the three exercises. During the following experimental session, EMG amplitudes of the vastus lateralis, vastus medialis, rectus femoris, gluteus maximus and biceps femoris of the left leg were measured while performing three repetitions on their respective 6RM loads. The multi-joint exercise leg press produced higher EMG amplitude of the vastus lateralis (ES = 0.92, p = 0.003) than the single-joint exercise knee extension, whereas the rectus femoris demonstrated higher EMG amplitude during the knee extension (ES = 0.93, p = 0.005). The biceps femoris EMG amplitude was higher during the single-joint exercise kickback compared to the leg press (ES = 2.27, p < 0.001), while no significant differences in gluteus maximus (ES = 0.08, p = 0.898) or vastus medialis (ES = 0.056, p = 0.025 were observed between exercises. The difference in EMG amplitude between single- and multi-joint exercises appears to vary depending on the specific exercises and the muscle groups tested. Leg press is a viable and time-efficient option for targeting several hip- and knee extensors during resistance training of the lower limbs, but the single-joint exercises may be preferable for targeting the rectus femoris and biceps femoris.


Deviant lifestyles and violent victimization at school.
This study examines how the lifestyles of juveniles influence violent victimization at school. Using data from the National Survey of Adolescents, this study demonstrates that both indirect victimization, through witnessing violence, and sexual and physical assaults of students are pervasive problems at schools. Although a number of individual and structural characteristics predict the risk of becoming a victim at school, the most consistent predictor of violent victimization is the juvenile's own deviant lifestyle. Those who participate in a deviant lifestyle substantially increase their odds of all three forms of victimization. Therefore, even within the relatively controlled setting of schools, juveniles who participate in deviant lifestyles are at a high risk for victimization.


Daily Water Intake by Common Marmosets (Callithrix jacchus) and Recommendations Regarding Fluid Regulation.
The typical daily water intake of common marmosets (Callithrix jacchus) in a research setting has not been well characterized. Because these New World primates are in demand as animal models for neurobehavioral experiments, which can include the potential use of fluid regulation for training, veterinary and research staff need to understand how marmosets keep hydrated under normal circumstances. In the current study, we measured the water consumption of older (age, 5 to 12 y; n = 11) and younger (age, 1 to 2 y; n = 11) marmosets every 3 h during the 12-h light phase in 2 different months (January and July). The overall daily water intake (mean ± 1 SD) was 61.3 ± 20.4 mL/kg (range, 36.3 to 99.0 mL/kg); water intake by an individual marmoset or cohoused pair was fairly consistent from day to day. Water intake did not change across the four 3-h periods measured during the day, and minimal water was consumed overnight when the room lights were off. In addition, daily water intake did not differ between the 2 mo of measurements. Older animals drank significantly more than the younger group, and weight was directly correlated with water intake. Water intake was not affected by body condition score or housing status. The variation in water consumption among marmosets underscores the need for individualization of fluid regulation guidelines.


RyR2 mutations linked to ventricular tachycardia and sudden death reduce the threshold for store-overload-induced Ca2+ release (SOICR).
The cardiac ryanodine receptor (RyR2) governs the release of Ca2+ from the sarcoplasmic reticulum, which initiates muscle contraction. Mutations in RyR2 have been linked to ventricular tachycardia (VT) and sudden death, but the precise molecular mechanism is unclear. It is known that when the sarcoplasmic reticulum store Ca2+ content reaches a critical level, spontaneous Ca2+ release occurs, a process we refer to as store-overload-induced Ca2+ release (SOICR). In view of the well documented arrhythmogenic nature of SOICR, we characterized the effects of disease-causing RyR2 mutations on SOICR in human embryonic kidney (HEK)293 cells and found that, at elevated extracellular Ca2+ levels, HEK293 cells expressing RyR2 displayed SOICR in a manner virtually identical to that observed in cardiac cells. Using this cell model, we demonstrated that the RyR2 mutations linked to VT and sudden death, N4104K, R4496C, and N4895D, markedly increased the occurrence of SOICR. At the molecular level, we showed that these RyR2 mutations increased the sensitivity of single RyR2 channels to activation by luminal Ca2+ and enhanced the basal level of [3H]ryanodine binding. We conclude that disease-causing RyR2 mutations, by enhancing RyR2 luminal Ca2+ activation, reduce the threshold for SOICR, which in turn increases the propensity for triggered arrhythmia. Abnormal RyR2 luminal Ca2+ activation likely contributes to the enhanced SOICR commonly observed in various cardiac conditions, including heart failure, and may represent a unifying mechanism for Ca2+ overload-associated VT.


The regulation of the CNS innate immune response is vital for the restoration of tissue homeostasis (repair) after acute brain injury: a brief review.
Neurons and glia respond to acute injury by participating in the CNS innate immune response. This involves the recognition and clearance of "not self " pathogens and "altered self " apoptotic cells. Phagocytic receptors (CD14, CD36, TLR-4) clear "not self" pathogens; neurons and glia express "death signals" to initiate apoptosis in T cells.The complement opsonins C1q, C3, and iC3b facilitate the clearance of apoptotic cells by interacting with CR3 and CR4 receptors. Apoptotic cells are also cleared by the scavenger receptors CD14, Prs-R, TREM expressed by glia. Serpins also expressed by glia counter the neurotoxic effects of thrombin and other systemic proteins that gain entry to the CNS following injury. Complement pathway and T cell activation are both regulated by complement regulatory proteins expressed by glia and neurons. CD200 and CD47 are NIRegs expressed by neurons as "don't eat me" signals and they inhibit microglial activity preventing host cell attack. Neural stem cells regulate T cell activation, increase the Treg population, and suppress proinflammatory cytokine expression. Stem cells also interact with the chemoattractants C3a, C5a, SDF-1, and thrombin to promote stem cell migration into damaged tissue to support tissue homeostasis.


Gelatin-siloxane hybrid scaffolds with vascular endothelial growth factor induces brain tissue regeneration.
In the brain after infarction or trauma, the tissue becomes pannecrotic and forms a cavity. In such situation, a scaffold is necessary to produce new tissue. In this study, we implanted a new porous gelatin-siloxane hybrid derived from gelatin and 3-(glycidoxypropyl) trimethoxysilane (gelatin-GPTMS) scaffolds into a brain defect, and investigated whether it makes a new brain tissue. In addition, vascular endothelial growth factor (VEGF) was added on gelatin-GPTMS scaffolds and its effect on tissue regeneration was examined. At 30 days after the implantation, the marginal territory of the scaffolds became occupied by newly formed tissue. Immunohistochemical analysis revealed that the new tissue was constituted by endothelial, astroglial and microglial cells, some of which were labeled for bromodeoxyuridine (BrdU). Addition of VEGF promoted numbers of these cells. Thus, combination of gelatin-GPTMS scaffolds and VEGF is preferable for brain regeneration.


MicroRNA-Assisted Hormone Cell Signaling in Colorectal Cancer Resistance.
Despite substantial progress in cancer therapy, colorectal cancer (CRC) is still the third leading cause of cancer death worldwide, mainly due to the acquisition of resistance and disease recurrence in patients. Growing evidence indicates that deregulation of hormone signaling pathways and their cross-talk with other signaling cascades inside CRC cells may have an impact on therapy resistance. MicroRNAs (miRNAs) are small conserved non-coding RNAs thatfunction as negative regulators in many gene expression processes. Key studies have identified miRNA alterations in cancer progression and drug resistance. In this review, we provide a comprehensive overview and assessment of miRNAs role in hormone signaling pathways in CRC drug resistance and their potential as future targets for overcoming resistance to treatment.


[Adaptive responses of the secretory cardiomyocytes of the right atrium during simulation of the long-term and repeated gravity by antiorthostatic suspension of rats].
Reactive changes in right atrium cardiomyocytes during antiorthostatic tail suspension of rats commonly used to simulate low gravity have been studied by electron microscopy and morphometry. A 14 day suspension proved to increase contractile and secreting activities of cardiomyocytes. At the same time, signs of depleted activity are observed in some cells. Elongation of the experiment to 30 days leads to development of adaptive compensatory responses and increases their secreting capacity. A 30 day return to normal orthostatic position does not completely restores the structure and functioning of cardiomyocytes and leads to accumulation of internal secretion. A repeated 14 day suspension to a certain extent facilitates cardiomyocyte adaptation to altered conditions as compared to a single exposure; apparently, secretion release decreases while its production is activated.


