Reduction in serum aquaporin-4 antibody titers during development of a tumor-like brain lesion in a patient with neuromyelitis optica: a serum antibody-consuming effect?
Neuromyelitis optica (NMO) is an inflammatory demyelinating disease of the CNS with severe involvement of the optic nerve and spinal cord. Highly specific serum IgG autoantibodies (NMO-IgG) that react with aquaporin-4 (AQP4), the most abundant CNS water channel protein, are found in patients with NMO. However, in vivo evidence combining the results of AQP4 antibody serum levels and brain pathology is lacking. We report a patient with NMO whose AQP4 antibody levels decreased simultaneously with clinical deterioration caused by the development of a tumor-like brain lesion. In the seminecrotic biopsied brain lesion, there was activated complement complex, whereas only very scattered immunoreactivity to AQP4 protein was detectable. The decrease in serum AQP4 antibody levels and the loss of AQP4 in the tumor-like lesion could represent a "serum antibody-consuming effect" during lesion formation.


Cytoplasmic PAR-3 protein expression is associated with adverse prognostic factors in clear cell renal cell carcinoma and independently impacts survival.
Clear cell renal cell carcinomas (ccRCCs) represent 70% of renal cancers, and several clinical and histolopathological factors are implicated in their prognosis. We recently demonstrated that the overexpression of PAR-3 protein encoded by the PARD3 gene could be implicated in renal oncogenesis. The object of this work was to study the association of intratumoral PAR-3 expression with known prognostic parameters and clinical outcome. In this aim, PAR-3 expression was assessed by immunohistochemistry in ccRCC tumors of 101 patients from 2003 to 2005. The immunostaining of PAR-3 was scored either as membranous (mPAR-3) or as both membranous and cytoplasmic (cPAR-3). Cytoplasmic PAR-3 was significantly associated with worse histopathological and clinical prognostic factors: Fuhrman grades 3 and 4, tumor necrosis, sarcomatoid component, adrenal invasion, renal and hilar fat invasion, eosinophilic component, a noninactivated VHL gene, higher tumor grade, lymph node involvement, metastasis, and worse clinical Eastern Cooperative Oncology Group and S classification scores. After multivariate analysis, 2 parameters were independently associated with cPAR-3: necrosis and eosinophilic components. In addition, cPAR-3 patients had shorter overall and progression-free survivals independently from strong prognostic validated factors like metastases. A cytoplasmic expression of PAR-3 is therefore implicated in worse clinical and pathological cancer features in ccRCC and could be useful to identify patients with high-risk tumors.


Cancer therapy-associated cardiotoxicity and signaling in the myocardium.
The cardiotoxic potential of cytotoxic cancer chemotherapy is well known. Prime examples are the anthracyclines, which are highly efficacious agents for hemopoietic malignancies and solid tumors, but their clinical use is limited primarily by cardiotoxicity. Besides the conventional chemotherapeutics, new cancer drugs were developed in the last decade with the goal to specifically inhibit selected molecular targets such as growth factor receptors or intracellular tyrosine kinases in cancer cells. However, the outcome of combining conventional and newer cancer therapies could have unexpected side effects not anticipated so far and the long-term outcome is not known. Sometimes, however, unexpected side effects also shed light on previously unknown physiological functions. For example, the anti-HER2 cancer therapeutic trastuzumab (Herceptin), which can induce cardiac dysfunction, has demonstrated the importance of the ErbB/neuregulin signaling system in the adult heart. Subsequently, the role of endothelial-myocardial communication in maintaining phenotype and survival of adult cardiomyocytes has increasingly been recognized.


Lyn regulates BCR-ABL and Gab2 tyrosine phosphorylation and c-Cbl protein stability in imatinib-resistant chronic myelogenous leukemia cells.
Lyn kinase functions as a regulator of imatinib sensitivity in chronic myelogenous leukemia (CML) cells through an unknown mechanism. In patients who fail imatinib therapy but have no detectable BCR-ABL kinase mutation, we detected persistently activated Lyn kinase. In imatinib-resistant CML cells and patients, Lyn activation is BCR-ABL independent, it is complexed with the Gab2 and c-Cbl adapter/scaffold proteins, and it mediates persistent Gab2 and BCR-ABL tyrosine phosphorylation in the presence or absence of imatinib. Lyn silencing or inhibition is necessary to suppress Gab2 and BCR-ABL phosphorylation and to recover imatinib activity. Lyn also negatively regulates c-Cbl stability, whereas c-Cbl tyrosine phosphorylation is mediated by BCR-ABL. These results suggest that Lyn exists as a component of the BCR-ABL signaling complex and, in cells with high Lyn expression or activation, BCR-ABL kinase inhibition alone (imatinib) is not sufficient to fully disengage BCR-ABL-mediated signaling and suggests that BCR-ABL and Lyn kinase inhibition are needed to prevent or treat this form of imatinib resistance.


