Preferences on Delivery of Cancer Rehabilitation Services for Cancer-Related Disability Among Older Individuals Surviving Breast Cancer: A Qualitative Study.
Older individuals surviving breast cancer often encounter cancer-related disability as a short-term or long-term effect of cancer and related treatment. Cancer rehabilitation interventions have the potential to prevent, mitigate, or remediate cancer-related disability. However, use of these services remains limited. Understanding the priorities and perspectives of older individuals surviving breast cancer is key to developing effective and implementable cancer rehabilitation interventions. This qualitative descriptive study examined individuals' preferred and valued methods of cancer rehabilitation intervention delivery. Using a qualitative descriptive design, older individuals surviving breast cancer (n=14) completed a single telephone-based semi-structure interview. Interviews explored survivors' preferences for cancer rehabilitation service delivery. Interview transcriptions were thematically analyzed. Open codes were inductively generated and reviewed for agreement by an independent reviewer. The codes were deductively organized. Differences were resolved through consensus meetings. Findings revealed preferred intervention delivery characteristics for intervention setting, mode of delivery, format, and timing. Participants predominantly preferred interventions delivered in community-based settings, with both in-person and remote components. Participants also appeared to value one-on-one interventions and those delivered post-treatment. Survivors' overarching preferences were based on desire for patient-centric care, one-on-one therapist time, complex medical schedules, and financial concerns. Study findings provide guidance on the modification of existing and creation of new cancer rehabilitation interventions addressing cancer-related disability in older individuals surviving breast cancer. Adoption of stakeholder-driven intervention delivery characteristics may improve value and acceptability of interventions. Future intervention research should incorporate and test these characteristics to ensure their effectiveness in real-world settings.


An evolutionary approach uncovers a diverse response of tRNA 2-thiolation to elevated temperatures in yeast.
Chemical modifications of transfer RNA (tRNA) molecules are evolutionarily well conserved and critical for translation and tRNA structure. Little is known how these nucleoside modifications respond to physiological stress. Using mass spectrometry and complementary methods, we defined tRNA modification levels in six yeast species in response to elevated temperatures. We show that 2-thiolation of uridine at position 34 (s(2)U34) is impaired at temperatures exceeding 30°C in the commonly used Saccharomyces cerevisiae laboratory strains S288C and W303, and in Saccharomyces bayanus. Upon stress relief, thiolation levels recover and we find no evidence that modified tRNA or s(2)U34 nucleosides are actively removed. Our results suggest that loss of 2-thiolation follows accumulation of newly synthesized tRNA that lack s(2)U34 modification due to temperature sensitivity of the URM1 pathway in S. cerevisiae and S. bayanus. Furthermore, our analysis of the tRNA modification pattern in selected yeast species revealed two alternative phenotypes. Most strains moderately increase their tRNA modification levels in response to heat, possibly constituting a common adaptation to high temperatures. However, an overall reduction of nucleoside modifications was observed exclusively in S288C. This surprising finding emphasizes the importance of studies that utilize the power of evolutionary biology, and highlights the need for future systematic studies on tRNA modifications in additional model organisms.


Electrochemistry, chemical reactivity, and time-resolved infrared spectroscopy of donor-acceptor systems [(Q(x))Pt(pap(y))] (Q = substituted o-quinone or o-iminoquinone; pap = phenylazopyridine).
The donor-acceptor complex [((O,N)Q(2-))Pt(pap(0))] (1; pap = phenylazopyridine, (O,N)Q(0) = 4,6-di-tert-butyl-N-phenyl-o-iminobenzoquinone), which displays strong π-bonding interactions and shows strong absorption in the near-IR region, has been investigated with respect to its redox-induced reactivity and electrochemical and excited-state properties. The one-electron-oxidized product [((O,N)Q(•-))Pt(pap(0))](BF4) ([1]BF4) was chemically isolated. Single-crystal X-ray diffraction studies establish the iminosemiquinone form of (O,N)Q in [1](+). Simulation of the cyclic voltammograms of 1 recorded in the presence of PPh3 elucidates the mechanism and delivers relevant thermodynamic and kinetic parameters for the redox-induced reaction with PPh3. The thermodynamically stable product of this reaction, complex [((O,N)Q(•-)) Pt(PPh3)2](PF6) ([2]PF6), was isolated and characterized by X-ray crystallography, electrochemistry, and electron paramagnetic resonance spectroscopy. Picosecond time-resolved infrared spectroscopic studies on complex 1b (one of the positional isomers of 1) and its analogue [((O,O)Q(2-))Pt(pap(0))] (3; (O,O)Q = 3,5-di-tert-butyl-o-benzoquinone) provided insight into the excited-state dynamics and revealed that the nature of the lowest excited state in the amidophenolate complex 1b is primarily diimine-ligand-based, while it is predominantly an interligand charge-transfer state in the case of 3. Density functional theory calculations on [1](n+) provided further insight into the nature of the frontier orbitals of various redox forms and vibrational mode assignments. We discuss the mechanistic details of the newly established redox-induced reactivity of 1 with electron donors and propose a mechanism for this process.


Chronic venous insufficiency and venous leg ulcers: Aetiology, on the pathophysiology-based treatment.
The chronic venous disease covers a wide spectrum of venous disorders that are characterized by severely impaired blood return that primarily affects veins in the lower extremities. Morphological and functional abnormalities of the venous system led to chronic venous insufficiency (CVI), and present as leg heaviness/achiness, edema, telangiectasia, and varices. The term 'chronic venous insufficiency' (CVI) refers to a disease of greater severity. Venous dysfunction is associated with venous hypertension and is associated with venous reflux due to poorly functioning or incompetent venous valves, which ultimately reduces venous return, leading to a cascade of morphological, physiological, and histologic abnormalities such as blood pooling, hypoxia, inflammation, swelling, skin changes (lipodermatosclerosis), and in severe cases, venous leg ulcers (VLU). This review summarizes recent knowledge about the aetiology, risk factors, and pathophysiology of VLU and compared the possibilities of their treatment.


[Lipoma of the filum terminale: a prospective tomodensitometry study].
A lipomatous aspect of the filum terminale is sometimes recognized in routine lumbosacral CT studies as a small (1 to 2 mm) tubular fatty hypodensity that lies posteriorly in the dural sac. To study the epidemiologic frequency and pathological significance, the authors prospectively reviewed the standard lumbosacral CT studies of a large series of 1033 adult patients suffering from mechanical problems. The lipomatous aspect was encountered in 39 of them (3.77%). The average size was about 1 mm and never exceeded 2 mm (92%) except for 3 cases. The commonest site was L4-L5 but the anomaly was more commonly seen at two levels. Despite the lack of histological proof, the authors consider the lesion benign and trite with two restrictions: the pediatric cases (not studied in their series) and the patients presenting a lipoma greater than 3 mm; for these two groups further investigations are recommended to exclude a tethered cord syndrome.


Compressive strains at physiological frequencies influence the metabolism of chondrocytes seeded in agarose.
Articular cartilage is subjected to dynamic compressive loading that is known to influence chondrocyte metabolism. While the exact signalling mechanisms are unclear, it has been proposed that cell deformation plays a role and may stimulate a metabolic response through distinctive pathways. In this study, a well characterized model system in which chondrocytes are embedded in agarose was used to study the effect of dynamic cellular strain on three key metabolic processes, namely the synthesis of glycosaminoglycan, of DNA, and of total protein. Using a specially designed apparatus, 15% compressive strain amplitude was applied to agarose-chondrocyte cylinders statically or dynamically over a range of frequencies (0.3-3 Hz). Static and low-frequency strain (0.3 Hz) inhibited the synthesis of glycosaminoglycan, while a frequency of 1 Hz stimulated synthesis. Static strain reduced the level of thymidine uptake, whereas dynamic strain at all frequencies induced an increase in chondrocyte proliferation. Incorporation of tritiated proline was suppressed by all strain regimens tested. The three parameters investigated were each influenced by the dynamic strain regimens in a distinct manner, implying that the signalling mechanisms involved are uncoupled.


Electrocardiograms and 13 year cardiovascular mortality in Busselton study.
In 2119 unselected Busselton subjects 40 to 79 years of age, the 13 year mortality from cardiovascular disease was significantly higher in those whose initial electrocardiogram showed Q and QS patterns, left axis deviation, ST depression, T wave depression, flat or biphasic T waves, atrial fibrillation or flutter, and ventricular extrasystoles. In angina-free subjects whose electrocardiographic codes occurred in isolation from any other electrocardiographic abnormality, ventricular extrasystoles were associated with significantly higher mortality from cardiovascular disease compared with controls.


Secondary Phase Formation Mechanism in the Mo-Back Contact Region during Sulfo-Selenization Using a Metal Precursor: Effect of Wettability between a Liquid Metal and Substrate on Secondary Phase Formation.
Recently, highly efficient CZTS solar cells using pure metal precursors have been reported, and our group created a cell with 12.6% efficiency, which is equivalent to the long-lasting world record of IBM. In this study, we report a new secondary phase formation mechanism in the back contact interface. Previously, CZTSSe decomposition with Mo has been proposed to explain the secondary phase and void formation in the Mo-back contact region. In our sulfo-selenization system, the formation of voids and secondary phases is well explained by the unique wetting properties of Mo and the liquid metal above the peritectic reaction (η-Cu6Sn5 → ε-Cu3Sn + liquid Sn) temperature. Good wetting between the liquid Sn and the Mo substrate was observed because of strong metallic bonding between the liquid metal and Mo layer. Thus, some ε-Cu3Sn and liquid Sn likely remained on the Mo layer during the sulfo-selenization process, and Cu-SSe and Cu-Sn-SSe phases formed on the Mo side. When bare soda lime glass (SLG) was used as a substrate, nonwetting adhesion was observed because of weak van der Walls interactions between the liquid metal and substrate. The Cu-Sn alloy did not remain on the SLG surface, and Cu-SSe and Cu-Sn-SSe phases were not observed after the final sulfo-selenization process. Additionally, Mo/SLG substrates coated with a thin Al2O3 layer (1-5 nm) were used to control secondary phase formation by changing the wetting properties between Mo and the liquid metal. A 1 nm Al2O3 layer was enough to control secondary phase formation at the CZTSSe/Mo and void/Mo interfaces, and a 2 nm Al2O3 layer was enough to perfectly control secondary phase formation at the Mo interface and Mo-SSe formation.