A UK epidemic of testosterone prescribing, 2001-2010.
Testosterone replacement therapy is the standard treatment for male hypogonadism. There has lately been increased marketing in the medical media promoting testosterone replacement for men with erectile dysfunction or for older men with low serum testosterone, despite the lack of long-term safety and efficacy data. Therefore, we aimed to examine trends in testosterone prescribing in UK primary care over the last 10 years. Data about the use of testosterone preparations from the Departments of Health Prescription Cost Analysis for community pharmacies 2001-2010, for England, Scotland and Wales, were collated. Community requests for serum total testosterone assay in men to the Biochemistry Department at the Newcastle upon Tyne Hospitals Trust were also examined over the same time period. The number of prescriptions for testosterone preparations increased by nearly 90% from 157 602 to 298 134 dispensed items annually, over a 10-year period. However, due to a particularly significant (fivefold) increase in prescribing of (more expensive) transdermal preparations, the cost to the NHS showed a 267% escalation, from £3·2 to £11·7 million, annually over the same period. Local requests from primary care in the Newcastle and North Tyneside area for serum testosterone measurement in men also increased, from 347 requests in 2000 to 823 requests in 2010, a 137% increase. However, the number of men with likely unequivocal hypogonadism (testosterone less than 6·0 nm) remained constant at 5·2% in 2000 and 6·3% in 2010. Many men in the UK might be receiving testosterone replacement therapy with neither clearly established indications nor robustly diagnosed hypogonadism. A national registry for men treated with testosterone and further evidence to improve current guidance (national and/or international) on the indications for testosterone replacement would be beneficial.


Papillary carcinoma of the thyroid gland.
The results of this analysis have demonstrated that papillary carcinoma of the thyroid gland rarely causes the death of the patient. Bilateral subtotal lobectomies, partial lobectomies and probably total lobectomy combined with contralateral partial lobectomy should not be performed in the treatment of this disease. The incidence of local recurrence is higher after these procedures, and any subsequent operative procedure is complicated by scarring secondary to the initial procedure. Total lobectomy is the procedure of choice for patients with disease confined to one lobe on palpation. Total thyroidectomy should only be performed for palpable disease in both lobes. Excision of a grossly normal contralateral lobe solely to obtain microscopic tumor which rarely becomes clinically apparent is not worth the inherent risk of bilateral recurrent palsy of the nerve or permanent hypoparathyroidism. Cervical metastasis of the lymph nodes which are detected either synchronously or during subsequent follow-up examination can almost always be resected by some type of modified neck dissection. A radical neck dissection with the resection of the jugular vein and the sternocleidomastoid muscle is rarely if ever necessary. The administration of thyroid hormone as a surgical adjuvant may not be of any benefit and its routine use is probably not necessary.


Evaluation of the Living 4 Life project: a youth-led, school-based obesity prevention study.
The Living 4 Life study was a youth-led, school-based intervention to reduce obesity in New Zealand. The study design was quasi-experimental, with comparisons made by two cross-sectional samples within schools. Student data were collected at baseline (n=1634) and at the end of the 3-year intervention (n=1612). A random-effects mixed model was used to test for changes in primary outcomes (e.g. anthropometry and obesity-related behaviours) between intervention and comparison schools. There were no significant differences in changes in anthropometry or behaviours between intervention and comparison schools. The prevalence of obesity in intervention schools was 32% at baseline and 35% at follow-up and in comparison schools was 29% and 30%, respectively. Within-school improvements in obesity-related behaviours were observed in three intervention schools and one comparison school. One intervention school observed several negative changes in student behaviours. In conclusion, there were no significant improvements to anthropometry; this may reflect the intervention's lack of intensity, insufficient duration, or that by adolescence changes in anthropometry and related behaviours are difficult to achieve. School-based obesity prevention interventions that actively involve young people in the design of interventions may result in improvements in student behaviours, but require active support from leaders within their schools.


In vitro studies of cellular and molecular developmental toxicity of adjuvants, herbicides, and fungicides commonly used in Red River Valley, Minnesota.
Recent epidemiologic studies showed increased frequency of birth defects in pesticide applicators and general population of the Red River Valley, Minnesota. These studies further indicated that this crop growing area used more chlorophenoxy herbicides and fungicides than elsewhere in Minnesota. Based on frequency of use and known biology, certain herbicides, pesticide additives, fungicides, and mycotoxins are suspect agents. To define whether these agents affect developmental endpoints in vitro, 16 selected agrochemicals were examined using the MCF-7 breast cancer cell line. In the flow cytometric assay, cell proliferation in this estrogen-responsive cell line indicates xenobiotic-mediated estrogenic effects. Cell viability, morphology, ploidy, and apoptosis were incorporated in this assay. Data showed that the adjuvants X-77 and Activate Plus induced significant cell proliferation at 0.1 and 1 microg/ml. The commercial-grade herbicides 2,4-D LV4 and 2,4-D amine induced cell proliferation at 1 and 10 microg/ml. The reagent-grade 2,4-D products failed to induce proliferation over the same concentration range, suggesting that other ingredients in the commercial products, presumably adjuvants, could be a factor in these results. The fungicides triphenyltin and mancozeb induced apoptosis at concentrations of 4.1 microg/ml (10(-5) M) and 50 microg/ml, respectively. Triphenyltin also induced aneuploidy (C2/M arrest) at 0.41 microg/ml (10(-6) M). Data provide a mechanistic step to understanding human reproductive and developmental effects in populations exposed to these agrochemicals, and initiative to focusing limited resources for future in vivo animal developmental toxicity studies.


Identification of LAMA1 mutations ends diagnostic odyssey and has prognostic implications for patients with presumed Joubert syndrome.
Paediatric neurology syndromes are a broad and complex group of conditions with a large spectrum of clinical phenotypes. Joubert syndrome is a genetically heterogeneous neurological ciliopathy syndrome with molar tooth sign as the neuroimaging hallmark. We reviewed the clinical, radiological and genetic data for several families with a clinical diagnosis of Joubert syndrome but negative genetic analysis. We detected biallelic pathogenic variants in LAMA1, including novel alleles, in each of the four cases we report, thereby establishing a firm diagnosis of Poretti-Boltshauser syndrome. Analysis of brain MRI revealed cerebellar dysplasia and cerebellar cysts, associated with Poretti-Boltshauser syndrome and the absence of typical molar tooth signs. Using large UK patient cohorts, the relative prevalence of Joubert syndrome as a cause of intellectual disability was 0.2% and of Poretti-Boltshauser syndrome was 0.02%. We conclude that children with congenital brain disorders that mimic Joubert syndrome may have a delayed diagnosis due to poor recognition of key features on brain imaging and the lack of inclusion of LAMA1 on molecular genetic gene panels. We advocate the inclusion of LAMA1 genetic analysis on all intellectual disability and Joubert syndrome gene panels and promote a wider awareness of the clinical and radiological features of these syndromes.


Magnesium lithospermate B is excreted rapidly into rat bile mostly as methylated metabolites, which are potent antioxidants.
To elucidate the in vivo pharmacological activities of magnesium lithospermate B (MLB), an active constituent of Radix Salviae Miltiorrhizae, in the rat, its metabolic fate both in vivo and in vitro was investigated. High-performance liquid chromatography revealed that four major metabolites with lower polarity were excreted into bile after intravenous and oral administration of MLB. The metabolites present in combined samples of bile from rats after intravenous injection were isolated and purified by column chromatography and identified as four meta-O-methylated products, namely 3-monomethyl- (M1), 3,3"'-dimethyl- (M2), 3,3"-dimethyl-, and 3,3",3"'-trimethyl-lithospermic acid B according to their spectroscopic characteristics ((1)H, (13)C NMR, (1)H-(1)H correlation spectroscopy, (1)H-detected multiple quantum coherence, and heteronuclear multiple bond coherence combined with positive ion fast atom bombardment-mass spectroscopy). After administration of MLB at an intravenous dose of 4 mg/kg or an oral dose of 100 mg/kg, the total biliary recovery of the four metabolites after 30 h reached 95.5 +/- 2.4% (with approximately 90% recovered within 2 h) or 5.5 +/- 0.7%, respectively. The metabolic pathway was proposed to involve sequential formation of the four methylated metabolites. Incubation of MLB, M1, M2, or M4 in rat hepatic cytosol in the presence of S-adenosyl-l-methionine demonstrated the formation of all four metabolites, which indicated that the enzyme responsible for the biotransformation is catechol O-methyltransferase. MLB and its main metabolites M1 and M2 showed potent 1,1-diphenyl-2-picrylhydrazyl radical-scavenging activities, the activity of M1 being stronger than those of caffeic acid (the monomer form of MLB) and alpha-tocopherol (a representative antioxidant) but weaker than that of MLB. The rapid and high biliary excretion levels of these metabolites suggested that they could undergo enterohepatic circulation in rats and that they might thereby be largely responsible for the pharmacological effects of MLB.