Use of chloramphenicol in a hospice.
Chloramphenicol has been the antibiotic of first choice at St Christopher's Hospice for over 20 years. Its use has been justified on the grounds of efficacy and tolerability in a patient group with a short prognosis in whom good symptom control is the priority. The sensitivities of hospice bacterial cultures to chloramphenicol and other antibiotics were recorded and were compared with the chloramphenicol sensitivities of cultures obtained from a series of hospital patients in the same area. Assessment of the occurrence of side effects attributed to chloramphenicol was made from hospice casenotes. Chloramphenicol was widely effective, but there was some evidence of the emergence of resistant strains, particularly of coliforms. Side effects were encountered less frequently than might have been expected from the use of popular alternative oral antibiotic drugs.


[The potentials of molecular genetic diagnosis in military medicine (a review of the literature)].
The practical importance of the main genetic infringements in diagnostics of a wide circle of illnesses, including cardiology, nephrology, and oncology. Methods used. The exclusive effectiveness of application of the polymerasic chain reaction in the purposes of diagnostic. Expediency of application of the molecular-genetic methods for radiating, chemical and extreme effects evaluation.


Collaborative decision making improves interpersonal psychotherapy efficiency: A randomized clinical trial with postpartum women.
Randomized controlled trials of Interpersonal Psychotherapy (IPT) and other psychotherapies for depression have required strict adherence to protocol and do not allow for clinical judgment in deciding frequency of sessions. To determine if such protocols were more effective than allowing therapists to use their clinical judgment, we compared "Clinician-Managed" IPT (CM-IPT), in which clinicians and patients with postpartum depression were allotted 12 sessions and determined collaboratively when to use them, to a once weekly 12 session protocol ("Standard IPT"). We hypothesized that CM-IPT would be more efficient, requiring fewer sessions to reach an equivalent acute outcome, and that CM-IPT would be superior over 12 months because "saved" sessions could be used for maintenance treatment. We conducted a clinical trial including 140 postpartum outpatients with DSM-IV major depression who were randomly assigned to "Standard" IPT (N= 69) or CM-IPT (N= 71). Both CM-IPT and S-IPT were highly efficacious with similar outcomes by 12 weeks but CM-IPT group utilized significantly fewer sessions. Both were superior to a waitlist control. Superiority comparisons at 12 months did not favor the CM-IPT condition. Results should be replicated in a more diverse sample to increase generalizability. CM-IPT is more efficient in treating acute depression than mandated weekly IPT. Further, permitting clinicians and patients to use their collaborative judgment is likely to be a more efficient and effective way to conduct future research and to implement evidence-based psychotherapy in the community.


Vasopressin and its immune effects in septic shock.
Vasopressin is a stress hormone. However, vasopressin levels are inappropriately low in septic shock. Vasopressin stimulates AVPR1a, AVPR1b, AVPR2 and purinergic receptors. Vasopressin increases blood pressure by occupying AVPR1a receptors on vascular smooth muscle. An increase in ventricular afterload due to vasopressor administration limits ventricular systolic ejection, an effect that becomes increasingly important as systolic contractility is decreased. Stimulation of AVPR1a receptors may also decrease edemagenesis. Stimulation of AVPR1b by vasopressin releases ACTH and cortisol. AVPR2 stimulation increases retention of water by increasing cyclic AMP. Yet, vasopressin infusion may increase urine output, creatinine clearance and improve renal function in septic shock. Vasopressin has many effects on immune function such as altering cytokines, neuroimmunity, prostaglandins, humoral immunity and immune cells. For example, vasopressin decreases sepsis-induced pulmonary inflammation, could have renal anti-inflammatory effects and may decrease prostaglandin levels in a dose-dependent manner. Vasopressin may also modulate responses to stress by expression and release from immune cells. Interestingly, there are vasopressin receptors on immune cells. Many small clinical studies of vasopressin infusion in septic shock have shown that vasopressin infusion increases blood pressure, decreases requirements for norepinephrine and improves renal function. However, vasopressin could decrease coronary, cerebral and mesenteric perfusion. A multicenter trial of vasopressin versus norepinephrine in septic shock found no overall difference in mortality. Vasopressin may decrease mortality in patients with less severe septic shock. Vasopressin plus corticosteroid treatment may decrease mortality compared to corticosteroids plus norepinephrine. Potential mechanisms are that vasopressin plus corticosteroids beneficially alter immunity in septic shock.