The role of imaging in the diagnosis of primary prostate cancer.
Ultrasound and magnetic resonance imaging (MRI) are key imaging modalities in prostate cancer diagnosis. MRI offers a range of intrinsic contrast mechanisms (T2, diffusion-weighted imaging (DWI), MR spectroscopy (MRS)) and extrinsic contrast-generating options based on tumour vascular state following injection of weakly paramagnetic agents such as gadolinium. Together these parameters are referred to as multiparametric (mp)MRI and are used for detecting and guiding biopsy and staging prostate cancer. Although sensitivity of mpMRI is <75% for disease detection, specificity is >90% and a standardised reporting system together with MR-guided targeted biopsy is the optimal diagnostic pathway. Shear wave ultrasound elastography is a new technique which also holds promise for future studies. This article describes the developments in imaging the primary site of prostate cancer and reviews their current and future utility for screening, diagnosis and T-staging the disease.


Design and Synthesis of Oligopeptidic Parvulin Inhibitors.
Pin1 catalyzes the cis-trans isomerization of pThr-Pro or pSer-Pro amide bonds of various proteins involved in several physio/pathological processes. In this framework, recent research activity is directed toward the identification of new selective Pin1 inhibitors. Here, we developed a set of peptide-based Pin1 inhibitors. Direct-binding experiments allowed the identification of the peptide-based inhibitor 5 k (methylacetyl-l-alanyl-l-histidyl-l-prolyl-l-phenylalaninate) as a potent ligand of Pin1. Notably, 5 k binds Pin1 with higher affinity than Pin4. The comparative analysis of molecular models of Pin1 and Pin4 with the selected compound gave a rational explanation of the biochemical activity and pinpointed the chemical elements that, if opportunely modified, may further improve inhibitory potency, pharmacological properties, and selectivity of future peptide-based parvulin inhibitors. Since 5 k showed limited cell penetration and no antiproliferative activity, it was conjugated to a polyarginine stretch (R8), known to promote cell penetration of peptides, to obtain the R8-5 k derivative, which displayed antiproliferative effects on cancer cell lines over non-tumor cells. The effect of R8 on cell proliferation was also investigated. This work warrants caution about applying the R8 strategy in the development of cell-penetrating antiproliferative peptides, as it is not inert.


[Clinical practice guidelines: surgical treatment of tympanic membrane perforations in children].
A study group emanating from the French Society of Otolaryngologists and Associated Paediatric Otologists, anaesthetists and bacteriologists carried out a review of the world literature regarding the indications, technique and results of simple myringoplasty in children. The group assessed the levels of evidence present in published articles and the opinions of experts in the field, due to the lack of sufficient evidence. The study group then established recommendations for good practice. These were sent to otolaryngologists, paediatricians, general practitioners and anaesthetists involved in the care of children under the age of 15 presenting with a simple non-infected tympanic membrane perforation and without affection of the ossicular chain. The full text of the recommendations is provided.


Robust Scale Adaptive Tracking by Combining Correlation Filters with Sequential Monte Carlo.
A robust and efficient object tracking algorithm is required in a variety of computer vision applications. Although various modern trackers have impressive performance, some challenges such as occlusion and target scale variation are still intractable, especially in the complex scenarios. This paper proposes a robust scale adaptive tracking algorithm to predict target scale by a sequential Monte Carlo method and determine the target location by the correlation filter simultaneously. By analyzing the response map of the target region, the completeness of the target can be measured by the peak-to-sidelobe rate (PSR), i.e., the lower the PSR, the more likely the target is being occluded. A strict template update strategy is designed to accommodate the appearance change and avoid template corruption. If the occlusion occurs, a retained scheme is allowed and the tracker refrains from drifting away. Additionally, the feature integration is incorporated to guarantee the robustness of the proposed approach. The experimental results show that our method outperforms other state-of-the-art trackers in terms of both the distance precision and overlap precision on the publicly available TB-50 dataset.


Rett syndrome: exclusion mapping following the hypothesis of germinal mosaicism for new X-linked mutations.
The hypothesis of germinal mosaicism in the unaffected mother of two half-sisters affected with Rett syndrome is postulated to explain the unusual recurrence of this genetic disorder affecting only females (1/10,000); it might be caused by new X-linked mutations with lethality in male fetuses. The analysis of 34 X-linked restriction fragment length polymorphisms (RFLPs) in these two affected females and in their unaffected mother and half-brother, together with the reconstruction of phase for 15 informative RFLPs in somatic cell hybrids retaining a single X chromosome from each female, has made it possible to exclude some regions of the X chromosome as possible sites of the mutation(s) causing Rett syndrome.


Laparoendoscopic Single-Site Retroperitoneoscopic Adrenalectomy Versus Conventional Retroperitoneoscopic Adrenalectomy in Obese Patients.
To compare the operative outcomes of obese patients undergoing laparoendoscopic single-site (LESS) retroperitoneoscopic adrenalectomy or standard laparoscopic (LAP) retroperitoneoscopic adrenalectomy. Between September 2011 and April 2015, 51 obese patients underwent LESS retroperitoneoscopic adrenalectomy and their operative outcomes were compared with 65 obese patients who underwent standard retroperitoneoscopic adrenalectomy by the same surgeon. In the LESS group, a single-port access was positioned in the lumbar incision. The standard retroperitoneal adrenalectomy technique was performed with a combination of conventional and curved LAP instruments. The following parameters were adopted: patient demographics, surgical details, perioperative complications, postoperative outcome data, and short-term outcomes. The LESS group was comparable with the LAP group in terms of total operative time (70.4 ± 21.3 vs 65.5 ± 24.8 minutes, p = 0.26), hospital length of stay (5.7 ± 1.2 vs 6.1 ± 1.5 days, p = 0.12), and incidence of complications (4/51 vs 5/65, p = 0.98) for patients with similar baseline demographics. The LESS group had significantly shorter surgical incisions (2.8 ± 0.3 vs 5.3 ± 0.6 cm, p < 0.0001), lower in-hospital analgesic requirement (7.6 ± 3.3 mg morphine equivalent vs 10.5 ± 6.2 mg, p = 0.003), and significantly superior scar satisfaction score (9.3 ± 0.7 vs 7.6 ± 1.4, p < 0.0001) than the LAP group. Although estimated blood loss was greater in the LESS group (28.1 ± 10.6 vs 16.9 ± 7.2 mL in the LAP group, p < 0.0001), <50 mL overall blood loss was not clinically significant. During a mean follow-up of 20.2 months, no recurrences or deaths were documented in either group. In properly selected patients, LESS retroperitoneoscopic adrenalectomy for obese individuals is technically feasible and safe in experienced hands, offering perioperative outcomes comparable with those of the conventional multiport approach, but with a superior cosmetic outcome.


Predictors of mortality within the first year post-hepatectomy for hepatocellular carcinoma.
Hepatic resection (HR) for hepatocellular carcinoma (HCC) is safe with good perioperative and long-term oncologic outcomes. There is a paucity of data with regards to intermediate-term outcomes (i.e., beyond 90-day and within 1-year mortality). This paper studies the risk factors for within 1-year mortality after elective HR with curative intent in patients with HCC. An audit of patients who underwent curative HR for HCC from January 2007 to April 2016 was conducted. Univariate and multivariate analysis were sequentially performed on perioperative variables using Cox-regression analysis to identify factors predicting intermediate-term outcomes defined as within 1-year mortality. Kaplan-Meier survival curves and hazard ratios were obtained. Three hundred forty-eight patients underwent HR during the study period and 163 patients had curative hepatectomy for HCC. Fifteen patients (9.2%) died within 1-year after HR. Multivariate analysis identified Child-Pugh class B/C (HR 5.5, p = 0.035), multinodularity (HR 7.1, p = 0.001), macrovascular invasion (HR 4.2, p = 0.04) postoperative acute renal failure (HR 5.8, p = 0.049) and posthepatic liver failure (HR 9.6, p = 0.009) as significant predictors of 1-year mortality. One-year mortality following HR for HCC remains high and can be predicted preoperatively by multinodularity, Child-Pugh class, and macrovascular invasion. Postoperative acute renal failure and liver failure are associated with 1-year mortality.


[LDL-cholesterol homogeneous assays versus Friedewald's equation].
Low-density lipoprotein (LDL) is an important risk factor for coronary artery disease as well as ischemic stroke. In clinical practice, LDL-cholesterol (LDL-C) is calculated by Friedewald's equation or determined by homogeneous assays for LDL-C. Although Friedewald's equation has some limitations, it has been widely used for LDL-C measurement for nearly 40 years. On the other hand, the first LDL-C homogeneous assay was developed in the late 1990s. New reagents have appeared on the market one after another, and 12 homogeneous assays are now available in Japan; however, they measure LDL-C by different principles, which are not disclosed to the public. There is some debate about which method is superior for LDL-C measurement of clinical samples.


Optical Properties of Saturated and Unsaturated Carbonyl Defects in Polyethylene.
Polyethylene (PE), one of the simplest and most used aliphatic polymers, is generally provided with a number of additives, in particular antioxidants, because of its tendency to get oxidized. Carbonyl defects, a product of the oxidation of PE, are occurring in various forms, in particular saturated ones, known as ketones, where a C═O double bond substitutes a CH2 group, and various unsaturated ones, i.e., with further missing hydrogens. Many experimental investigations of the optical properties in the visible/UV range mainly attribute the photoluminescence of PE to one specific kind of unsaturated carbonyls, following analogies to the emission spectra of similar small molecules. However, the reason why saturated carbonyls should not be optically detected is not clear. We investigated the optical properties of PE with and without carbonyl defects using perturbative GW and the Bethe-Salpeter equation in order to take into account excitonic effects. We discuss the calculated excitonic states in comparison with experimental absorption/emission energies and the stability of both saturated and unsaturated carbonyl defects. We conclude that the unsaturated defects are indeed the best candidate for the luminescence of oxidized PE, and the reason is mainly due to oscillator strengths.