Effect of PEGylated Graphene Oxide Nanoparticles on the Metabolism of Jurkat Cells.
The effect of graphene oxide (GO) nanoparticles of 100-200 nm in size coated with linear (LP-GO) and branched (BP-GO) polyethylene glycol at concentrations of 5 and 25 μg/mL on the metabolism of Jurkat tumor cells was studied. It was found that LP-GO nanoparticles at a concentration of 25 μg/mL can enhance basal glycolysis of Jurkat T-lymphocyte tumor cell line cells, while LP-GO and BP-GO at the same concentration can reduce the indicators of compensatory glycolysis. Despite this, GO nanoparticles coated with linear and branched PEG at a concentration of 5 μg/mL do not have pronounced effects on oxidative phosphorylation and glycolysis of Jurkat cells and could therefore be safe for activated T cells.


Study of the efficiency of UV and visible-light photocatalytic oxidation of methanol on mesoporous RuO2-TiO2 nanocomposites.
Mesoporous RuO(2)-TiO(2) nanocomposites at different RuO(2) concentrations (0-10 wt%) are prepared through a simple one-step sol-gel reaction of tetrabutyl orthotitanate with ruthenium(III) acetylacetonate in the presence of an F127 triblock copolymer as structure-directing agent. The thus-formed RuO(2)-TiO(2) network gels are calcined at 450 °C for 4 h leading to mesoporous RuO(2)-TiO(2) nanocomposites. The photocatalytic CH(3)OH oxidation to HCHO is chosen as the test reaction to examine the photocatalytic activity of the mesoporous RuO(2)-TiO(2) nanocomposites under UV and visible light. The photooxidation of CH(3)OH is substantially affected by the loading amount and the degree of dispersion of RuO(2) particles onto the TiO(2), which indicates the exclusive effect of the RuO(2) nanoparticles on this photocatalytic reaction under visible light. The measured photonic efficiency ξ=0.53% of 0.5 wt% RuO(2)-TiO(2) nanocomposite for CH(3)OH oxidation is maximal and the further increase of RuO(2) loading up to 10 wt% gradually decreases this value. The cause of the visible-light photocatalytic behavior is the incorporation of small amounts of Ru(4+) into the anatase lattice. On the other hand, under UV light, undoped TiO(2) shows a very good photonic efficiency, which is more than three times that for commercial photocatalyst, P-25 (Evonik-Degussa); however, addition of RuO(2) suppresses the photonic efficiency of TiO(2). The proposed reaction mechanism based on the observed behavior of RuO(2)-TiO(2) photocatalysts under UV and visible light is explored.


Unraveling spurious properties of interaction networks with tailored random networks.
We investigate interaction networks that we derive from multivariate time series with methods frequently employed in diverse scientific fields such as biology, quantitative finance, physics, earth and climate sciences, and the neurosciences. Mimicking experimental situations, we generate time series with finite length and varying frequency content but from independent stochastic processes. Using the correlation coefficient and the maximum cross-correlation, we estimate interdependencies between these time series. With clustering coefficient and average shortest path length, we observe unweighted interaction networks, derived via thresholding the values of interdependence, to possess non-trivial topologies as compared to Erdös-Rényi networks, which would indicate small-world characteristics. These topologies reflect the mostly unavoidable finiteness of the data, which limits the reliability of typically used estimators of signal interdependence. We propose random networks that are tailored to the way interaction networks are derived from empirical data. Through an exemplary investigation of multichannel electroencephalographic recordings of epileptic seizures--known for their complex spatial and temporal dynamics--we show that such random networks help to distinguish network properties of interdependence structures related to seizure dynamics from those spuriously induced by the applied methods of analysis.


Motion sickness. How to help your patients avoid travel travail.
Motion sickness is an exceedingly common disorder about which primary care physicians are likely to be consulted for advice and treatment. Appropriate management should be based on patient characteristics and the type and length of the exposure and should include general preventive recommendations and directed pharmacologic agents. Education for patients about the causes of motion sickness and how to prevent it can alleviate anxiety and enhance their enjoyment of travel and recreation.


In vitro assembly properties of human type I and II hair keratins.
Multiple type I and II hair keratins are expressed in hair-forming cells but the role of each protein in hair fiber formation remains obscure. In this study, recombinant proteins of human type I hair keratins (K35, K36 and K38) and type II hair keratins (K81 and K85) were prepared using bacterial expression systems. The heterotypic subunit interactions between the type I and II hair keratins were characterized using two-dimensional gel electrophoresis and surface plasmon resonance (SPR). Gel electrophoresis showed that the heterotypic complex-forming urea concentrations differ depending on the combination of keratins. K35-K85 and K36-K81 formed relatively stable heterotypic complexes. SPR revealed that soluble K35 bound to immobilized K85 with a higher affinity than to immobilized K81. The in vitro intermediate filament (IF) assembly of the hair keratins was explored by negative-staining electron microscopy. While K35-K81, K36-K81 and K35-K36-K81 formed IFs, K35-K85 afforded tight bundles of short IFs and large paracrystalline assemblies, and K36-K85 formed IF tangles. K85 promotes lateral association rather than elongation of short IFs. The in vitro assembly properties of hair keratins depended on the combination of type I and II hair keratins. Our data suggest the functional significance of K35-K85 and K36-K81 with distinct assembly properties in the formation of macrofibrils.


Consequences of intra-uterine growth retardation for postnatal growth, metabolism and pathophysiology.
Intra-uterine growth retardation (IUGR), caused by maternal undernutrition or placental insufficiency, is usually associated with disproportionately large reductions in the growth of some fetal organs and tissues (thymus, liver, spleen, thyroid) and impaired cellular development of other tissues (small intestine, secondary wool follicles, skeletal muscle). Growth of other tissues, most notably brain, is relatively unimpaired. In our restudy of postnatal consequences of IUGR in the offspring of prolific ewes, growth-retarded newborn lambs tended to be hypoglycaemic and showed sluggish postnatal engagement of the growth hormone (GH)-insulin-like growth factor (IGF) system. When artificially reared in an optimum environment, low birth weight lambs grew at rates similar to those of normal lambs. However, low birth weight lambs were fatter at any given weight, apparently related to their high energy intakes, especially soon after birth, had low maintenance energy requirements, and limited capacity for bone and muscle growth. These growth characteristics were accompanied by higher plasma concentrations of GH and leptin, and lower concentrations of insulin-like growth factor I (IGF-I) during the first 2 weeks of postnatal life, and higher concentrations of insulin during subsequent growth up to 20 kg body weight. Emerging evidence indicates that in sheep, as in rodents, fetal programming of postnatal cardiovascular and metabolic dysfunctions is associated with IUGR and may be mediated partly by overexposure of the fetus to cortisol. Similar postnatal responses can be elicited by maternal undernutrition or cortisol treatment in early to mid-pregnancy without changing the growth of the fetus or placenta.


The switch from larval to adult globin gene expression in Xenopus laevis is mediated by erythroid cells from distinct compartments.
The transition of hemoglobins during metamorphosis of Xenopus laevis involves replacement of the larval erythrocytes by adult ones, suggesting that the developmental control of this event depends upon the growth characteristics of the precursor cells. To identify the erythroid precursor cells and to investigate their developmental fate, we analyzed the distribution of stage-specific globin mRNAs by northern blotting in dorsal and ventral fragments of stage 32 embryos after in vitro culture as well as presumptive erythropoietic tissues of tadpoles during metamorphosis. The histological analysis shows that erythrocytes differentiate only in ventral fragments, suggesting that the ventral blood islands and most likely also the dorsolateral mesoderm are the primary sites of erythropoiesis. We also demonstrate that the first generations of erythrocytes, already express the predominating larval-specific alpha-globin mRNAs. The globin mRNA patterns obtained from presumptive erythropoietic tissues suggest an important role of circulating precursor cells in larval erythropoiesis, whereas the liver appears to be the main site of formation and maturation of the adult erythrocytes. Tentatively we propose that anuran erythropoiesis is dependent upon a self-perpetuating stem-cell line and that the larval and the adult erythrocytes are derived from successive generations of erythroid precursors, whose commitment may be imposed by the erythropoietic sites.