Mechanisms of ampicillin resistance in Haemophilus influenzae type B.
The genetic mechanisms associated with ampicillin resistance in strains of Haemophilus influenzae type b were investigated. In experiments concerned with transfer of total deoxyribonucleic acid in vitro, expression of resistance by wild-type strains occurred at a frequency of about 10%. The minimum inhibitory concentration of ampicillin for the transformed strains was similar to that of the resistant donor strains, and resistance in transformants was associated with acquisition of the ability to produce beta-lactamase. Exposure to 39 mug of acridine per ml for 18 h cured resistance at a frequency of 80%, and there was spontaneous loss of resistance after repeated subculture of some strains. Analysis by cesium chloride-ethidium bromide density gradient centrifugation demonstrated the presence of extrachromosomal deoxyribonucleic acid in the resistant strains, providing further evidence that the resistance factor is plasmid mediated.


Pupillometry: Psychology, Physiology, and Function.
Pupils respond to three distinct kinds of stimuli: they constrict in response to brightness (the pupil light response), constrict in response to near fixation (the pupil near response), and dilate in response to increases in arousal and mental effort, either triggered by an external stimulus or spontaneously. In this review, I describe these three pupil responses, how they are related to high-level cognition, and the neural pathways that control them. I also discuss the functional relevance of pupil responses, that is, how pupil responses help us to better see the world. Although pupil responses likely serve many functions, not all of which are fully understood, one important function is to optimize vision either for acuity (small pupils see sharper) and depth of field (small pupils see sharply at a wider range of distances), or for sensitivity (large pupils are better able to detect faint stimuli); that is, pupils change their size to optimize vision for a particular situation. In many ways, pupil responses are similar to other eye movements, such as saccades and smooth pursuit: like these other eye movements, pupil responses have properties of both reflexive and voluntary action, and are part of active visual exploration.


Changes in sea floor productivity are crucial to understanding the impact of climate change in temperate coastal ecosystems according to a new size-based model.
The multifaceted effects of climate change on physical and biogeochemical processes are rapidly altering marine ecosystems but often are considered in isolation, leaving our understanding of interactions between these drivers of ecosystem change relatively poor. This is particularly true for shallow coastal ecosystems, which are fuelled by a combination of distinct pelagic and benthic energy pathways that may respond to climate change in fundamentally distinct ways. The fish production supported by these systems is likely to be impacted by climate change differently to those of offshore and shelf ecosystems, which have relatively simpler food webs and mostly lack benthic primary production sources. We developed a novel, multispecies size spectrum model for shallow coastal reefs, specifically designed to simulate potential interactive outcomes of changing benthic and pelagic energy inputs and temperatures and calculate the relative importance of these variables for the fish community. Our model, calibrated using field data from an extensive temperate reef monitoring program, predicts that changes in resource levels will have much stronger impacts on fish biomass and yields than changes driven by physiological responses to temperature. Under increased plankton abundance, species in all fish trophic groups were predicted to increase in biomass, average size, and yields. By contrast, changes in benthic resources produced variable responses across fish trophic groups. Increased benthic resources led to increasing benthivorous and piscivorous fish biomasses, yields, and mean body sizes, but biomass decreases among herbivore and planktivore species. When resource changes were combined with warming seas, physiological responses generally decreased species' biomass and yields. Our results suggest that understanding changes in benthic production and its implications for coastal fisheries should be a priority research area. Our modified size spectrum model provides a framework for further study of benthic and pelagic energy pathways that can be easily adapted to other ecosystems.


Phytochemical Compounds and Nanoparticles as Phytochemical Delivery Systems for Alzheimer's Disease Management.
Alzheimer's disease remains one of the most widespread neurodegenerative reasons for dementia worldwide and is associated with considerable mortality and morbidity. Therefore, it has been considered a priority for research. Indeed, several risk factors are involved in the complexity of the therapeutic ways of this pathology, including age, traumatic brain injury, genetics, exposure to aluminum, infections, diabetes, vascular diseases, hypertension, dyslipidemia, and obesity. The pathophysiology of Alzheimer's disease is mostly associated with hyperphosphorylated protein in the neuronal cytoplasm and extracellular plaques of the insoluble β-amyloid peptide. Therefore, the management of this pathology needs the screening of drugs targeting different pathological levels, such as acetylcholinesterase (AchE), amyloid β formation, and lipoxygenase inhibitors. Among the pharmacological strategies used for the management of Alzheimer's disease, natural drugs are considered a promising therapeutic strategy. Indeed, bioactive compounds isolated from different natural sources exhibit important anti-Alzheimer effects by their effectiveness in promoting neuroplasticity and protecting against neurodegeneration as well as neuroinflammation and oxidative stress in the brain. These effects involve different sub-cellular, cellular, and/or molecular mechanisms, such as the inhibition of acetylcholinesterase (AchE), the modulation of signaling pathways, and the inhibition of oxidative stress. Moreover, some nanoparticles were recently used as phytochemical delivery systems to improve the effects of phytochemical compounds against Alzheimer's disease. Therefore, the present work aims to provide a comprehensive overview of the key advances concerning nano-drug delivery applications of phytochemicals for Alzheimer's disease management.