A Data-Driven Approach to Predict and Classify Epileptic Seizures from Brain-Wide Calcium Imaging Video Data.
The prediction of epileptic seizures has been an essential problem of epilepsy study. The calcium imaging video data images the whole brain-wide neurons activities with electrical discharge recorded by calcium fluorescence intensity (CFI). In this paper, using the zebrafish's brain-wide calcium image video data, we propose a data-driven approach to effectively detect the systemic change-point, and further predict the epileptic seizures. Our approach includes two phases: offline training and online testing. Specifically, during offline training, we extract features and confirm the existence of systemic change-point, then estimate the ratio of unchanged system duration to interictal period duration. For online testing, we implement a statistical model to estimate the change-point, and then predict the onset of epileptic seizure. The testing results show that our proposed approach could effectively predict the time range of future epileptic seizure. Furthermore, we explore the macroscopic patterns of epileptic and control cases, and extract features based on the pattern difference, then implement and compare the classification performance from four machine learning models. Based on the data structure, we also propose a new method to discretize related features, and combine with hierarchical clustering to better visualize and explain the pattern difference between epileptic and control cases.


Increased BACE1 activity inhibits peripheral nerve regeneration after injury.
Axons of the peripheral nervous system possess the capacity to regenerate following injury. Previously, we showed that genetically knocking out Beta-Site APP-Cleaving Enzyme 1 (BACE1) leads to increased nerve regeneration. Two cellular components, macrophages and neurons, contribute to enhanced nerve regeneration in BACE1 knockout mice. Here, we utilized a transgenic mouse model that overexpresses BACE1 in its neurons to investigate whether neuronal BACE1 has an inverse effect on regeneration following nerve injury. We performed a sciatic nerve crush in BACE1 transgenic mice and control wild-type littermates, and evaluated the extent of both morphological and physiological improvements over time. At the earliest time point of 3days, we observed a significant decrease in the length of axonal sprouts growing out from the crush site in BACE1 transgenic mice. At later times (10 and 15days post-crush), there were significant reductions in the number of myelinated axons in the sciatic nerve and the percentage of re-innervated neuromuscular junctions in the gastrocnemius muscle. Transgenic mice had a functional electrophysiological delay in the recovery up to 8weeks post-crush compared to controls. These results indicate that BACE1 activity levels have an inverse effect on peripheral nerve repair after injury. The results obtained in this study provide evidence that neuronal BACE1 activity levels impact peripheral nerve regeneration. This data has clinical relevance by highlighting a novel drug target to enhance peripheral nerve repair, an area which currently does not have any approved therapeutics.


Eribulin combined with antiangiogenic agents in women with HER2-negative metastatic breast cancer: a retrospective multicenter study.
The relative lack of specifically targeted agents for HER2-negative metastatic breast cancer (MBC) makes the need for new agents or combination therapies to maximize clinical benefit while reducing toxicity critical. To retrospectively analyze the efficacy and safety of eribulin combined with antiangiogenic drugs in the treatment of Chinese women with HER2-negative MBC. A total of 85 consecutive MBC patients with HER2-negative who were treated with eribulin + antiangiogenic agents between October 2020 and April 2023 in four institutions were retrospectively included in this study. Patients received eribulin 1.4 mg/m2 (day 1 and 8) plus bevacizumab 7.5 mg/kg (day 1, 64 patients) or anlotinib 10 mg daily (day 1-14, 16 patients) or apatinib 250 mg daily (5 patients) on a 21-day cycle until progression or unacceptable toxicity. The primary end-point was progression-free survival (PFS), according to Response Evaluation Criteria in Solid tumors (RECIST) 1.1. Secondary end-points included toxicities, objective response rate (ORR), disease control rate (DCR), and overall survival (OS). Adverse events (AEs) were graded according to Common Terminology Criteria for Adverse Events (CTCAE) version 5.0. The study included 85 HER2-negative MBC patients, with 41 patients (48.2%) in the first to second line group and 44 patients (51.8%) in the greater than or equal to third line group. The median age was 54.0 years. Thirty patients in the first to second line group and 14 patients in the greater than or equal to third line group had triple-negative breast cancer (TNBC). The ORR and DCR were 34.1% (29/85) and 75.3% (64/85). The median PFS (mPFS) of total population was 6.0 months (95% CI: 4.3-7.7), and median OS (mOS) was immature. The mPFS was 7.7 and 4.3 months in the first to second and greater than or equal to third line treatment (p = 0.003), respectively. TNBC patients in first to second line therapy showed a significantly longer PFS (6.5 months versus 2.0 months, p = 0.021) compared to greater than or equal to third line. The incidences of cardiovascular toxicity were 29.4% in grades 1-2 and no grades 3-4. Hematologic toxicity (leukopenia and neutropenia) was the most common grade ⩾3 AEs, and AEs were more common in patients in greater than or equal to third line. The results suggest that eribulin combined with antiangiogenic therapy has a meaningful clinical activity and an acceptable safety profile in HER2-negative MBC.


Suicide Risk and Prevention During the COVID-19 Pandemic: One Year On.
Emerging data from high and upper-middle-income countries indicate that suicide rates generally did not increase during the initial months of the COVID-19 pandemic, yet the pandemic's impact on suicide is complex. We discuss the nuances of this relationship, how it may evolve over time, and describe the specific steps that governments and societies must take to mitigate harm and prevent suicides in the late stages and aftermath of the pandemic.


Where we came from: continuing professional development for the 18th century physician and surgeon, the genesis of British medical societies.
Keeping professionally up to date in 18th-century Britain was not an easy undertaking. Learning on the job was insufficient for the further development of individual medical knowledge. The century witnessed the gradual growth of medical societies to provide a better education than that offered by university institutions. The Worshipful Society of Apothecaries of London in 1815 was empowered to licence and regulate medical practitioners, today's general practitioners. Societies were established in Edinburgh but not so many as around London, where a particularly successful education body was established in 1773, the prestigious Medical Society of London. In 1805 a breakaway group from the society formed an equally highly respected learned body, the Medical and Chirurgical Society of London, that became the nidus for the amalgamation of numerous specialist societies to form, in June 1907, the extant Royal Society of Medicine. By the end of the 18th century, the medical society had fostered professionalism, education and unification within diverse medical and scientific disciplines.


ST-elevation Myocardial Infarction and Multivessel Coronary Artery Disease - A Critical Review of Current Practice, Evidence and Meta-analyses.
In recent years, practice and guidelines for patients with ST-elevation myocardial infarction (STEMI) have evolved from a 'culprit-only approach' to complete revascularisation; however, several issues remain, particularly regarding assessment of non-culprit lesions and timing of their revascularisation. Complete revascularisation should be performed in patients presenting with STEMI; however, available studies often present contradictory results regarding the optimal timing of non-culprit lesion percutaneous coronary intervention (PCI). The aim of this review is to provide a practical approach for the assessment of patients presenting with STEMI and multivessel coronary artery disease by analysing randomised trials, meta-analyses and our clinical experience. We recommend multivessel revascularisation at the time of primary PCI for simple cases, while we suggest deferring treatment of complex lesions; the optimal timing of staged PCI should be individualised according to clinical judgement.


Flexible resistive random access memory devices by using NiO x /GaN microdisk arrays fabricated on graphene films.
We report flexible resistive random access memory (ReRAM) arrays fabricated by using NiO x /GaN microdisk arrays on graphene films. The ReRAM device was created from discrete GaN microdisk arrays grown on graphene films produced by chemical vapor deposition, followed by deposition of NiO x thin layers and Au metal contacts. The microdisk ReRAM arrays were transferred to flexible plastic substrates by a simple lift-off technique. The electrical and memory characteristics of the ReRAM devices were investigated under bending conditions. Resistive switching characteristics, including cumulative probability, endurance, and retention, were measured. After 1000 bending repetitions, no significant change in the device characteristics was observed. The flexible ReRAM devices, constructed by using only inorganic materials, operated reliably at temperatures as high as 180 °C.


Emerging roles for the amyloid precursor protein and derived peptides in the regulation of cellular and systemic metabolism.
The amyloid precursor protein (APP) is a transmembrane protein that can be cleaved by proteases through two different pathways to yield a number of small peptides, each with distinct physiological properties and functions. It has been extensively studied in the context of Alzheimer's disease, with the APP-derived amyloid β (Aβ) peptide being a major constituent of the amyloid plaques observed in this disease. It has been known for some time that APP can regulate neuronal metabolism; however, the present review examines the evidence indicating that APP and its peptides can also regulate key metabolic processes such as insulin action, lipid synthesis and storage and mitochondrial function in peripheral tissues. This review presents the hypothesis that amyloidogenic processing of APP in peripheral tissues plays a key role in the response to nutrient excess and that this could contribute to the pathogenesis of metabolic diseases such as obesity and type 2 diabetes (T2D).


Widespread dilatation of perivascular spaces: a leukoencephalopathy causing dementia.
A 68-year-old demented woman had widespread dilatation of perivascular spaces in the cerebral white matter for at least 12 years. There were no micro-infarcts, but some vessel walls in the white matter were thickened by a loose fibrosis. Our case does not correspond to Binswanger's disease or any other known vascular leukoencephalopathy. The longstanding evolution points to a nonfamilial leukoencephalopathy of probable vascular origin.


Measuring and mitigating inhibition during quantitative real time PCR analysis of viral nucleic acid extracts from large-volume environmental water samples.
Naturally-occurring inhibitory compounds are a major concern during qPCR and RT-qPCR analysis of environmental samples, particularly large volume water samples. Here, a standardized method for measuring and mitigating sample inhibition in environmental water concentrates is described. Specifically, the method 1) employs a commercially available standard RNA control; 2) defines inhibition by the change in the quantification cycle (C(q)) of the standard RNA control when added to the sample concentrate; and 3) calculates a dilution factor using a mathematical formula applied to the change in C(q) to indicate the specific volume of nuclease-free water necessary to dilute the effect of inhibitors. The standardized inhibition method was applied to 3,193 large-volume water (surface, groundwater, drinking water, agricultural runoff, sewage) concentrates of which 1,074 (34%) were inhibited. Inhibition level was not related to sample volume. Samples collected from the same locations over a one to two year period had widely variable inhibition levels. The proportion of samples that could have been reported as false negatives if inhibition had not been mitigated was between 0.3% and 71%, depending on water source. These findings emphasize the importance of measuring and mitigating inhibition when reporting qPCR results for viral pathogens in environmental waters to minimize the likelihood of reporting false negatives and under-quantifying virus concentration.