Importance of cosmesis to patients undergoing renal surgery: a comparison of laparoendoscopic single-site (LESS), laparoscopic and open surgery.
Study Type - Therapy (case series). Level of Evidence 4. What's known on the subject? and What does the study add? Studies in other surgical populations have found that scarring is a relatively unimportant preoperative patient consideration when compared with surgical cure and safety, but that younger age was a significant factor influencing preference for 'scarless' surgery. The present study corroborates the findings of previous series, among patients who were contemplating kidney surgery. • To evaluate patient attitudes towards cosmesis relative to other considerations, before and after undergoing laparoendoscopic single-site surgery (LESS) vs laparoscopic/robot-assisted vs open kidney surgery. • Participants were provided with a survey querying demographic information, surgical history and importance of scarring relative to other surgical outcomes and considerations. • The relative importance of each outcome was recorded on a nine-level ranking scale, ranging from 1 (most important) to 9 (least important). • The median scores for each outcome were compared before and after surgery using the Wilcoxon signed-rank test, and by surgical approach using the Kruskal-Wallis test. • The importance of scarring was further analysed according to age (≤ 50 vs >50 years), surgical indication (oncological vs non-oncological), gender, and proportion of patients who had undergone previous abdominal surgery. • A total of 90 patients completed surveys before surgery, of whom 65 (72.2%) also completed surveys after surgery. • 'Surgeon reputation' and 'no complications' were the most important considerations before surgery (median scores 2 and 3, respectively) and after surgery (median scores of 2 for both). • 'Size/number of scars' was the least important consideration before surgery (median score 8) and the second least important consideration after surgery (median score 7). • The median score for 'size/number of scars' was significantly higher for the LESS cohort before surgery (laparoscopic/robot-assisted vs LESS vs open surgery: 8.5 vs 6 vs 9; P = 0.003), but was nonsignificant after surgery (laparoscopic/robotic vs LESS vs open surgery: 7 vs 6.5 vs 7.5; P = 0.83). • The median score for 'size/number of scars' before surgery was significantly higher for younger patients (P = 0.05) and those with non-oncological surgical indications (P < 0.001), but there was no significant difference in this outcome for these sub-groups after surgery. • For most patients contemplating urological surgery, cosmesis is of less concern than surgeon reputation and avoidance of surgical complications. • Cosmesis may be a more important preoperative consideration for younger patients and those with benign conditions, which warrants further investigation.


Spectrin-adducin membrane skeleton: A missing link between epithelial junctions and the actin cytoskeletion?
Adherens junctions (AJs) and tight junctions (TJs) represent key adhesive structures that regulate the apico-basal polarity and barrier properties of epithelial layers. AJs and TJs readily undergo disassembly and reassembly during normal tissue remodeling and disruption of epithelial barriers in diseases. Such junctional plasticity depends on the orchestrated dynamics of the plasma membrane with its underlying F-actin cytoskeleton, however the interplay between these cellular structures remains poorly understood. Recent studies highlighted the spectrin-adducin-based membrane skeleton as an emerging regulator of AJ and TJ integrity and remodeling. Here we discuss new evidences implicating adducin, spectrin and other membrane skeleton proteins in stabilization of epithelial junctions and regulation of junctional dynamics. Based on the known ability of the membrane skeleton to link cortical actin filaments to the plasma membrane, we hypothesize that the spectrin-adducin network serves as a critical signal and force transducer from the actomyosin cytoskeleton to junctions during remodeling of AJs and TJs.


Ultraviolet Light-Densified Oxide-Organic Self-Assembled Dielectrics: Processing Thin-Film Transistors at Room Temperature.
Low-temperature, solution-processable, high-capacitance, and low-leakage gate dielectrics are of great interest for unconventional electronics. Here, we report a near room temperature ultraviolet densification (UVD) methodology for realizing high-performance organic-inorganic zirconia self-assembled nanodielectrics (UVD-ZrSANDs). These UVD-ZrSAND multilayers are grown from solution in ambient, densified by UV radiation, and characterized by X-ray reflectivity, atomic force microscopy, X-ray photoelectron spectroscopy, and capacitance measurements. The resulting UVD-ZrSAND films exhibit large capacitances of >700 nF/cm2 and low leakage current densities of <10-7 A/cm2, which rival or exceed those synthesized by traditional thermal methods. Both the p-type organic semiconductor pentacene and the n-type metal oxide semiconductor In2O3 were used to investigate UVD-ZrSANDs as the gate dielectric in thin-film transistors, affording mobilities of 0.58 and 26.21 cm2/(V s), respectively, at a low gate voltage of 2 V. These results represent a significant advance in fabricating ultra-thin high-performance dielectrics near room temperature and should facilitate their integration into diverse electronic technologies.


Influenza Infections and Emergent Viral Infections in Intensive Care Unit.
Critically ill patients are admitted to an intensive care unit (ICU) for multiple reasons. In this study, we aim to analyze the current evidence and findings associated with influenza and other emergent viral infections, namely, herpes simplex virus type 1 (HSV-1), Epstein-Barr virus (EBV), and cytomegalovirus (CMV).Among medical conditions, community-acquired respiratory infections are the most frequent reason for ventilatory support in ICUs. Community-acquired pneumonia in a severe form including the need of invasive mechanical ventilation and/or vasopressors is associated with high mortality rates. However, after the pandemic that occurred in 2009 by H1N1 influenza, the number of cases being admitted to ICUs with viral infections is on the rise. Patients in whom an etiology would not have been identified in the past are currently being tested with more sensitive viral molecular diagnostic tools, and patients being admitted to ICUs have more preexisting medical conditions that can predispose to viral infections. Viral infections can trigger the dysregulation of the immune system by inducing a massive cytokine response. This cytokine storm can cause endothelial damage and dysfunction, deregulation of coagulation, and, consequently, alteration of microvascular permeability, tissue edema, and shock. In severe influenza, this vascular hyperpermeability can lead to acute lung injury, multiorgan failure, and encephalopathy. In immunocompetent patients, the most common viral infections are respiratory, and influenza should be considered in patients with severe respiratory failure being admitted to ICU. Seasonality and coinfection are two important features when considering influenza as a pathogen in critically ill patients.Herpesviridae (HSV, CMV, and EBV) may reactivate in ICU patients, and their reactivation is associated with morbidity/mortality. However, whether a specific treatment may impact on outcome remains to be determined.


Starch Structure Influences Its Digestibility: A Review.
Twenty-five years ago, it was found that a significant fraction of the starch present in foods is not digested in the small intestine and continues to the large intestine, where it is fermented by the microbiota; this fraction was named resistant starch (RS). It was also reported that there is a fraction of starch that is slowly digested, sustaining a release of glucose in the small intestine. Later, health benefits were found to be associated with the consumption of this fraction, called slowly digestible starch (SDS). The authors declare both fractions to be "nutraceutical starch." An overview of the structure of both fractions (RS and SDS), as well as their nutraceutical characteristics, is presented with the objective of suggesting methods and processes that will increase both fractions in starchy foods and prevent diseases that are associated with the consumption of glycemic carbohydrates.


Pivotal role of TLR4 receptors in alcohol-induced neuroinflammation and brain damage.
Toll-like receptors play an important role in the innate immune response, although emerging evidence indicates their role in brain injury and neurodegeneration. Alcohol abuse induces brain damage and can sometimes lead to neurodegeneration. We recently found that ethanol can promote TLR4 signaling in glial cells by triggering the induction of inflammatory mediators and causing cell death, suggesting that the TLR4 response could be an important mechanism of ethanol-induced neuroinflammation. This study aims to establish the potential role of TLR4 in both ethanol-induced glial activation and brain damage. Here we report that TLR4 is critical for ethanol-induced inflammatory signaling in glial cells since the knockdown of TLR4, by using both small interfering RNA or cells from TLR4-deficient mice, abolished the activation of microtubule-associated protein kinase and nuclear factor-kappaB pathways and the production of inflammatory mediators by astrocytes. Our results demonstrate, for the first time, that whereas chronic ethanol intake upregulates the immunoreactive levels of CD11b (microglial marker) and glial fibrillary acidic protein (astrocyte marker), and also increases caspase-3 activity and inducible nitric oxide synthase, COX-2, and cytokine levels [interleukin (IL)-1beta, tumor necrosis factor-alpha, IL-6] in the cerebral cortex of female wild-type mice, TLR4 deficiency protects against ethanol-induced glial activation, induction of inflammatory mediators, and apoptosis. Our findings support the critical role of the TLR4 response in the neuroinflammation, brain injury, and possibly in the neurodegeneration induced by chronic ethanol intake.