Transcriptome changes associated with elongation of bovine conceptuses I: differentially expressed transcripts in the conceptus on day 17 after insemination.
The objective was to characterize transcriptome changes associated with elongation in bovine conceptuses during preimplantation stages. Nonlactating Holstein cows were euthanized 17 d after artificial insemination (AI) and the uterine horn ipsilateral to the CL was flushed with saline solution. Recovered conceptuses were classified as small (1.2 to 6.9 cm; n = 9), medium (10.5 to 16.0 cm; n = 9), or large (18.0 to 26.4 cm; n = 10). Total mRNA was extracted and subjected to transcriptome analyses using the Affymetrix Gene Chip Bovine array. Data were normalized using the GCRMA method and analyzed by robust regression using the Linear Models for Microarray library within Bioconductor in R. Transcripts with P ≤ 0.05 after adjustment for false discovery rate and fold change ≥1.5 were considered differentially expressed. Functional analyses were conducted using the Ingenuity Pathway Analysis platform. Comparisons between large vs. small (LvsS), large vs. medium (LvsM), and medium vs. small (MvsS) conceptuses yielded a total of 634, 240, and 63 differentially expressed transcripts, respectively. Top canonical pathways of known involvement with embryo growth that were upregulated in large conceptuses included actin cytoskeleton (LvsS), integrin signaling (LvsS and LvsM), ephrin receptor (LvsS), mesenchymal transition by growth factor (LvsM), and regulation of calpain protease (LvsS). Transcripts involved with lipid metabolism pathways (LXR/RXR, FXR/RXR, Hepatic Fibrosis) were associated with the LvsS and LvsM, and some transcripts such as APOC2, APOH, APOM, RARA, RBP4, and PPARGC1A, were involved in these pathways. An overall network summary associated biological downstream effects of invasion of cells, proliferation of embryonic cells, and inhibition of organismal death in the LvsS. In conclusion, differently expressed transcripts in the LvsS comparison were associated with the cell growth, adhesion, and organismal development, although part of these findings could be attributed to differences in circulatory concentrations of progesterone of the cows that bore large and small conceptuses. The large and medium conceptuses developed under similar concentrations of progesterone and presented 240 differently expressed transcripts, associated with cell differentiation, metabolite regulation, and other biological processes.


Effects of cytotoxic agents on functional integrity and antioxidant enzymes in clonal beta-cells.
Effects of cytotoxic agents and hydrogen peroxide were examined using pancreatic BRIN-BD11 cells and the parental insulinoma RINm5F cell line. Cell viability was determined using the MTT colorimetric assay and the TUNEL assay was used to assess apoptosis and acridine orange assay was used to determine levels of apoptosis versus necrosis. RT-PCR studies were employed to investigate the effects of the toxins on the expression of antioxidative enzymes, superoxide dismutase (SOD), glutathionine peroxidase (GPX) and catalase (CAT). Streptozotocin, hydrogen peroxide, alloxan and ninhydrin exerted time- and concentration-dependent toxic effects on BRIN-BD11 and RINm5F cells. RT-PCR showed that 90 minutes exposure of BRIN-BD11 cells or RINm5F cells to 5 mM ninhydrin down regulates SOD, GPX and CAT antioxidative enzymes. Glutathionine peroxidase gene expression was also down regulated in both types of cell by hydrogen peroxide. There were no significant differences in antioxidant gene expression after exposure to the other toxins under the conditions employed. TUNEL assay revealed that streptozotocin (8 mM) and hydrogen peroxide (125 microM) had no significant effect on the number of cells undergoing apoptosis. However after exposure to ninhydrin (5 mM) almost 100% of the non-viable BRIN-BD11 cells and around 50% of the RINm5F cells were dying by apoptosis. With the BRIN-BD11 cells there was around a 30% increase in the number of apoptotic cells compared with 50% in the RINm5F cells after exposure to alloxan (16 mM). The results indicate multiple effects of cytotoxic agents on functional integrity and antioxidant enzyme gene expression in clonal beta-cells.