Laboratory tests for mumps vaccines.
The action of live attenuated vaccines against mumps is poorly understood although their clinical efficacy is beyond doubt. The attenuated character of the vaccine is assured by consistency of production related to clinical trials, and limited studies of vaccine seeds in primates. Potency is assessed by infectivity in vitro and is subject to poorly understood sources of variation. Molecular biological studies are at an early stage.


Combined 4-1BB and CD28 costimulation could unleash lymphocytes from immunosuppression induced by adipose derived stem cell soluble products.
Adipose derived stem cells (ASCs) have the potential to differentiate into multiple cell lineages with the capacity to suppress immune cells. However, the exact mechanism of this suppression is not fully understood. We hypothesized that supplying additional lymphocyte costimulation through CD28 and 4-1BB could overturn the inhibitory effect of ASCs. To that end, PHA-activated human PBMCs were cocultured with ASCs or with conditioned media (CM) prepared from cultured ASCs. Growth was analyzed in the presence or absence of anti-CD28 and anti-4-1BB antibodies. Results from CFSE dilution analysis with flow cytometry showed that significant and dose-dependent suppression of PHA-activated lymphocytes occurred in the presence of ASC-like cells or ASC's CM. However, additional costimulation of T cells through CD28 and 4-1BB was able to fully recover lymphocyte proliferative capacity in the presence of ASC's CM. Neither of the costimulatory antibodies could fully recover lymphocyte proliferation following coculture with ASCs. Reversal of ASC's immunosuppression through costimulation suggests that further investigation of ASC suppression mechanisms is warranted, since many clinical applications of ASCs are based on this feature. Moreover, such findings have the potential to boost the usefulness of ASCs in the treatment of autoimmune disease.


Utilization of grasses for potential biofuel production and phytoremediation of heavy metal contaminated soils.
This research focuses on investigating the use of common biofuel grasses to assess their potential as agents of long-term remediation of contaminated soils using lead as a model heavy metal ion. We present evidence demonstrating that switch grass and Timothy grass may be potentially useful for long-term phytoremediation of heavy metal contaminated soils and describe novel techniques to track and remove contaminants from inception to useful product. Enzymatic digestion and thermochemical approaches are being used to convert this lignocellulosic feedstock into useful product (sugars, ethanol, biocrude oil+biochar). Preliminary studies on enzymatic hydrolysis and fast pyrolysis of the Switchgrass materials that were grown in heavy metal contaminated soil and non-contaminated soils show that the presence of lead in the Switchgrass material feedstock does not adversely affect the outcomes of the conversion processes. These results indicate that the modest levels of contaminant uptake allow these grass species to serve as phytoremediation agents as well as feedstocks for biofuel production in areas degraded by industrial pollution.


BRCA1 5382insC mutation in sporadic and familial breast and ovarian carcinoma in Scotland.
A restriction site-generating polymerase chain reaction (RG-PCR) assay was developed to detect the BRCA1 5382insC mutation that has been reported in multiple, apparently unrelated breast/ovarian carcinoma families. The assay has been used to screen tumour DNA from 250 breast cancer patients (aged 19-86 years) and from 80 ovarian cancer patients (aged 25-90 years) in a local population of patients with no known family history. Altogether, 0/80 (0%) ovarian and 1/250 (0.4%) breast tumour DNAs were found to have the 5382insC mutation. The sole positive case was a 26-year-old woman (BC185) with no known family history. One of the reasons for carrying out this analysis was that the 5382insC mutation had previously been shown to segregate with the disease in a very large Scottish 'West Lothian' kindred having breast/ovarian carcinoma. To investigate whether this apparently isolated case and the known family might be related, haplotypes for the markers D17S855, D17S1322, D17S1323 and D17S1327 were analysed. The mutant haplotype in the large kindred was identical to that reported in all other 5382insC mutation families for all markers with the exception of D17S1327. This implies that there has been a recombination event at the telomeric end of common ancestral haplotype in this family. Since the isolated case we identified carries the 'complete' common haplotype, it is unlikely that she is closely related to the West Lothian family.


[Relationship between hypoxia-induced apoptosis and caspases-3 activation, intracellular calcium overload in cardiomyocytes].
To explore the effects of hypoxia on Caspases activation in cardiomyocyte and role of intracellular calcium in this event in cardiomyocytes. After hypoxia 0 min, 30 min, 1 h, 3 h, 6 h, 12 h, 24 h, apoptotic cell percentage was determined with Hoechst 33342 straining. Expressions of Caspases-3 mRNA and release of mitochondrial cytochrome c in primary culture of cardiomyocytes were determined by using RT-PCR and Western blotting respectively. Elevation of Cyt c in cytosol was in accordance with the decline in mitochondrial Cyt c content. Significant increase in Cyt c in cytosol appeared at 12 h post hypoxia and peaked at 24 h while Cyt c in mitochondria could not be detected at 24 h post hypoxia. Hypoxia up-regulated Caspases-3 mRNA expressions beginning at 3 h post hypoxia. Intracellular calcium overload occurred earlier than release of mitochondrial Cyt c and the activation of Caspase-3 during the hypoxic insult. Inhibition of Caspase-3 activation and pretreatment with calcium chelator BAPTA/AM offered a marked protective effect on hypoxia induced cardiomyocyte apoptosis. Hypoxia can induce mitochondrion-dependent Caspase-3 activation in cardiomyocytes and therefore leads to cell apoptosis. Increase of intracellular Ca2+ plays an important role in the activation of Caspase-3 and the induction of apoptosis in cardiomyocytes.


Arnol'd cat map lattices.
We construct Arnol'd cat map lattice field theories in phase space and configuration space. In phase space we impose that the evolution operator of the linearly coupled maps be an element of the symplectic group, in direct generalization of the case of one map. To this end we exploit the correspondence between the cat map and the Fibonacci sequence. The chaotic properties of these systems also can be understood from the equations of motion in configuration space. These describe inverted harmonic oscillators, where the runaway behavior of the potential competes with the toroidal compactification of the phase space. We highlight the spatiotemporal chaotic properties of these systems using standard benchmarks for probing deterministic chaos of dynamical systems, namely, the complete dense set of unstable periodic orbits, which, for long periods, lead to ergodicity and mixing. The spectrum of the periods exhibits a strong dependence on the strength and the range of the interaction.


A molecular modeling based screening for potential inhibitors to alpha hemolysin from Staphylococcus aureus.
Staphylococcus aureus, a Gram-positive bacterium is pathogenic in nature. It is known that secreted toxins remain active after antibiotic treatment. The alpha hemolysin or alpha toxin damages cell membrane and induces apoptosis and degradation of DNA. The titer of alphahemolysin increases and causes hemostasis disturbances, thrombocytopenia, and pulmonary lesions during staphylococcal infection. Therefore, it is of interest to inhibit alpha hemolysin using novel compounds. We used the structure of alpha hemolysin(PDB: 7AHL) to screen structures for 100,000 compounds from the ZINC database using molecular docking with AutoDock VINA. Nine (9) successive hits were then subjected for pharmacokinetic and toxicity properties by PROTOX (a webserver for the prediction of oral toxicities of small molecules) and FAFDrugs (a tool for prediction of ADME and Toxicity). This exercise further identified hit #1 ({[3a-(Dihydroxymethyl)-6-hydroxy-2,2-dimethyl-1,3,4-trioxatetrahydro-2H-pentalen-5- yl]methyl}amino(9H-fluoren-9-yl)acetate with binding affinity: -10.3 kcal/mol) and hit #2 (6-(Dihydroxymethyl)-2-{2-[3- (methylamino)propyl]-2-azatricyclo[9.4.0.03,8]pentadeca-1(11),3,5,7,12,14-hexaen-6-yloxy}tetrahydro-2H-pyran-3,4,5-triol with binding affinity: -9.6 kcal/mol) with acceptable toxicity and ADME properties for potential predicted hemolysin inhibition. These compounds should then be evaluated in vitro using inhibitory studies.


Non-pharmacological treatment of psychiatric disorders in individuals with 22q11.2 deletion syndrome; a systematic review.
22q11.2 deletion syndrome (22q11.2DS) is associated with high rates of anxiety disorders, psychotic disorders, and other psychiatric conditions. In the general population, psychiatric disorders are treated with proven pharmacological and non-pharmacological therapies, such as cognitive behavioral therapy (CBT). To begin to assess the feasibility and efficacy of non-pharmacological therapies in 22q11.2DS, we performed a systematic search to identify literature on non-pharmacological interventions for psychiatric disorders in individuals with 22q11.2DS. Of 1,240 individual publications up to mid-2016 initially identified, 11 met inclusion criteria. There were five literature reviews, five publications reporting original research (two originating from a single study), and one publication not fitting either category that suggested adaptations to an intervention without providing scientific evidence. None of the original research involved direct study of the evidence-based non-pharmacological therapies available for psychiatric disorders. Rather, these four studies involved computer-based or group interventions aimed at improving neuropsychological deficits that may be associated with psychiatric disorders. Although the sample sizes were relatively small (maximum 28 participants in the intervention group), these reports documented the promising feasibility of these interventions, and improvements in domains of neuropsychological functioning, including working memory, attention, and social cognition. The results of this review underline the need for research into the feasibility and efficacy of non-pharmacological treatments of psychiatric disorders in individuals with 22q11.2DS to inform clinical care, using larger samples, and optimally, standard randomized, placebo-controlled, clinical trials methodology.