Irreversible denaturation of proteins through aluminum-induced formation of backbone ring structures.
A combination of ab initio calculations, circular dichroism, nuclear magnetic resonance, and X-ray photoelectron spectroscopy has shown that aluminum ions can induce the formation of backbone ring structures in a wide range of peptides, including neurodegenerative disease related motifs. These ring structures greatly destabilize the protein and result in irreversible denaturation. This behavior benefits from the ability of aluminum ions to form chemical bonds simultaneously with the amide nitrogen and carbonyl oxygen atoms on the peptide backbone.


Future applications of biotechnology in poultry.
The major biotechnological advances that can be applied in the poultry industry will include molecular genetics, molecular immunology, and solid-state reactions. The elucidation of the genetic code and the development of techniques to manipulate genes offer new opportunities for changing pathogenic agents and changing chickens to reduce the effect of disease and improve productivity. The monoclonal antibody technique and the discovery that cells of the immune response communicate with one another through peptide factors will permit improved diagnostic techniques and enhanced immune responses to vaccines. Immunologic and biochemical reactions that occur on a solid substrate can be used to simplify and accelerate diagnostic tests and to purify antigens and antibodies. These advances will lead to improvements in diagnosis, disease resistance, and productivity of poultry.


Nurse practitioner-led, virtually delivered, motivational enhancement and device support intervention to improve CPAP adherence: A feasibility randomized control trial.
Evidence indicates continuous positive airway pressure (CPAP) therapy improves several important patient-centered outcomes. However, adherence to this safe and effective intervention remains poor. Assess nine feasibility outcomes of a nurse practitioner-led, virtually delivered motivational enhancement and device support (MENDS) intervention to improve CPAP adherence in adults with Obstructive Sleep Apnea (OSA). Secondary aims compared the changes in CPAP adherence to patient-reported outcomes, patient activation, and perceived self-efficacy. This two-group feasibility randomized controlled trial included 29 patients newly diagnosed with OSA and prescribed CPAP therapy. The study was conducted from July 2020 through December 2021 at a midwestern sleep/pulmonary clinic. Participants were randomized to the MENDS intervention group (n=14) (30-45 minute interactive tele-discussions on weeks 2, 4, 6, and 8) or to the usual care (n=15) group. Feasibility, patient-reported outcomes, and behavioral constructs were measured at baseline and 12 weeks. CPAP adherence was measured weekly. Feasibility of the MENDS sessions was demonstrated (56 sessions offered, 52 completed remotely without technical difficulties) with minimal participant attrition and no missing CPAP data. Generalized linear mixed models showed no statistically significant time-by-group interactions on adherence or patient-reported outcomes. Higher adherence and lower CPAP apnea-hypopnea index (AHI) scores were associated with declines in pre- to post-changes in fatigue and sleep disturbance. Lower CPAP AHI scores were associated with pre- to post-decreases in PROMIS Anxiety scores (r=.532, p=.005). The virtual MENDS intervention was feasible. Higher CPAP adherence and lower AHI levels led to positive improvements in fatigue, sleep disturbance, and anxiety.


Branchial cadmium and copper binding and intestinal cadmium uptake in wild yellow perch (Perca flavescens) from clean and metal-contaminated lakes.
Branchial binding kinetics and gastro-intestinal uptake of copper and cadmium where examined in yellow perch (Perca flavescens) from a metal-contaminated lake (Hannah Lake, Sudbury, Ontario, Canada) and an uncontaminated lake (James Lake, North Bay, Ontario, Canada). An in vivo approach was taken for gill binding comparisons while an in vitro gut binding assay was employed for gastro-intestinal tract (GIT) uptake analysis. By investigating metal uptake at the gill and the gut we cover the two main routes of metal entry into fish. Comparisons of water and sediment chemistries, metal burdens in benthic invertebrate, and metal burdens in the livers of perch from the two study lakes clearly show that yellow perch from Hannah L. are chronically exposed to a highly metal-contaminated environment compared to a reference lake. We found that metal-contaminated yellow perch showed no significant difference in gill Cd binding compared to reference fish, but they did show significant decreases in new Cd binding and absorption in their GITs. The results show that gill Cd binding may involve low-capacity, high-affinity binding sites, while gastro-intestinal Cd uptake involves binding sites that are high-capacity, low-affinity. From this we infer that Cd may be more critically controlled at the gut rather than gills. Significant differences in branchial Cu binding (increased binding) were observed in metal-contaminated yellow perch. We suggest that chronic waterborne exposure to Cu (and/or other metals) may be the dominant influence in gill Cu binding rather than chronic exposure to high Cu diets. We give supporting evidence that Cd is taken up in the GIT, at least in part, by a similar pathway as Ca(2+), principally that elevated dietary Ca(2+) reduces Cd binding and uptake. Overall our study reveals that metal pre-exposure via water and diet can alter uptake kinetics of Cu and Cd at the gill and/or the gut.


[A depression inventory for psychogeriatric patients].
An interview-based assessment tool was developed to evaluate the mood of cognitively impaired psychogeriatric patients. The rating scale consists of simple questions around 15 items, presented to the patient as printed single words that are in content related to DSM-III-criteria for depression. Using these items a structured interview was conducted with a consecutive sample of 197 psychogeriatric day care attendants (mean age 77.4 years; 91.4% carrying a diagnosis of dementia). Reliability (Cronbach's alpha) over the 15 items was 0.82. A principal component analysis and Varimax rotation revealed a structure of four factors, explaining 56% of the variance and representing zest for life (7 items), nonspecific somatic complaints (3), social contacts and appetite (4), and specific complaints about insomnia (1). Cronbach's alpha of 0.78 indicated that the 7 items of the first component were a reliable subscale. Confirmatory factor analysis confirmed a model of relative independence between emotional and cognitive variables. The psychometric features and reliability of the depression inventory support its utility for the assessment of positive and negative feelings in cognitively impaired elderly subjects.


Flavonoids and antioxidant activity of Rosa agrestis leaves.
In this work we report the isolation and characterisation of seven flavonoids, the levels of total phenolics, flavonoids and proanthocyanidins, and the antioxidant activity of the leaf extract of Rosa agrestis Savi (Rosaceae). The results showed that the R. agrestis leaf extract exhibited significant antioxidative activity as measured by 2,2-diphenyl-1-picrylhydrazyl (DPPH) (EC(50) = 47.4 microg mL(-1)), inhibited both beta-carotene bleaching and deoxyribose degradation, quenched a chemically generated superoxide anion in vitro and showed high ferrous ion chelating activity. Reactivity towards 2,2'-azino-bis (3-ethylbenzothiazoline-6-sulphonic acid) diammonium salt (ABTS) radical cation and ferric-reducing antioxidant power (FRAP) values were equivalent to 2.30 mM L(-1) Trolox, the water soluble alpha-tocopherol analogue, and 1.91 mM L(-1) Fe(2+), respectively. The high antioxidant activity of the extract appeared to be attributed to its high content of total phenolics, flavonoids and proanthocyanidins. The flavonoids isolated from R. agrestis leaves were diosmetin, kaempherol, quercetin, kaempherol 3-glucoside (astragalin), quercetin 3-rhamnoside (quercitrin), quercetin 3-xyloside and quercetin 3-galactoside (hyperoside). Diosmetin (5,7,3'-trihydroxy-4'-methoxyflavone) was isolated for the first time from Rosa species.


A deep community based approach for large scale content based X-ray image retrieval.
A computer assisted system for automatic retrieval of medical images with similar image contents can serve as an efficient management tool for handling and mining large scale data, and can also be used as a tool in clinical decision support systems. In this paper, we propose a deep community based automated medical image retrieval framework for extracting similar images from a large scale X-ray database. The framework integrates a deep learning-based image feature generation approach and a network community detection technique to extract similar images. When compared with the state-of-the-art medical image retrieval techniques, the proposed approach demonstrated improved performance. We evaluated the performance of the proposed method on two large scale chest X-ray datasets, where given a query image, the proposed approach was able to extract images with similar disease labels with a precision of 85%. To the best of our knowledge, this is the first deep community based image retrieval application on large scale chest X-ray database.