Metallothionein inhibits ischemia-reperfusion injury in mouse heart.
Oxidative stress is believed to play a major role in ischemia-reperfusion injury to the heart. Metallothionein (MT), a potential free radical scavenger, may function in cardiac protection against ischemia-reperfusion damage. To test this hypothesis, a specific cardiac MT-overexpressing transgenic mouse model was used. The hearts isolated from these animals were subjected to 50 min of warm (37 degrees C) zero-flow ischemia followed by 60- or 90-min reflow. Compared with the nontransgenic controls, the transgenic mouse hearts with MT concentrations approximately 10-fold higher than normal showed significantly improved recovery of contractile force postischemia (69.2 +/- 4.2 vs. 26.0 +/- 6.0% at the end of 60-min reperfusion, P < 0.01). Efflux of creatine kinase from these transgenic hearts was reduced by more than 50% (P < 0.01). In addition, the zone of infarction induced by ischemia-reperfusion at the end of 90-min reperfusion was suppressed by approximately 40% (P < 0.01) in the transgenic hearts. The results strongly indicate that MT provides protection against ischemia-reperfusion-induced heart injury.


How Much Food Can We Grow in Urban Areas? Food Production and Crop Yields of Urban Agriculture: A Meta-Analysis.
Urban agriculture can contribute to food security, food system resilience and sustainability at the city level. While studies have examined urban agricultural productivity, we lack systemic knowledge of how agricultural productivity of urban systems compares to conventional agriculture and how productivity varies for different urban spaces (e.g., allotments vs. rooftops vs. indoor farming) and growing systems (e.g., hydroponics vs. soil-based agriculture). Here, we present a global meta-analysis that seeks to quantify crop yields of urban agriculture for a broad range of crops and explore differences in yields for distinct urban spaces and growing systems. We found 200 studies reporting urban crop yields, from which 2,062 observations were extracted. Lettuces and chicories were the most studied urban grown crops. We observed high agronomic suitability of urban areas, with urban agricultural yields on par with or greater than global average conventional agricultural yields. "Cucumbers and gherkins" was the category of crops for which differences in yields between urban and conventional agriculture were the greatest (17 kg m-2 cycle-1 vs. 3.8 kg m-2 cycle-1). Some urban spaces and growing systems also had a significant effect on specific crop yields (e.g., tomato yields in hydroponic systems were significantly greater than tomato yields in soil-based systems). This analysis provides a more robust, globally relevant evidence base on the productivity of urban agriculture that can be used in future research and practice relating to urban agriculture, especially in scaling-up studies aiming to estimate the self-sufficiency of cities and towns and their potential to meet local food demand.


[Occurrence of angioimmunoblastic T-cell lymphoma six months after onset of Lyme disease].
A 68-year-old man, who had suffered a tick bite one week previously, consulted his home doctor because of fever and an erythematous rash around the bite scar. He underwent a skin biopsy, and Borrelia garinii was detected, from which Lyme disease was diagnosed. He received amoxicillin for two weeks and his symptoms disappeared. After 6 months he noticed swelling of his cervical, axillary and inguinal lymph nodes. A biopsy sample was taken from a left cervical lymph node, and this revealed angioimmunoblastic T-cell lymphoma. The patient achieved a complete remission after chemotherapy. The relationship between Lyme disease and lymphoma is discussed.


Mechanisms of action of currently used antiseizure drugs.
Antiseizure drugs (ASDs) prevent the occurrence of seizures; there is no evidence that they have disease-modifying properties. In the more than 160 years that orally administered ASDs have been available for epilepsy therapy, most agents entering clinical practice were either discovered serendipitously or with the use of animal seizure models. The ASDs originating from these approaches act on brain excitability mechanisms to interfere with the generation and spread of epileptic hyperexcitability, but they do not address the specific defects that are pathogenic in the epilepsies for which they are prescribed, which in most cases are not well understood. There are four broad classes of such ASD mechanisms: (1) modulation of voltage-gated sodium channels (e.g. phenytoin, carbamazepine, lamotrigine), voltage-gated calcium channels (e.g. ethosuximide), and voltage-gated potassium channels [e.g. retigabine (ezogabine)]; (2) enhancement of GABA-mediated inhibitory neurotransmission (e.g. benzodiazepines, tiagabine, vigabatrin); (3) attenuation of glutamate-mediated excitatory neurotransmission (e.g. perampanel); and (4) modulation of neurotransmitter release via a presynaptic action (e.g. levetiracetam, brivaracetam, gabapentin, pregabalin). In the past two decades there has been great progress in identifying the pathophysiological mechanisms of many genetic epilepsies. Given this new understanding, attempts are being made to engineer specific small molecule, antisense and gene therapies that functionally reverse or structurally correct pathogenic defects in epilepsy syndromes. In the near future, these new therapies will begin a paradigm shift in the treatment of some rare genetic epilepsy syndromes, but targeted therapies will remain elusive for the vast majority of epilepsies until their causes are identified. This article is part of the special issue entitled 'New Epilepsy Therapies for the 21st Century - From Antiseizure Drugs to Prevention, Modification and Cure of Epilepsy'.