Neuronal mechanisms underlying attention deficit hyperactivity disorder: the influence of arousal on prefrontal cortical function.
Neuropsychological and imaging studies indicate that attention deficit hyperactivity disorder (ADHD) is associated with alterations in prefrontal cortex (PFC) and its connections to striatum and cerebellum. Research in animals, in combination with observations of patients with cortical lesions, has shown that the PFC is critical for the regulation of behavior, attention, and affect using representational knowledge. The PFC is important for sustaining attention over a delay, inhibiting distraction, and dividing attention, while more posterior cortical areas are essential for perception and the allocation of attentional resources. The PFC in the right hemisphere is especially important for behavioral inhibition. Lesions to the PFC produce a profile of distractibility, forgetfulness, impulsivity, poor planning, and locomotor hyperactivity. The PFC is very sensitive to its neurochemical environment, and either too little (drowsiness) or too much (stress) catecholamine release in PFC weakens cognitive control of behavior and attention. Recent electrophysiological studies in animals suggest that norepinephrine enhances "signals" through postsynaptic alpha2A adrenoceptors in PFC, while dopamine decreases "noise" through modest levels of D1 receptor stimulation. alpha2A-Adrenoceptor stimulation strengthens the functional connectivity of PFC networks, while blockade of alpha2 receptors in the monkey PFC recreates the symptoms of ADHD, resulting in impaired working memory, increased impulsivity, and locomotor hyperactivity. Genetic alterations in catecholamine pathways may contribute to dysregulation of PFC circuits in this disorder. Medications may have many of their therapeutic effects by optimizing stimulation of alpha2A adrenoceptors and D1 receptors in the PFC, thus strengthening PFC regulation of behavior and attention.


Carcinogenesis--a synopsis of human experience with external exposure in medicine.
Studies in the 1980s of medically irradiated populations have increased our knowledge of radiation carcinogenesis. (1) Investigations of prenatal x-ray exposures, especially in twins, provide evidence that very low doses of ionizing radiation may cause cancer in humans. (2) Fractionated doses appear as effective as single exposures of the same total dose in causing breast cancer, but seem less effective for lung cancer. (3) Excess breast cancers can occur among women exposed under age 10, indicating that the immature breast is susceptible to the carcinogenic action of radiation. (4) Moderate doses on the order of 1 Gy to the brains of children can cause tumors later in life; moderately high doses to the skin can cause cancer when followed by frequent exposure to ultraviolet light. (5) Radiotherapy for cervical cancer can increase the rate of subsequent leukemia with the best fitting dose-response functions including a negative exponential term to account for cell-killing. (6) Low-dose exposures of about 10 cGy may increase the risk of thyroid cancer. (7) Second cancers following radiotherapy for a variety of cancers occur primarily among long-term survivors. (8) Radiotherapy may not significantly increase the risk of leukemia following childhood cancer, whereas chemotherapy with alkylating agents is a major risk factor. (9) Bone cancer occurs after high-dose radiotherapy for childhood cancer, but children with retinoblastoma are not more susceptible to radiation-induced disease than children with other malignancies. (10) High-dose external beam therapy can cause thyroid cancer, whereas high-dose radioactive 131I may not. (11) Studies of cervical cancer patients indicate that the risk of radiation-induced second malignancies follows a time-response model consistent with a constant multiplication of the underlying background incidence, i.e. a relative risk model seems to hold for projecting risks forward in time.


Knowledge and attitudes of adult peruvian women vis-à-vis Human Papillomavirus (HPV), cervical cancer, and the HPV vaccine.
To determine knowledge and attitudes of adult Peruvian women regarding the human papillomavirus (HPV), cervical cancer, and acceptability of the HPV vaccine. A 4-section survey was administered to 511 25- to 65-year-old Peruvian women living in 3 low-income districts in Lima. Knowledge of HPV, the HPV vaccine, cervical cancer, and the association between HPV and cervical cancer was low. Approximately two-thirds of the participants knew nothing about HPV, the vaccine, and cervical cancer. However, vaccine acceptability was very high: 90% indicated they would get vaccinated if the HPV vaccine was available. In addition, 58% of the population was willing to pay "something," versus nothing, to be vaccinated. Although their knowledge was limited, mid adult Peruvian women have a very high level of acceptance for the HPV vaccine. Efforts to educate the population about HPV and cervical cancer are warranted along with further studies exploring the reasons for high vaccination acceptability to help reduce the rate of cervical cancer.


Implications of Antiphospholipid and Antineutrophilic Cytoplasmic Antibodies in the Context of Postinfectious Glomerulonephritis.
While antineutrophil cytoplasmic antibody (ANCA) positivity has been documented in some patients with postinfectious glomerulonephritis (PIGN) and is associated with more severe disease, antiphospholipid antibodies (APA) are not known to be a common occurrence. We describe a child with severe acute kidney injury who was noted to have prolonged positivity of both ANCA and APA; a renal biopsy showed noncrescentic immune complex mediated glomerulonephritis with subepithelial deposits compatible with PIGN. He recovered without maintenance immunosuppressive therapy and at last follow-up had normal renal function. We discuss the cooccurrence and implications of ANCA and APA in children with PIGN.


Characterization of Biosurfactant Produced during Degradation of Hydrocarbons Using Crude Oil As Sole Source of Carbon.
Production and spillage of petroleum hydrocarbons which is the most versatile energy resource causes disastrous environmental pollution. Elevated oil degrading performance from microorganisms is demanded for successful microbial remediation of those toxic pollutants. The employment of biosurfactant-producing and hydrocarbon-utilizing microbes enhances the effectiveness of bioremediation as biosurfactant plays a key role by making hydrocarbons bio-available for degradation. The present study aimed the isolation of a potent biosurfactant producing indigenous bacteria which can be employed for crude oil remediation, along with the characterization of the biosurfactant produced during crude oil biodegradation. A potent bacterial strain Pseudomonas aeruginosa PG1 (identified by 16s rDNA sequencing) was isolated from hydrocarbon contaminated soil that could efficiently produce biosurfactant by utilizing crude oil components as the carbon source, thereby leading to the enhanced degradation of the petroleum hydrocarbons. Strain PG1 could degrade 81.8% of total petroleum hydrocarbons (TPH) after 5 weeks of culture when grown in mineral salt media (MSM) supplemented with 2% (v/v) crude oil as the sole carbon source. GCMS analysis of the treated crude oil samples revealed that P. aeruginosa PG1 could potentially degrade various hydrocarbon contents including various PAHs present in the crude oil. Biosurfactant produced by strain PG1 in the course of crude oil degradation, promotes the reduction of surface tension (ST) of the culture medium from 51.8 to 29.6 mN m-1, with the critical micelle concentration (CMC) of 56 mg L-1. FTIR, LC-MS, and SEM-EDS studies revealed that the biosurfactant is a rhamnolipid comprising of both mono and di rhamnolipid congeners. The biosurfactant did not exhibit any cytotoxic effect to mouse L292 fibroblastic cell line, however, strong antibiotic activity against some pathogenic bacteria and fungus was observed.


[Mechano-geometric generative rules of morphogenesis].
The ideographical approach aimed at detecting specific causative relationships within the process of development prevails in modern embryology. The present work considers the possibilities of using the nomothetic approach aimed at putting forward nonspecific general laws based on the general scientific theory of self-organization and can be formulated in morphomechanical terms based on feedback links between passive and active mechanical stress. The perspectives of this approach and the involvement of genetic factors in the regulation of feedback links are discussed.


Physical and mental health shortly after a disaster: first results from the Enschede firework disaster study.
Two to three weeks after the explosion of a fireworks storage facility in a residential area (May 2000, Enschede, The Netherlands) we assessed the self-reported physical and mental health among those affected by the disaster. A questionnaire survey was conducted among 3792 residents, passers-by, and rescue workers, who were involved in and/or affected by the disaster and were > or =18 years of age. At least 30% of those affected by the disaster reported serious physical and mental health problems 2-3 weeks after the explosion. Compared with reference values in the general Dutch population, high scores were found for somatic symptoms, sleeping problems, and restrictions in daily functioning due to physical and mental problems, such as anxiety, depression, and feelings of insufficiency. The strength of these differences varied between groups, based on the level of involvement and the level of being affected. Results indicate that the fireworks disaster had a substantial impact on the health of those affected by the disaster. The health impact was most pronounced for residents and passers-by and also for rescue workers living in the affected area, but to a lesser degree. Physical and mental health problems were strongly associated with the shocking experiences during and shortly after the disaster.


Determination of E/N Influence on K0 Values within the Low Field Region of Ion Mobility Spectrometry.
The established theory of ion motion within weak electric fields predicts that reduced ion mobility (K0) remains constant as a function of the ratio of electric field strength to drift gas number density (E/N). However, upon increasing the accuracy and precision of K0 value measurements during a previous study, a new relationship was seen in which the K0 values of ions decreased as a function of increasing E/N at field strengths below 4 Td. Here the effect of E/N on the K0 value of an ion has been investigated in order to validate the reality of the phenomenon and determine its cause. The pertinent measurements of voltage and drift time were verified in order to ensure the authenticity of the trend and that it was not a result of a systematic error in parametric measurements. The trend was also replicated on a separate ion mobility spectrometer drift tube in order to further validate its authenticity. As a result, the theory of ion motion within weak electric fields should be revised to reflect the behavior seen here.


Collagen production at the edge of ruptured rotator cuff tendon is correlated with postoperative cuff integrity.
The purpose was to evaluate the correlation between messenger RNA (mRNA) expression of collagen at the edge of the ruptured rotator cuff tendon and postoperative cuff integrity. The edge of the ruptured tendon was sampled during open rotator cuff surgery in 12 patients with full-thickness rotator cuff tears (mean age, 58.2 years). The mean period from symptom onset was 9.3 months (range, 1 to 36 months), and the mean tear size was 4.1 cm. As controls, rotator cuff tendons with no gross rupture were taken from 5 fresh cadavers. Production of type I and type III collagen was examined by real-time reverse transcription polymerase chain reaction. By use of magnetic resonance imaging, postoperative cuff integrity was evaluated based on the classification of Sugaya et al. and then scored, ranging from 5 points for type I to 1 point for type V. Looking at the mRNA of type I and type III collagen in tendons, we found that the expression of mRNA for both collagen types in ruptured tendons was significantly greater than in control tendons (P = .0462 for type I collagen and P = .0306 for type III collagen). Correlating the mRNA of type I and type III collagen with repaired cuff integrity on postoperative magnetic resonance imaging, we found a close relation between expression of mRNA for both collagen types and postoperative rotator cuff integrity (r = 0.63 [P = .038] for type I collagen and r = 0.626 [P = .03] for type III collagen). Furthermore, expression of type I collagen mRNA showed a significant inverse correlation with the period from symptom onset (r = -0.845, P < .0005). This study showed that expression of mRNA for type I and type III collagen at the edge of the ruptured rotator cuff tendon was significantly correlated with postoperative cuff integrity and that mRNA expression for type I collagen was significantly associated with the period from symptom onset. These results may suggest that conservative treatment should not be prolonged if patients do not respond within a certain period. Level III, prognostic case-control study.