Effect of three commercially available chewing gums on salivary flow rate and pH in caries-active and caries-free children: An in vivo study.
Adequate salivary flow is an important requisite in the maintenance of oral health. Salivary flow increases in response to both gustatory (taste) and mechanical (chewing) stimuli. Hence, the aim of the present study was to know the efficacy of commercially available chewing gums (sugar free and sugared) on salivary flow rate (SFR) and pH in caries-active and caries-free children. One hundred school children aged between 10 and 12 years were divided into two groups on the basis of their caries status into caries free and caries active. Unstimulated saliva was collected before start of the study. Both groups were subjected to three commercially available chewing gums (2 sugar free, 1 sugared) on consecutive days, and saliva was collected at intervals of 2 min (T2), 10 min (T10), and 30 min (T30). The pH and flow rate of saliva samples were measured before and specified time intervals after gum chewing. In both the groups, gum chewing increased the SFR, significantly at T2, and gradually declined at T30 which was significantly higher than baseline values. The pH raised significantly at T2 and gradually declined at T30 which was significantly higher than baseline values with sugar-free gums, but with sugared gums, the pH raised slightly at T2 and dropped significantly at T30. However, no statistically significant differences in pH and flow rate were noticed in both the groups. Chewing of sugar-free gums in both caries-active and caries-free children may aid in reducing the incidence of dental caries.


Astaxanthin protects human ARPE-19 retinal pigment epithelium cells from blue light-induced phototoxicity by scavenging singlet oxygen.
Age-related macular degeneration (AMD) is one of an increasing number of diseases that causes irreversible impairment and loss of vision in the elderly. AMD occurs by oxidative stress-mediated apoptosis of retinal pigment epithelium cells. The onset of AMD may be positively correlated with the exposure to blue light. We screened food-derived carotenoids for cytoprotective action against blue light irradiation using human ARPE-19 retinal pigment epithelium cells. This study revealed that blue light irradiation triggered apoptosis and oxidative stress in all-trans-retinal (atRAL)-exposed ARPE-19 cells by generating singlet oxygen (1O2), leading to significant cell death. We found that astaxanthin, a potent anti-oxidative xanthophyll abundant in several marine organisms including microalgae, salmon, and shrimp, significantly suppresses blue light-induced apoptotic cell death of atRAL-exposed ARPE-19 cells by scavenging 1O2. Mechanistic studies using the blue-light irradiated cells also demonstrated that the cytoprotective effects of astaxanthin can be attributed to scavenging of 1O2 directly. Our results suggest the potential value of astaxanthin as a dietary strategy to prevent blue light-induced retinal degeneration including AMD.


Perinatal Brain Injury As a Consequence of Preterm Birth and Intrauterine Inflammation: Designing Targeted Stem Cell Therapies.
Chorioamnionitis is a major cause of preterm birth and brain injury. Bacterial invasion of the chorion and amnion, and/or the placenta, can lead to a fetal inflammatory response, which in turn has significant adverse consequences for the developing fetal brain. Accordingly, there is a strong causal link between chorioamnionitis, preterm brain injury and the pathogenesis of severe postnatal neurological deficits and cerebral palsy. Currently there are no treatments to protect or repair against brain injury in preterm infants born after pregnancy compromised by intrauterine infection. This review describes the injurious cascade of events in the preterm brain in response to a severe fetal inflammatory event. We will highlight specific periods of increased vulnerability, and the potential effects of therapeutic intervention with cell-based therapies. Many clinical trials are underway to investigate the efficacy of stem cells to treat patients with cerebral palsy. Stem cells, obtained from umbilical cord tissue and cord blood, normally discarded after birth, are emerging as a safe and potentially effective therapy. It is not yet known, however, which stem cell type(s) are the most efficacious for administration to preterm infants to treat brain injury-mediated inflammation. Individual stem cell populations found in cord blood and tissue, such as mesenchymal stem cells (MSCs) and endothelial progenitor cells (EPCs), have a number of potential benefits that may specifically target preterm inflammatory-induced brain injury. MSCs have strong immunomodulatory potential, protecting against global and local neuroinflammatory cascades triggered during infection to the fetus. EPCs have angiogenic and vascular reparative qualities that make them ideal for neurovascular repair. A combined therapy using both MSCs and EPCs to target inflammation and promote angiogenesis for re-establishment of vital vessel networks is a treatment concept that warrants further investigation.


Is the association between mothers' autistic traits and childhood autistic traits moderated by maternal pre-pregnancy body mass index?
Previous studies showed that there is a positive association between mothers' and children's autistic traits. We also tested if this association is more pronounced in mothers with a higher pre-pregnancy body mass index (BMI). The study was embedded in two cohorts with information available for 4,659 participants from the Generation R and for 179 participants from the Cambridge Ultrasound Siblings and Parents Project (CUSP) cohort. In both cohorts, maternal autistic traits were assessed using the short form of the Autism Spectrum Quotient, and information about maternal height and weight before pregnancy was obtained by questionnaire. Child autistic traits were assessed with the short form of Social Responsiveness Scale in Generation R (M = 13.5 years) and with the Quantitative Checklist for Autism in Toddlers (Q-CHAT) in the CUSP cohort (M = 1.6 years). Higher maternal autistic traits were associated with higher autistic traits in toddlerhood (CUSP cohort; βadjusted = 0.20, p < 0.01), in early childhood (Generation R; βadjusted = 0.19, p < 0.01), and in early adolescence (Generation R; βadjusted = 0.16, p < 0.01). Furthermore, a higher maternal pre-pregnancy BMI was associated with higher child autistic traits, but only in Generation R (βadjusted = 0.03, p < 0.01). There was no significant moderating effect of maternal pre-pregnancy BMI on the association between autistic traits of mothers and children, neither in Generation R nor in CUSP. In addition, child autistic traits scores were significantly higher in mothers who were underweight and in mothers who were overweight compared to mothers with a healthy weight. We confirm the association between maternal and child autistic traits in toddlerhood, early childhood, and early adolescence. Potential interacting neurobiological processes remain to be confirmed.


Metabolomics reveals the impact of the saturation of dietary lipids on the aging and longevity of C. elegans.
Dietary lipids play an important role in human health, but their influence on aging and longevity remains to be ascertained. This study tests the hypothesis that the consumption of fats with elevated unsaturation might slow down aging and prolong lifespan better than that with greater saturation. The metabolomic analysis of Caenorhabditis elegans (C. elegans) administrated with different dietary oils (palm oil, rapeseed oil, sunflower oil and linseed oil) revealed novel changes in lipid, carbohydrate, amino acid and purine metabolism. Elevated levels of eicosanoic acid, stearic acid, palmitic acid, L-isoleucine, L-lysine, L-tyrosine, and D-fructose, along with decreased content of arachidonic acid (ARA), eicosapentaenoic acid (EPA), and alpha-linolenic acid (ALA) were found in C. elegans with the intake of dietary oils with higher saturation. Declined gene expression levels of daf-2 and akt-1, as well as increased levels of daf-16, sod-3, hsp-16.2, hsf-1, nhr-80, fat-5, fat-6, and fat-7, were noted in the higher unsaturation dietary oil groups. Carbohydrates and amino acids showed moderate to strong correlations with daf-2 and akt-1 (negative), as well as daf-16, sod-3, hsp-16.2, and hsf-1 (positive). Otherwise, our data suggested significant positive relationships between polyunsaturated fatty acids (ARA, EPA, ALA) and nhr-80, fat-5, fat-6 and fat-7. Taken together, this study demonstrates that unsaturated dietary oils can slow down aging and prolong the lifespan of C. elegans via the insulin signaling pathway and the biosynthesis of unsaturated fatty acids.


Concentrations of sex-hormone binding globulin and corticosteroid binding globulin in serum in relation to cardiovascular risk factors and to 12-year incidence of cardiovascular disease and overall mortality in postmenopausal women.
We determined sex-hormone binding globulin (SHBG) and corticosteroid binding globulin (CBG) by radioimmunoassay of serum samples from a group of 253 women, who were 54 or 60 years old when first studied in 1968-69. The SHBG concentration was highly significantly and inversely related to body mass, body mass index, waist-to-hip circumference ratio, and serum triglyceride concentration; CBG concentration was inversely related to body mass and body mass index. The concentration of neither protein was related to whether or not the subject smoked. Decrease in the concentration of SHBG, but not of CBG, was a significant risk factor for 12-year overall mortality. The plot of the 12-year incidence of myocardial infarction vs SHBG concentration was U-shaped. We recommend that SHBG be included when serum androgens or estrogens are being evaluated as risk factors for cardiovascular disease and death.