Evaluation of commercial enzyme-linked immunosorbent assays to identify psychedelic phenethylamines.
The 2C, 2C-T, and DO series of designer drugs pose a number of challenges to forensic toxicology laboratories. Although these drugs are seized by law enforcement agencies throughout the United States, they are not readily detected in forensic toxicology laboratories. A systematic evaluation of the cross-reactivity of 9 commercial enzyme-linked immunosorbent assays (ELISAs) was conducted using 11 designer drugs. Cross-reactivity was measured towards 2,5-dimethoxy-4-bromophenethylamine (2C-B), 2,5-dimethoxyphenethylamine (2C-H), 2,5-dimethoxy4-iodophenethylamine (2C-I), 2,5-dimethoxy-4ethylthiophenethylamine (2C-T-2), 2,5-dimethoxy-4isopropylthiophenethylamine (2C-T-4), 2,5-dimethoxy-4propylthiophenethylamine (2C-T-7), 2,5-dimethoxy-4bromoamphetamine (DOB), 2,5-dimethoxy-4-ethylamphetamine (DOET), 2,5-dimethoxy-4-iodoamphetamine (DOI), 2,5-dimethoxy-4-methylamphetamine (DOM), and 4methylthioamphetamine (4-MTA). Cross-reactivity towards the 2C, 2C-T, and DO series of psychedelic amphetamines was < 0.4%. Concentrations as high as 50,000 ng/mL in urine, which greatly exceed those expected in forensic case samples, were not sufficient to produce a positive result. The only substance to produce any measurable cross-reactivity was 4-MTA. Cross-reactivities of 5 and 7% were obtained using four methamphetamine/MDMA directed assays, 25 and 200% using two amphetamine-directed assays. The absence of any measurable cross-reactivity towards the 10 2C, 2C-T, and DO psychedelic phenethylamines makes it harder to detect these drugs using routine screening. As a consequence, laboratories that rely upon immunoassay rather than more broad spectrum chromatographic screening techniques, may fail to detect these powerful psychedelic substances.


Sedative use disorders in opiate-dependent patients: association with psychiatric and other substance use disorders.
Opiate-dependent patients (N = 231), classified by sedative disorder status, were characterized according to DSM-IIIR on substance use and psychiatric disorders. Twenty-one percent currently (CUR+) had sedative use disorder, 39% had a history (HX+) of sedative use disorder, and 40% had no history (HX-) of this disorder. Several group differences were found. The HX+ and CUR+ groups had more lifetime drug use disorders (means = 4.5 and 4.3 vs. 3.2 in the HX- group), including alcohol, cannabis, stimulants, cocaine, and hallucinogens. In contrast, other psychiatric disorders (e.g., anxiety and depression) were low in prevalence and did not differ across groups, with the exception of a higher prevalence of antisocial personality disorder in the HX+ and CUR+ groups (39.6% and 38.5% vs. 17.9% in HX- group). The results suggest that sedative use disorder is related more to a severe spectrum of multiple substance abuse than it is to self-medication of underlying mood or anxiety disorders.


Qigong stress reduction in hospital staff.
The aim of this study was to investigate the effectiveness of a qigong training program in reducing stress in hospital staff. Subjects were randomly assigned to a 6-week intervention of either qigong practice (n = 16) or a waiting list (n = 21). The primary measure of stress was the Perceived Stress Scale. Secondary measures included the Short Form 36 (SF-36) quality-of-life measure and a 100-mm analog pain scale. The qigong group demonstrated a statistically significant reduction of perceived stress compared to the control group (p = 0.02). On the Social Interaction subscale of the SF-36, the qigong group demonstrated greater improvement compared to controls (p = 0.04). Within-groups analyses demonstrated that the qigong group (p = 0.03), but not the control group, experienced a significant reduction of pain intensity. A regression analysis demonstrated an association between higher baseline stress levels and greater improvement within the qigong group (R(2) = 0.34; p = 0.02). These results suggest that short-term exposure to qigong was effective in reducing stress in hospital staff. Further studies are needed to evaluate the possible effectiveness of qigong in reducing pain and in improving quality of life.