Implications for managed care and specialty pharmacy in rheumatoid arthritis.
Treatment of rheumatoid arthritis (RA) can be very costly. Cost-effectiveness studies provide insight into the value of treatment from a number of perspectives (eg, societal, healthcare). In most cases, the indirect costs of RA can offset the direct costs in 2 ways. Prevention of disease progression can limit future costs, such as those related to surgery and hospitalization. When disease progression is minimized, patients feel better and can have improved work productivity. Disease control of RA has improved over time, and this is attributed primarily to the introduction of more effective therapies. Despite the effectiveness of new therapies, there are a number of barriers to optimal treatment. Barriers include lack of education for patients and practitioners about RA, poor patient-provider communication, uncertainty regarding which treatments to choose, cost, and lack of adherence. Specialty pharmacy and disease therapy management programs can assist patients by providing structure, education, and mechanisms to improve treatment adherence and persistence to optimize therapy.


Real-time x-ray diffraction measurements of shocked polycrystalline tin and aluminum.
A new, fast, single-pulse x-ray diffraction (XRD) diagnostic for determining phase transitions in shocked polycrystalline materials has been developed. The diagnostic consists of a 37-stage Marx bank high-voltage pulse generator coupled to a needle-and-washer electron beam diode via coaxial cable, producing line and bremsstrahlung x-ray emission in a 35 ns pulse. The characteristic K(alpha) lines from the selected anodes of silver and molybdenum are used to produce the diffraction patterns, with thin foil filters employed to remove the characteristic K(beta) line emission. The x-ray beam passes through a pinhole collimator and is incident on the sample with an approximately 3 x 6 mm(2) spot and 1 degrees full width half maximum angular divergence in a Bragg-reflecting geometry. For the experiments described in this report, the angle between the incident beam and the sample surface was 8.5 degrees . A Debye-Scherrer diffraction image was produced on a phosphor located 76 mm from the polycrystalline sample surface. The phosphor image was coupled to a charge-coupled device camera through a coherent fiber-optic bundle. Dynamic single-pulse XRD experiments were conducted with thin foil samples of tin, shock loaded with a 1 mm vitreous carbon back window. Detasheet high explosive with a 2-mm-thick aluminum buffer was used to shock the sample. Analysis of the dynamic shock-loaded tin XRD images revealed a phase transformation of the tin beta phase into an amorphous or liquid state. Identical experiments with shock-loaded aluminum indicated compression of the face-centered-cubic aluminum lattice with no phase transformation.


Negative capacitance in a ferroelectric capacitor.
The Boltzmann distribution of electrons poses a fundamental barrier to lowering energy dissipation in conventional electronics, often termed as Boltzmann Tyranny. Negative capacitance in ferroelectric materials, which stems from the stored energy of a phase transition, could provide a solution, but a direct measurement of negative capacitance has so far been elusive. Here, we report the observation of negative capacitance in a thin, epitaxial ferroelectric film. When a voltage pulse is applied, the voltage across the ferroelectric capacitor is found to be decreasing with time--in exactly the opposite direction to which voltage for a regular capacitor should change. Analysis of this 'inductance'-like behaviour from a capacitor presents an unprecedented insight into the intrinsic energy profile of the ferroelectric material and could pave the way for completely new applications.


Ultrastructural phenotype of "intestinal-type" cells in columnar-lined esophagus.
An intestinal-type epithelium is often present at columnar-lined esophagus, gastroesophageal junction or within the so-called short segment Barrett's esophagus, but ultrastructural study failed to detect enterocytes in columnar-lined esophagus. The authors have analyzed the intestinal aspects present in areas of columnar-lined esophagus in a population of patients with reflux esophagitis to better understand the morphology and histogenesis of the proliferating elements. Columnar-lined mucosa was studied in 35 patients. Columnarsurface cells displayed a wide spectrum of ultrastructural features. Well-differentiated columnar secretory cells, secretory-absorptive cells, poorly differentiated columnar cells, atypical columnar cells, and goblet cells were detected. Well-differentiated absorptive cells were never found, These results demonstrate that the areas of intestinal metaplasia show a wide spectrum of ultrastructural phenotypes, ranging from poorly to well-differentiated cells. However, true enterocytes were not found and the most represented phenotype is that of secretory-absorptive cells, whose principal characteristic is the presence of secretory and absorptive aspects together. They can be described as secretory enterocytes or cells with double specialization. To the authors' knowledge, similar cells were not previously described in normal intestinal mucosa, and ultrastructural studies are consistent in describing a broad spectrum of ultrastructural features, suggesting that Barrett's specialized metaplasia is derived from cells with the capacity for a wide range of differentiation. Therefore, despite the wide use of term intestinal metaplasia in the medical literature, experimental data clearly failed to detect enterocytes in the columnar-lined esophagus, and ultrastructural data do not support the concept of intestinal metaplasia. The cellular heterogeneity seems to be the result of a "phenotypic shift" of undifferentiated elements, which show a different pattern of evolution. The result of this process is the formation of new cell types dissimilar from those normally present in esophageal, gastric, or duodenal mucosa.


Antihypertensive activity of erythro-1-(1-[2-(1,4-benzodioxan-2-yl)-2-OH-ET]-4-piperidyl)-2-benzimidazolinone (R 28935).
Erythro-1-(1-[2-(1,4-benzodioxan-2-yl)-2-OH-ET]-4-piperidyl)-2-benzimidazolinone (R 28935), provokes marked antihypertensive effects lasting several hours in conscious SHR (0.63 to 40 mg/kg i.p.) and beagles with renal hypertension (1.25 mg/kg p.o.). In SHR, this compound induces much less bradycardia, compared to equiactive hypotensive doses of clonidine, guanethidine and propranolol. Significant postural hypotension during tilting, is induced by guanethidine and mecamylamine but not by R 28935. In anaesthetized beagles with renal hypertension, the lowering of the blood pressure by R 28935, (0.02-0.64 mg/kg i.v.) is associated with a considerable decrease in the total peripheral vascular resistance, whereas the myocardial function is not affected. R 28935 is considered a potent antihypertensive drug, with attractive haemodynamic characteristics.


Optical linear response function with linear and diagonal quadratic electron-vibration coupling in mixed quantum-classical systems.
Optical linear response function of linearly and quadratically coupled mixed quantum-classical condensed phase systems is derived. The linear response function is derived using Kapral's formalism of statistical mechanics in mixed quantum-classical systems. Our mixed quantum-classical linear dipole moment correlation function J(t) is compared with the full quantum J(t) [Y. J. Yan and S. Mukamel, J. Chem. Phys. 85, 5908 (1986)] in the high temperature limit. Model calculations and discussion of our results are presented. Various formulas of Franck-Condon factors for both linear and quadratic coupling are discussed.


The structure of experimental in vitro lesions around glass ionomer cement restorations in human teeth.
Class V cavities were prepared at the amelo-cementum junction in sixty-eight extracted human teeth. Fifty-one were filled with glass ionomer cement (ASPA). 'Secondary carious' lesions were produced around thirty-five of the restorations by exposure to acidified gelatin. Thirty-three teeth served as controls of the effect of the preparation procedure, the conditioner, the ASPA liquid and the filling material proper on the cavity walls. Sixty 120 micrometers-thick longitudinal sections from the teeth with the restorations in situ were studied by polarized light microscopy and microradiography. The glass ionomer cement caused by itself a narrow zone of increased radiopacity in the dentine cavity wall. The 'secondary caries' pattern consisted of a subsurface outer lesion and a subsurface wall lesion as observed previously in corresponding experiments with silicate fillings. Outer lesions in enamel were more frequent than with silicate cement. In the cementum all the experimental teeth showed outer lesions. The wall lesions extended only slightly beyond the level of erosion of the restorations. Between the wall lesions (in dentine) or outer lesions (in cementum/dentine) and the surface of the cavity wall, a zone of increased radiopacity was found, assumed to be due to reprecipitation of Ca and P promoted by release of fluoride from the filling material.


Hierarchical Address Event Routing for Reconfigurable Large-Scale Neuromorphic Systems.
We present a hierarchical address-event routing (HiAER) architecture for scalable communication of neural and synaptic spike events between neuromorphic processors, implemented with five Xilinx Spartan-6 field-programmable gate arrays and four custom analog neuromophic integrated circuits serving 262k neurons and 262M synapses. The architecture extends the single-bus address-event representation protocol to a hierarchy of multiple nested buses, routing events across increasing scales of spatial distance. The HiAER protocol provides individually programmable axonal delay in addition to strength for each synapse, lending itself toward biologically plausible neural network architectures, and scales across a range of hierarchies suitable for multichip and multiboard systems in reconfigurable large-scale neuromorphic systems. We show approximately linear scaling of net global synaptic event throughput with number of routing nodes in the network, at 3.6×107 synaptic events per second per 16k-neuron node in the hierarchy.


Quantitative analysis of endometrial stromal cells including behavioral changes related to the menstrual cycle in smear specimens.
We aimed to obtain quantitative data regarding certain characteristics of stromal cells in smear specimens of normal endometrium, including the cytological changes associated with progression through the menstrual cycle. Eleven histological and 25 cytological specimens of normal endometrium were examined immunochemically using monoclonal antibodies to vimentin and keratin by streptavidin-biotin method. As a result, we decided to use the antibody to vimentin for the differential staining of endometrial smears: cells showing positive staining to vimentin were considered stromal cells. The quantitative nuclear measurements in the smear specimens revealed that the nuclei of endometrial stromal cells were more elongated and had a more dispersed distribution than the glandular cells in the proliferative phase. Although a part of the nuclei of stromal cells became rounder in shape in the secretory phase, they were larger in size than those of glandular cells.