Left ventricular diastolic function in type 2 diabetes mellitus is associated with myocardial triglyceride content but not with impaired myocardial perfusion reserve.
To study myocardial perfusion reserve and myocellular metabolic alterations indicated by triglyceride content as possible causes of diastolic dysfunction in patients with type 2 diabetes mellitus, preserved systolic function, and without clinically evident coronary artery disease. Patients with type 2 diabetes mellitus (n = 42) underwent cardiac magnetic resonance (CMR) for quantification of 1) myocardial contractility by strain-encoded MR (SENC); 2) myocardial triglyceride content by proton magnetic resonance spectroscopy ((1) H-MRS); and 3) myocardial perfusion reserve during pharmacologic hyperemia. Age-matched healthy volunteers (n = 16) also underwent CMR to acquire normal values for myocardial strain and perfusion reserve. Stress CMR procedures were successfully performed in all subjects, and no regional inducible perfusion defects were observed in type 2 diabetes mellitus patients. Diastolic strain rate and myocardial perfusion reserve were significantly impaired in patients with type 2 diabetes mellitus compared to control subjects (P < 0.001 for both). Interestingly, impaired diastolic function in type 2 diabetes mellitus was not associated with impaired myocardial perfusion reserve (r = 0.12, P = NS). Conversely a significant association was observed between diastolic dysfunction and myocardial triglyceride content (r = -0.71, P < 0.001), which proved to be independent of age, gender, diabetes duration, blood pressure, and fasting blood glucose. Myocardial steatosis may represent an early marker of diabetic heart disease, triggering subclinical myocardial dysfunction irrespective of myocardial perfusion reserve.


[Chronic pancreatitis--pancreas cancer: influence of genetic factors].
Chronic pancreatitis: Only recently mutations in several genes were found in patients with chronic pancreatitis. In those with a familial chronic pancreatitis mutations of the cationic trypsinogen were identified and the variants N29I and R122H lead to an autosomal dominant disease. In this group of patients the mutation N34S of the trypsin inhibitor SPINK1 was detected. In so-called idiopathic pancreatitis both variants of the SPINK1 and of the CFTR (cystic fibrosis transmembrane conductance regular) were identified. Alterations in both genes were also found in patients with alcoholic chronic pancreatitis. The strongest risk factor for chronic pancreatitis were trypsinogen mutations N29I and R122H mutations. However, both SPINK1 and CFTR increased the risk for chronic pancreatitis to a higher level than alcohol consumption. A genetic investigation should be performed in familial disease and younger age, but also in patients without family history and higher age a mutation could be found. Pancreas cancer: In 10% of the patients with pancreas cancer other members of the family were affected from the disease. Some of them belong to well characterized familial syndroms like HNPCC or Peutz-Jeghers-syndrom. In a minority of the others a genetic factor may be found, too. In sporadic disease the development of the tumor is characterized by continued acquirement of genetic alterations described by the PanIN model (pancreatic intraepithelial neoplesia). This means that the evolution of the neoplasia progresses from normal tissue via epithelial hyperplasy (PanIN 1A), papillary hyperplasy without (PanIN 1B) and with dysplasy (PanIN 2) and carcinoma in situ (PanIN 3) to invasive pancreas cancer. The progression is associated with genetic alterations of the cells (mutations of ki-ras, p16, p53 etc.). This results in deterioration of control of the cell cycle and the apoptosis and explains the malignancy of the disease. These findings may be used in the future to develop newer therapeutic principles in order to improve the dismal prognosis of this disease.


Optimal sampling theory and population modelling: application to determination of the influence of the microgravity environment on drug distribution and elimination.
Newer mathematical techniques such as optimal sampling theory and NON-linear Mixed Effects Modelling (NONMEM) allow the determination of pharmacokinetics and pharmacodynamics in populations of individuals previously believed to be "too ill" or "too difficult to study." Optimal sampling determines the most information-rich times to sample the system, allowing robust parameter estimates to be determined from the minimal number of samples. NONMEM, by taking the population as the unit of analysis, allows even fragmentary patient data sets to contribute to population parameter estimates. Obviously, the microgravity environment presents extreme logistical difficulties to the performance of traditional pharmacokinetic and pharmacodynamic studies. Examples of the validation of these techniques are presented, which indicates their likely utility in the important task of determining the influence of the microgravity environment on drug distribution and elimination, even accounting for the limitations of support which will be faced in this circumstance.


Trends in Oral Antibiotic Prescription in Dermatology, 2008 to 2016.
Dermatologists prescribe more oral antibiotic courses per clinician than any other specialty, and this use puts patients at risk of antibiotic-resistant infections and antibiotic-associated adverse events. To characterize the temporal trends in the diagnoses most commonly associated with oral antibiotic prescription by dermatologists, as well as the duration of this use. Repeated cross-sectional analysis of antibiotic prescribing by dermatologists from January 1, 2008, to December 31, 2016. The setting was Optum Clinformatics Data Mart (Eden Prairie, Minnesota) deidentified commercial claims data. Participants were dermatology clinicians identified by their National Uniform Claim Committee taxonomy codes, and courses of oral antibiotics prescribed by these clinicians were identified by their National Drug Codes. Claims for oral antibiotic prescriptions were consolidated into courses of therapy and associated with the primary diagnosis from the most recent visit. Courses were stratified into those of extended duration (>28 days) and those of short duration (≤28 days). Frequency of antibiotic prescribing and associated diagnoses. Poisson regression models were used to assess for changes in the frequency of antibiotic prescribing over time. Between 2008 and 2016 among 985 866 courses of oral antibiotics prescribed by 11 986 unique dermatologists, overall antibiotic prescribing among dermatologists decreased 36.6% (1.23 courses per 100 visits) from 3.36 (95% CI, 3.34-3.38) to 2.13 (95% CI, 2.12-2.14) courses per 100 visits with a dermatologist (prevalence rate ratio for annual change, 0.931; 95% CI, 0.930-0.932), with much of this decrease occurring among extended courses for acne and rosacea. Oral antibiotic use associated with surgical visits increased 69.6% (2.73 courses per 100 visits) from 3.92 (95% CI, 3.83-4.01) to 6.65 (95% CI, 6.57-6.74) courses per 100 visits associated with a surgical visit (prevalence rate ratio, 1.061; 95% CI, 1.059-1.063). Continuing to develop alternatives to oral antibiotics for noninfectious conditions, such as acne, can improve antibiotic stewardship and decrease complications from antibiotic use. In addition, the rising use of postoperative antibiotics after surgical visits is concerning and may put patients at unnecessary risk of adverse events. Future studies are needed to identify the value of this practice and the risk of adverse events.


Predialytic versus Intradialytic Nutrition: A Study to Assess Effects on Intradialytic Blood Pressure, Dialysis Adequacy, and Urea Removal.
Provision of oral protein in hemodialysis (HD) is desirable due to improved compliance to protein requirements and better nutritional status, but the risks of hypotension and underdialysis need to be considered. This study compared 2 different timings for administering oral nutritional supplements (ONS), predialysis and mid-dialysis, with respect to hemodynamics, dialysis adequacy, urea removal, and tolerability. This single-center, prospective crossover study analyzed 72 stable patients with ESRD on twice a week maintenance HD with a mean age of 38.7 (±11.2) years and a dialysis vintage of 28.2 (±13.1) months. In the first week, all the patients received ONS (450 kcal energy, 20 g protein) 1 h prior to start of dialysis (group 1) and in the next week, the supplement was administered after 2 h of start of dialysis (group 2), with a predialysis fasting period of at least 3 h in both groups. Blood pressures, serum, and spent dialysate samples were collected and nausea occurrence was noted by severity. Predialytic intake (group 1) was associated with higher predialysis and 1st hour blood urea, dialysis adequacy, and urea removal than group 2. Both groups achieved mean Kt/V > 1.2, and the occurrence of symptomatic hypotensive episodes and nausea was not significantly different between the groups. On repeated measures ANOVA, changes in blood urea over time showed significant group effect. Predialytic supplementation was associated with better dialysis adequacy and urea removal than intradialytic supplementation. However, both timings were equally tolerated and not associated with underdialysis.