Pediatric intensive care stress ulcer prevention (PIC-UP): a protocol for a pilot randomized trial.
Despite sparse pediatric data on effectiveness, the majority of critically ill children receive medications to prevent gastrointestinal (GI) bleeding. Stress ulcer prophylaxis may have unintended consequences-increasing the risk of nosocomial infections-which may be more serious and common than the bleeding which these drugs are prescribed to prevent. Randomized controlled trials (RCTs) in pediatric critical care are exceptionally challenging to complete, thus a rigorous pilot RCT is crucial. The objective of this pilot RCT is to assess the feasibility of a large multicentre RCT of stress ulcer prophylaxis with pantoprazole to prevent upper GI bleeding vs. placebo. A multi-centre blinded pilot RCT of 120 children in six Canadian PICUs. Children expected to require mechanical ventilation for more than 48 h will be randomized to receive intravenous pantoprazole 1 mg/kg or identical placebo once daily until they no longer need mechanical ventilation. We have four feasibility outcomes and will consider the trial successful if we achieve:Effective screening: If >80% of eligible patients are approached for consent.Timely enrollment: if >80% of participants receive their first dose of the assigned study drug within 1 day of becoming eligible.Participant accrual: If the average monthly enrolment is two or more participants per centre per month.Protocol adherence: if >90% of doses are administered according to the protocol. There are many uncertainties about the risks and benefits of stress ulcer prophylaxis. In an era of widespread use-where clinicians prescribe prophylaxis to the more severely ill-a large, rigorous RCT is required. A trial to determine if a strategy of withholding stress ulcer prophylaxis is not inferior to a strategy of routine stress ulcer prophylaxis will be challenging. A carefully designed and implemented pilot trial is essential. ClinicalTrials.gov:NCT02929563 (Registered October 3, 2016).


Multivariate analysis of prognosis for patients with natural killer/T cell lymphoma-associated hemophagocytic lymphohistiocytosis.
A major cause of hemophagocytic lymphohistiocytosis (HLH) is malignant neoplasms of the blood system, among which NK/T cell lymphoma is one of the most common risk factors. Patients with NK/T cell lymphoma hemophagocytic lymphohistiocytosis (NK/T-LAHS) have a worse prognosis and higher mortality. We aimed to explore the factors that affect the prognosis of NK/T-LAHS. Clinical data of 42 patients with NK/T-LAHS diagnosed by Beijing Friendship Hospital from June 2008 to June 2016 were analyzed retrospectively. The survival time was counted until 1 August 2016. For the 42 NK/T-LAHS patients, 1-month survival rate was 48.9%, 2-month survival rate was 36.7%, 3-month survival rate was 28.8%, 6-month survival rate was 23.0%, and 12-month survival rate was 15.4%. NK/T-LAHS patients who underwent allogeneic hematopoietic stem cell transplantation (Allo-HSCT) (p = 0.000), exhibited peripheral blood Epstein-Barr virus (EBV)-positivity (p = 0.004), and achieved overall response (OR) remission after initial induction therapy (p = 0.007) had statistical significance. NK/T-LAHS is a disease of poor prognosis and high mortality. NK/T-LAHS patients who achieved OR remission after the initial induction therapy had a better prognosis than non-remission patients and Allo-HSCT was an effective way to prolong the survival of NK/T-LAHS patients. However, EBV positivity in peripheral blood was a poor prognostic factor in NK/T-LAHS patients.


Relativistic laser-plasma interactions in the quantum regime.
We consider nonlinear interactions between a relativistically strong laser beam and a plasma in the quantum regime. The collective behavior of electrons is modeled by a Klein-Gordon equation, which is nonlinearly coupled with the electromagnetic wave through the Maxwell and Poisson equations. This allows us to study nonlinear interactions between arbitrarily large-amplitude electromagnetic waves and a quantum plasma. We have used our system of nonlinear equations to study theoretically the parametric instabilities involving stimulated Raman scattering and modulational instabilities. A model for quasi-steady-state propagating electromagnetic wave packets is also derived, and which shows possibility of localized solitary structures in a quantum plasma. Numerical simulations demonstrate collapse and acceleration of electrons in the nonlinear stage of the modulational instability, as well as possibility of the wake-field acceleration of electrons to relativistic speeds by short laser pulses at nanometer length scales. Our study is relevant for understanding the localization of intense electromagnetic pulses in a quantum plasma with extremely high electron densities and relatively low temperature.