The influence on the dermal cellular infiltrate of topical steroid applications and vehicles in guinea pig skin: normal skin, allergic and toxic reactions.
The mechanisms of the anti-inflammatory effects of corticosteroids are uncertain but could be explained by an influence on infiltrating leukocytes. Our method for the qualitative and quantitative investigation of the dermal cellular infiltrate makes it possible to study the effects of topically applied corticosteroid preparations and vehicles on the infiltrating leukocytes of normal skin, allergic and toxic reactions in guinea pig skin. Ointment and cream vehicles as well as corticosteroid cream and ointment preparations often caused erythema and increased mononuclear infiltrate after only short periods of application (24-72 h). The strongest steroid ointment gave the most marked macroscopic response and propylene glycol preparations the most marked cellular response. In both toxic and allergic reactions, application of steroid preparations after the provocation gave no beneficial result either macroscopically or microscopically. Macroscopic scores were worsened by cream and ointment preparations. Although steroid solutions had no beneficial effect, they caused no detrimental effect. The guinea pig seems to be extremely sensitive to irritants and has not proved to be a suitable model for this approach to the study of the efficacy of topically applied steroids.


Association and clinical implication of the USP10 and MSH2 proteins in non-small cell lung cancer.
Ubiquitin-specific protease 10 (USP10) is involved in a number of biological processes by stabilizing several proteins, which have been implicated in multiple stages of tumorigenesis and progression. Previous studies have indicated that USP10 stabilizes and deubiquitinates MutS homolog 2 (MSH2) in in vitro and in vivo models. The level of MSH2 protein has been positively correlated with that of the USP10 protein in a panel of lung cancer cell lines. Furthermore, depletion of USP10 in lung cancer cells causes decreased apoptosis and increased cell survival upon treatment with DNA-damaging agents. However, the expression and clinical implication of USP10 protein in lung cancer tissues is not clear. Additionally, whether the level of MSH2 protein is positively correlated with that of the USP10 protein in lung cancer tissues also remains unresolved. Therefore, USP10 protein expression was detected in 148 human non-small cell lung cancer (NSCLC) and 139 non-cancerous lung tissues using immunohistochemistry, whereas mRNA was investigated by Gene Expression Omnibus dataset and The Cancer Genome Atlas database analyses. It was identified that USP10 protein expression was significantly downregulated in NSCLC tissues compared with in normal lung tissues (P<0.05). However, no significant difference in USP10 mRNA expression between the two tissues was identified. In addition, a positive correlation was observed between the USP10 and MSH2 proteins in NSCLC tissues (P<0.05). However, the clinicopathological features and survival analysis indicated that the USP10 and MSH2 proteins were not associated with clinical features, including age, sex, tumor size, Tumor-Node-Metastasis stage and tumor cell differentiation, along with the prognosis of NSCLC. Collectively, these results suggest that downregulation of USP10 protein serves an important function in the tumorigenesis of NSCLC, and the level of USP10 protein is positively correlated with that of MSH2 protein in NSCLC tissues, which may indicate that USP10 also stabilizes the MSH2 protein in patients with lung cancer.


Are tick-borne encephalitis vaccines interchangeable?
Two tick-borne encephalitis vaccines produced by two vaccine manufacturers are available in most European countries. A question that is frequently asked regarding these two vaccines concerns their exchangeability, however, to date, no detailed assessment has been published. This review analyzes clinical studies investigating these two vaccines and describes possible approaches to boost or continue uncompleted primary immunization schedules, with either of the two tick-borne encephalitis vaccines.


[Nociceptors and mediators in acute inflammatory pain].
To bring together the most recent data concerning the physiology of nociceptors at a time when there has been significant progress in the understanding of these. References were obtained from computerised bibliographic data banks (Medline and others) and the authors' personal documents. Nociceptive impulses are generated at the periphery in unmyelinated fibres called nociceptors, the responses of which depend on the tissue environment. Numerous mediators can activate, sensitise or "wake up" nociceptor: kinins (bradykinin, kallidin and their metabolites), pro-inflammatory cytokines (TNF alpha, IL-6, IL-1 beta, IL-8), anti-inflammatory cytokines (IL-4, IL-6, IL-10, IL-12, IL-13), prostanoids (PGE2, PGI2), lipo-oxygenases (leucotrienes such LTB4 or 15-HETE), the "central mediators of the immune response" (NF-kappa B), growth factors such as neurotrophins (NGF, BDNF, NT-3 and NT-4/5), peptides (substance P, CGRP, Neurokinin A), nitric oxide, histamine, serotonin, proteases, excitatory amino acids, adrenergic amines and opioids. The release of neuromediators by primary afferent fibres in the spinal cord may be summarised by successively considering calcium channels, presynaptic receptors, excitatory amino acids and peptides. Sensitisation phenomena are not exclusively peripheral but also central in origin and these are interlinked.


A High Throughput Assay for Discovery of Small Molecules that Bind AMP-activated Protein Kinase (AMPK).
AMPK is a conserved heterotrimeric serine-threonine kinase that regulates anabolic and catabolic pathways in eukaryotes. Its central role in cellular and whole body metabolism makes AMPK a commonly proposed therapeutic target for illnesses characterized by abnormal energy regulation, including cancer and diabetes. Many AMPK modulators, however, produce AMPK-independent effects. To identify drugs that modulate AMPK activity independent of the canonical ATP-binding pocket found throughout the kinome, we designed a robust fluorescence-based high throughput screening assay biased toward the identification of molecules that bind the regulatory region of AMPK through displacement of MANT-ADP, a fluorescent ADP analog. Automated pin tools were used to rapidly transfer small molecules to a low volume assay mixture on 384-well plates. Prior to assay validation, we completed a full assay optimization to maximize the signal-to-background and reduce variability for robust detection of small molecules displacing MANT-ADP. After validation, we screened 13,120 molecules and identified 3 positive hits that dose-dependently inhibited the protein-bound signal of MANT-ADP in the presence of both full-length AMPK and the truncated "regulatory fragment" of AMPK, which is missing the kinase active site. The average Z'-factor for the screen was 0.55 and the compound confirmation rate was 60%. Thus, this fluorescence-based assay may be paired with in vitro kinase assays and cell-based assays to help identify molecules that selectively regulate AMPK with fewer off-target effects on other kinases.


Oregano: a source for peroxisome proliferator-activated receptor gamma antagonists.
Peroxisome proliferator-activated receptors (PPARs) are drug targets for several perturbations of metabolic syndrome, defined as the coexistence of obesity, hyperglycemia, hypertension, and hyper/dyslipidemia. In this study, PPAR activation by oregano (e.g., Origanum vulgare) and its components was tested. Oregano extracts bind but do not transactivate PPARgamma, and binding affinity differs among different oregano extracts. The extracts contain PPARgamma antagonists (e.g., quercetin, luteolin, rosmarinic acid, and diosmetin), selective PPARgamma modulators (e.g., naringenin and apigenin), and PPARgamma agonists (e.g., biochanin A). Oregano extract and isolated compounds in the extract antagonize rosiglitazone-mediated DRIP205/TRAP220 recruitment to PPARgamma, pointing to oregano extracts as putative food supplements for weight reduction. Rosmarinic acid and biochanin A, PPARalpha agonists, may ameliorate the lipid profile. By endothelial nitric oxide synthase activation, oregano extract could prevent atherosclerosis. The results warrant further investigation of oregano extract for its potential to prevent and ameliorate metabolic syndrome and its complications.


The In Vivo and In Vitro Architecture of the Hepatitis C Virus RNA Genome Uncovers Functional RNA Secondary and Tertiary Structures.
Hepatitis C virus (HCV) is a positive-strand RNA virus that remains one of the main contributors to chronic liver disease worldwide. Studies over the last 30 years have demonstrated that HCV contains a highly structured RNA genome and many of these structures play essential roles in the HCV life cycle. Despite the importance of riboregulation in this virus, most of the HCV RNA genome remains functionally unstudied. Here, we report a complete secondary structure map of the HCV RNA genome in vivo, which was studied in parallel with the secondary structure of the same RNA obtained in vitro. Our results show that HCV is folded extensively in the cellular context. By performing comprehensive structural analyses on both in vivo data and in vitro data, we identify compact and conserved secondary and tertiary structures throughout the genome. Genetic and evolutionary functional analyses demonstrate that many of these elements play important roles in the virus life cycle. In addition to providing a comprehensive map of RNA structures and riboregulatory elements in HCV, this work provides a resource for future studies aimed at identifying therapeutic targets and conducting further mechanistic studies on this important human pathogen. IMPORTANCE HCV has one of the most highly structured RNA genomes studied to date, and it is a valuable model system for studying the role of RNA structure in protein-coding genes. While previous studies have identified individual cases of regulatory RNA structures within the HCV genome, the full-length structure of the HCV genome has not been determined in vivo. Here, we present the complete secondary structure map of HCV determined both in cells and from corresponding transcripts generated in vitro. In addition to providing a comprehensive atlas of functional secondary structural elements throughout the genomic RNA, we identified a novel set of tertiary interactions and demonstrated their functional importance. In terms of broader implications, the pipeline developed in this study can be applied to other long RNAs, such as long noncoding RNAs. In addition, the RNA structural motifs characterized in this study broaden the repertoire of known riboregulatory elements.


Tracer diffusion in a dislocated lamellar system.
Many lamellar systems exhibit strongly anisotropic diffusion. When the diffusion across the lamellae is slow, an alternative mechanism for transverse transport becomes important. A tracer particle can propagate across the lamellae by encircling a screw dislocation. We calculate the statistical properties of this mode of transverse transport. When either positive or negative dislocations are in excess, transport across the lamellae is ballistic. When the average dislocation charge is zero, the mean square of the normal displacement grows like TlogT for large times. To obtain this result, the trajectory of the tracer must be smoothed over distances of order of the dislocation core size.