Practical Applications of Deep Learning To Impute Heterogeneous Drug Discovery Data.
Contemporary deep learning approaches still struggle to bring a useful improvement in the field of drug discovery because of the challenges of sparse, noisy, and heterogeneous data that are typically encountered in this context. We use a state-of-the-art deep learning method, Alchemite, to impute data from drug discovery projects, including multitarget biochemical activities, phenotypic activities in cell-based assays, and a variety of absorption, distribution, metabolism, and excretion (ADME) endpoints. The resulting model gives excellent predictions for activity and ADME endpoints, offering an average increase in R2 of 0.22 versus quantitative structure-activity relationship methods. The model accuracy is robust to combining data across uncorrelated endpoints and projects with different chemical spaces, enabling a single model to be trained for all compounds and endpoints. We demonstrate improvements in accuracy on the latest chemistry and data when updating models with new data as an ongoing medicinal chemistry project progresses.


Network medicine approaches for identification of novel prognostic systems biomarkers and drug candidates for papillary thyroid carcinoma.
Papillary thyroid carcinoma (PTC) is one of the most common endocrine carcinomas worldwide and the aetiology of this cancer is still not well understood. Therefore, it remains important to understand the disease mechanism and find prognostic biomarkers and/or drug candidates for PTC. Compared with approaches based on single-gene assessment, network medicine analysis offers great promise to address this need. Accordingly, in the present study, we performed differential co-expressed network analysis using five transcriptome datasets in patients with PTC and healthy controls. Following meta-analysis of the transcriptome datasets, we uncovered common differentially expressed genes (DEGs) for PTC and, using these genes as proxies, found a highly clustered differentially expressed co-expressed module: a 'PTC-module'. Using independent data, we demonstrated the high prognostic capacity of the PTC-module and designated this module as a prognostic systems biomarker. In addition, using the nodes of the PTC-module, we performed drug repurposing and text mining analyzes to identify novel drug candidates for the disease. We performed molecular docking simulations, and identified: 4-demethoxydaunorubicin hydrochloride, AS605240, BRD-A60245366, ER 27319 maleate, sinensetin, and TWS119 as novel drug candidates whose efficacy was also confirmed by in silico analyzes. Consequently, we have highlighted here the need for differential co-expression analysis to gain a systems-level understanding of a complex disease, and we provide candidate prognostic systems biomarker and novel drugs for PTC.


[Nonspecific body resistance in the acetylator phenotype of patients with odontogenic inflammatory processes in the maxillofacial area].
Nonspecific resistance of the body, intensity of acetylation processes, and acetylator phenotype were studied in adults and children aged 3 to 16, suffering from maxillofacial odontogenic inflammations. The findings evidence that irrespective of the patient's age, development of maxillofacial inflammations is associated with a reduction of the body nonspecific resistance and of acetylation processes intensity, this reduction being the most marked in the patients with acute and chronic osteomyelitis. Patients with the slow acetylation type predominated among the examinees, permitting a hypothesis that this acetylation type favors the development of odontogenic inflammations.


Predominant expression of alternative PAX3 and PAX7 forms in myogenic and neural tumor cell lines.
PAX3 and PAX7 are closely related paired box family members expressed during early neural and myogenic development. Assay of PAX3 and PAX7 mRNA expression in embryonal rhabdomyosarcoma, neuroblastoma, Ewing's sarcoma, and melanoma cell lines revealed tumor-specific expression patterns similar to the corresponding embryonic lineages. Although the mammalian PAX3 and PAX7 genes were reported to contain eight exons, we found that the predominant PAX3 and PAX7 transcripts in these tumor lines contain previously uncharacterized ninth exons. These splicing events alter the COOH-terminal coding regions of the encoded products but do not alter the transcriptional activity as assayed using a reporter gene with a model PAX3/PAX7 binding site. However, the findings of nearly identical COOH-terminal regions within the corresponding genes of the avian and fish genomes suggest conserved functional roles for these regions that require further investigation.


Comparative analysis of DNA methylation in tobacco heterochromatic sequences.
Cytosine methylation levels and susceptibility to drug-induced hypomethylation have been studied in several Nicotiana tabacum (tobacco) DNA repetitive sequences. It has been shown using HapII, MspI, BamHI and Sau3AI methylation-sensitive restriction enzymes that the degree of 5'-mCmCG-3' methylation varied significantly between different repeats. There were almost saturation levels of 5-methylcytosine at the inner (3') cytosine position and variable degrees of methylation at the outer (5') cytosine at the enzyme recognition sites. The non-transcribed high copy satellite sequences (HRS60, GRS) displayed significant heterogeneity in methylation of their basic units while middle repetitive sequences (R8.1, GRD5, 5S rDNA) were more uniformly modified at both cytosine residues. Dihydroxypropyladenine (DHPA) treatment, which is thought to reduce DNA methyltransferase activity by increasing S-adenosylhomocysteine levels, resulted in extensive demethylation of the outer cytosine in all repeats, and the partial hypomethylation of cytosines at the inner positions in less densely methylated repeats such as HRS60 and GRS. The results suggest that hypomethylation of 5'-mCmCG-3' sites with DHPA is a gradual non-random process proceeding in the direction mCmCG-->CmCG-->CCG. The 18S-5.8S-25S rDNA was remarkably hypomethylated relative to the 5S rDNA at all restriction sites studied. Fluorescence in-situ hybridization showed that DNA decondensation within and between the 18S-5.8S-25S and 5S rDNA loci was variable in different nuclei. All nuclei had condensed and decondensed sequence. The chromatin of 18S-5.8S-25S rDNA was more readily digested with micrococcal nuclease than the 5S rDNA suggesting that the overall levels of decondensation were higher for 18S-5.8S-25S rDNA. Variable decondensation patterns within and between loci were also observed for GRS and HRS60. Cytosine methylation of the tobacco repeats is discussed with respect to transcription, overall levels of condensation and overall structure.


Serotonergic facilitation of quantal release at central inhibitory synapses.
The teleost Mauthner (M)-cell is subjected to a powerful glycinergic inhibition that regulates its threshold for initiation of a vital escape reflex. The effects of 5-HT on this inhibition were studied in current- and voltage-clamp experiments because the M-cell and its afferents have a profuse serotonergic innervation, including axoaxonal contacts with terminals of the inhibitory interneurons. Local applications of the amine and/or of its uptake blockers markedly enhanced inhibitory currents evoked by synchronous activation of two identified presynaptic networks. In order to determine the site of this 5-HT action, we exploited the fact that in the M-cell, synaptic noise is predominantly inhibitory. Furthermore, its quantal components can be resolved providing a means to distinguish pre- and post-synaptic loci underlying variations in synaptic efficacy. As in other cell types, it consists of spontaneous exocytotic events and multiquantal responses triggered by action potentials in afferent neurons. 5-HT or its uptake blockers produced a long-lasting enhancement of this noise, manifested as a shift to the right of amplitude distribution histograms of the individual inhibitory postsynaptic currents (IPSCs) and an increase in the mean quantal content of noise. In contrast, the size of the miniature IPSC (mIPSCs) remained constant in these experiments and in another series where 5-HT was given in presence of TTX. In this case, the amine also increased the rate of occurrence of single quanta. Taken together, these data indicate that 5-HT acts presynaptically to increase the probability of evoked and spontaneous release of glycine. This conclusion was reinforced by evidence that the overall frequency of the responses in noise could be unaltered by 5-HT, indicating that the afferent firing pattern had remained constant. Extracellular recordings of the presynaptic volleys showed that action potentials were not prolonged and suggested that 5-HT closes K+ channels in the terminal membrane, leading to an increase of resistance and a larger depolarization in that region as a possible mechanism for the facilitation of release. While the enhancement of transmitter release persisted for 20 min or more, there was also a transient induction of a K+ inward-rectifying current in the M-cell. These results indicate that 5-HT increases the efficacy of inhibitory synaptic transmission in the vertebrate CNS by a presynaptic action.


In vitro heterogeneity in human gliomas. Are all transformed cells of glial origin?
Primary cultures from 30 human gliomas (26 high grade, 3 low grade, and one oligoastrocytoma) were studied to examine the mixture of cells that make up the outgrowth, and their interactions. GFAP + ve Fibronectin - ve cells had a predominantly process forming (PF) morphology and formed complex networks around explants. Fibronectin + ve GFAP-ve cells had a flattened adherent (FA) morphology, tended to increase in time in culture, in 11 tumours showed a transformed pattern of growth, and may derive from perivascular mesenchyme. Neoplastic glial cells in vivo, or in vitro, may influence the behaviour and nature of other cells in tumour tissue which may be of significance in tumour behaviour and progression.