Experience with the Implementation of Continuous Medical Education among Mother-and-Child Healthcare Providers in Ukraine: A Case Study Based on Two International Collaboration Initiatives.
Healthcare labor market shortages due to migration, inadequate investments, and lack of continuous training are essential concerns in the Eastern European region. This article aims to describe and reflect on the experience with the implementation of continuous medical education among mother-and-child healthcare providers in Ukraine, including achievements, challenges, and barriers. We analyze this case based on two international collaboration initiatives: the Swiss-Ukrainian program in mother-and-child health that ran from 2000 to 2015, supplemented by the recent Ukrainian-Swiss project "Medical education development" in 2018-2023. We use a case study approach as the methodology for our study. We collected data from documents (project reports reviews) and in-depth interviews with stakeholders. We apply the method of directed qualitative content analysis. As a result of the Swiss-Ukrainian collaborations, the knowledge and awareness of medical personnel were greatly improved. Modern clinical concepts not well understood at the outset became commonplace and were incorporated into clinical activities. Nevertheless, obstacles to the implementation and rapid uptake of changes were found in the lack of knowledge of the English language among medical doctors, the fear of changes, and the lack of openness and readiness for novel evidence-based clinical practices. However, primary healthcare practitioners in this new project seem to be more inclined to change. A modernized continuous medical education which is based on the values of openness, respect, dialogue, and professionalism can be implemented with the input of an international assistance program despite the resistance of the system towards change.


PINK1-linked parkinsonism is associated with Lewy body pathology.
Phosphatase and tensin homolog-induced putative kinase 1 gene mutations have been associated with autosomal recessive early-onset Parkinson's disease. To date, no neuropathological reports have been published from patients with Parkinson's disease with both phosphatase and tensin homolog-induced putative kinase 1 gene copies mutated. We analysed the coding region of phosphatase and tensin homolog-induced putative kinase 1 gene in a large Spanish family with six members with parkinsonism. The phenotype was characterized by an early-onset (mean: 31.6, standard deviation: 9.6 years, range: 14-45 years), slowly progressive levodopa-responsive parkinsonism, initial gait impairment and psychiatric symptoms. We identified two segregating pathogenic phosphatase and tensin homolog-induced putative kinase 1 mutations that were either in homozygous or heterozygous compound state in all affected family members. We found an exon 7 deletion (g.16089_16383del293; c.1252_1488del) and a novel+1U1-dependent 5' splice-site mutation in exon 7 (g.16378G>A; c.1488+1G>A). Leukocyte-derived messenger RNA analysis showed that both mutations caused exon 7 skipping and c.1488+1G>A also lead to an in-frame transcript with a 33 base-pair deletion (p.L485_R497del) resulting from activation of a 5' cryptic exon 7 splice site. Single photon emission computed tomography quantification of striatal dopamine transporter binding (123I-Ioflupane) revealed a posterior-anterior gradient similar to that of idiopathic Parkinson's disease, but there was no correlation between striatal reduced uptake and disease duration. Post-mortem neuropathological examination of an early-onset Parkinson's disease carrier of two heterozygous compound phosphatase and tensin homolog-induced putative kinase 1 mutations showed neuronal loss in the substantia nigra pars compacta, Lewy bodies and aberrant neurites in the reticular nuclei of the brainstem, substantia nigra pars compacta and Meynert nucleus, but the locus ceruleus and the amygdala were spared. This is the first neuropathological report of the brain from an early-onset phosphatase and tensin homolog-induced putative kinase 1-linked parkinsonism showing that mutated phosphatase and tensin homolog-induced putative kinase 1 protein induces Lewy body pathology. Unbalanced preservation of the locus ceruleus may well play a role in the slow evolution of motor symptoms and, probably, in the psychiatric symptoms often encountered in Parkinson's disease associated with phosphatase and tensin homolog-induced putative kinase 1 mutation.


Fast focus estimation using frequency analysis in digital holography.
A novel fast frequency-based method to estimate the focus distance of digital hologram for a single object is proposed. The focus distance is computed by analyzing the distribution of intersections of smoothed-rays. The smoothed-rays are determined by the directions of energy flow which are computed from local spatial frequency spectrum based on the windowed Fourier transform. So our method uses only the intrinsic frequency information of the optical field on the hologram and therefore does not require any sequential numerical reconstructions and focus detection techniques of conventional photography, both of which are the essential parts in previous methods. To show the effectiveness of our method, numerical results and analysis are presented as well.


Differential effect of brefeldin A on the biosynthesis of heparan sulfate and chondroitin/dermatan sulfate proteoglycans in rat ovarian granulosa cells in culture.
The subcellular localization of the enzymes involved in the glycosylation of proteoglycans was studied in rat ovarian granulosa cells by interfering with the normal traffic in the Golgi apparatus using brefeldin A. Cell cultures were metabolically labeled with [35S] sulfate and [3H]glucosamine, and the radiolabeled macromolecules were analyzed by ion-exchange and gel chromatography in combination with chondroitinase or heparitinase treatment. In the absence of brefeldin A, the cells synthesized both dermatan sulfate proteoglycans (DSPGs) and heparan sulfate proteoglycans (HSPGs) which were isolated from the culture medium, the plasma membrane, and intracellular compartments. However, in the presence of brefeldin A, the synthesized proteoglycans were almost exclusively HSPGs and were found only in the intracellular compartment. Analyses of HSPGs synthesized in the presence of brefeldin A indicated that: (i) the HS chains are synthesized on the same core protein as for the normal HSPGs, (ii) the chains are two to three times the normal molecular size; and (iii) a significant proportion of the HS chains are normally sulfated. Brefeldin A induces a disassembly of the proximal part of the Golgi complex, resulting in a redistribution of cis-, medial-, and trans-Golgi resident enzymes back to the endoplasmic reticulum (ER), and blocks the transport of proteins to the trans-Golgi network. Our results indicate that the complete set of enzymes involved in the biosynthesis of HS chains are localized in the ER/proximal part of the Golgi complex, whereas the enzymes involved in the elongation/sulfation of DS chains are exclusively located in the trans-Golgi network. Furthermore, our results indicate that the enzymes involved in the biosynthesis of HS chains are specific to HS core proteins, since no DS core proteins were substituted with HS chains in the presence of brefeldin A.


Anti-microRNA-21/221 and microRNA-199a transfected by ultrasound microbubbles induces the apoptosis of human hepatoma HepG2 cells.
Gene therapy, particularly microRNA (miRNA), is a promising candidate in the treatment of cancer; however, it is challenging to develop gene delivery systems. Ultrasound microbubbles have been used for gene delivery with excellent results. The present study aimed to investigate the transfection efficiency of HepG2 cells using ultrasound microbubbles. The effects of three miRNAs (miR-21, miR-221 and miR-199a) on HepG2 cells were also determined by performing ultrasound microbubble-mediated gene transfection. Three recombinant plasmids containing anti-miR-21, anti-miR-221 and miR-199a were fused with enhanced green fluorescent protein. For the transfection of genes, the type of contrast agent, the concentration of microbubble contrast agent and the exposure intensity of ultrasound were optimized. The expression of miRNAs was detected using reverse transcription-polymerase chain reaction. To determine the effect of anti-miR-21, anti-miR-221 and miR-199a on HepG2 cells, MTT, cell cycle analysis and Annexin V-PE/7-ADD apoptosis assays were performed. The optimal condition was 10% sulfur hexafluoride microbubbles at an ultrasound frequency of 2.0 MHz and mechanical index of 0.28. When cells were transfected with three recombinant plasmids using ultrasound microbubbles, there was significant downregulation of miR-21 and miR-221 and upregulation of miR-199a (P<0.05). All three treatments inhibited cell proliferation and promoted the apoptosis of cells. The present data indicated that the delivery of anti-miR-21, anti-miR-221 and miR-199a may be mediated by ultrasound microbubble contrast agents. With this approach, cell proliferation may be effectively inhibited and cell apoptosis may be induced. These are novel cancer therapy targets.


Understanding the ecological context of mental, emotional, and behavioral health problems: A person-centered approach.
The social/environmental context of youth is important for mental, emotional, and behavioral (MEB) health. This study used person-oriented methods to examine the influences of family, neighborhood, and poverty on late adolescent MEB outcomes. Latent class analysis was used to discern significant clusters of at-risk, diverse young men (N = 625) based on contextual factors; differences in MEB outcomes were examined. Four classes emerged. Resourced and Protected youth had low risk across all indicators. Non-resourced and Protected youth lived in poverty, poor neighborhoods, but had good parenting; despite low delinquency, substance use was elevated. Resourced but High Risk youth had negative parenting but good neighborhoods. Outcomes included elevated delinquency and mental health problems. Non-resourced and High Risk youth were poor, lived in bad neighborhoods, and experienced abusive parenting; MEB outcomes were poor. Findings confirm the unique effects that negative parenting, neighborhoods, and poverty have on adolescent development. Implications are discussed.


Extracellular Vesicles, Stem Cells and the Role of miRNAs in Neurodegeneration.
There are different modalities of intercellular communication governed by cellular homeostasis. In this review, we will explore one of these forms of communication called extracellular vesicles (EVs). These vesicles are released by all cells in the body and are heterogeneous in nature. The primary function of EVs is to share information through their cargo consisting of proteins, lipids and nucleic acids (mRNA, miRNA, dsDNA etc.) with other cells, which have a direct consequence on their microenvironment. We will focus on the role of EVs of mesenchymal stem cells (MSCs) in the nervous system and how these participate in intercellular communication to maintain physiological function and provide neuroprotection. However, deregulation of this same communication system could play a role in several neurodegenerative diseases, such as Alzheimer's disease, Parkinson's disease, Amyotrophic lateral sclerosis, multiple sclerosis, prion disease and Huntington's disease. The release of EVs from a cell provides crucial information to what is happening inside the cell and thus could be used in diagnostics and therapy. We will discuss and explore new avenues for the clinical applications of using engineered MSC-EVs and their potential therapeutic benefit in treating neurodegenerative diseases.