Computer-aided detection and quantification of cavitary tuberculosis from CT scans.
To present a computer-aided detection tool for identifying, quantifying, and evaluating tuberculosis (TB) cavities in the infected lungs from computed tomography (CT) scans. The authors' proposed method is based on a novel shape-based automated detection algorithm on CT scans followed by a fuzzy connectedness (FC) delineation procedure. In order to assess interaction between cavities and airways, the authors first roughly identified air-filled structures (airway, cavities, esophagus, etc.) by thresholding over Hounsfield unit of CT image. Then, airway and cavity structure detection was conducted within the support vector machine classification algorithm. Once airway and cavities were detected automatically, the authors extracted airway tree using a hybrid multiscale approach based on novel affinity relations within the FC framework and segmented cavities using intensity-based FC algorithm. At final step, the authors refined airway structures within the local regions of FC with finer control. Cavity segmentation results were compared to the reference truths provided by expert radiologists and cavity formation was tracked longitudinally from serial CT scans through shape and volume information automatically determined through the authors' proposed system. Morphological evolution of the cavitary TB were analyzed accordingly with this process. Finally, the authors computed the minimum distance between cavity surface and nearby airway structures by using the linear time distance transform algorithm to explore potential role of airways in cavity formation and morphological evolution. The proposed methodology was qualitatively and quantitatively evaluated on pulmonary CT images of rabbits experimentally infected with TB, and multiple markers such as cavity volume, cavity surface area, minimum distance from cavity surface to the nearest bronchial-tree, and longitudinal change of these markers (namely, morphological evolution of cavities) were determined precisely. While accuracy of the authors' cavity detection algorithm was 94.61%, airway detection part of the proposed methodology showed even higher performance by 99.8%. Dice similarity coefficients for cavitary segmentation experiments were found to be approximately 99.0% with respect to the reference truths provided by two expert radiologists (blinded to their evaluations). Moreover, the authors noted that volume derived from the authors' segmentation method was highly correlated with those provided by the expert radiologists (R(2) = 0.99757 and R(2) = 0.99496, p < 0.001, with respect to the observer 1 and observer 2) with an interobserver agreement of 98%. The authors quantitatively confirmed that cavity formation was positioned by the nearby bronchial-tree after exploring the respective spatial positions based on the minimum distance measurement. In terms of efficiency, the core algorithms take less than 2 min on a linux machine with 3.47 GHz CPU and 24 GB memory. The authors presented a fully automatic method for cavitary TB detection, quantification, and evaluation. The performance of every step of the algorithm was qualitatively and quantitatively assessed. With the proposed method, airways and cavities were automatically detected and subsequently delineated in high accuracy with heightened efficiency. Furthermore, not only morphological information of cavities were obtained through the authors' proposed framework, but their spatial relation to airways, and longitudinal analysis was also provided to get further insight on cavity formation in tuberculosis disease. To the authors' best of knowledge, this is the first study in computerized analysis of cavitary tuberculosis from CT scans.


Monitoring microcirculation in critical illness.
Critical illness includes a wide range of conditions from sepsis to high-risk surgery. All these diseases are characterized by reduced tissue oxygenation. Macrohemodynamic parameters may be corrected by fluids and/or vasoactive compounds; however, the microcirculation and its tissues may be damaged and remain hypoperfused. An evaluation of microcirculation may enable more physiologically based approaches for understanding the pathogenesis, diagnosis, and treatment of critically ill patients. Microcirculation plays a pivotal role in delivering oxygen to the cells and maintains tissue perfusion. Negative results of several studies, based on conventional hemodynamic resuscitation procedures to achieve organ perfusion and decrease morbidity and mortality following conditions of septic shock and other cardiovascular compromise, have highlighted the need to monitor microcirculation. The loss of hemodynamic coherence between the macrocirculation and microcirculation, wherein improvement of hemodynamic variables of the systemic circulation does not cause a parallel improvement of microcirculatory perfusion and oxygenation of the essential organ systems, may explain why these studies have failed. Critical illness is usually accompanied by abnormalities in microcirculation and tissue hypoxia. Direct monitoring of sublingual microcirculation using hand-held microscopy may provide a more physiological approach. Evaluating the coherence between macrocirculation and microcirculation in response to therapy seems to be essential in evaluating the efficacy of therapeutic interventions.


[Laparoscopic cholecystectomy in acute cholecystitis: predictors of conversion to open cholecystectomy and preliminar results].
Inspite of increased technical difficulties and high incidence of conversion to open procedures and complications, laparoscopic cholecystectomy is a well established treatment for acute cholecystitis. In this study we reported our results in patients with acute cholecystitis undergoing laparoscopic cholecystecomy from 1998 to 2003. We found out that laparoscopic cholecystectomy was safe and was carried out with acceptable conversion rate and low morbidity. Predictors of complications were delay of surgery more than 48 hours following the onset of symptoms, leucocytosis > 15.000 U/microl and gallbladder wall ultrasonography thickness > 7mm.


alpha1-Antitrypsin deficiency associated with persistent cutaneous vasculitis. Occurrence in a child with liver disease.
alpha1-Antitrypsin (alpha1-AT) deficiency is an autosomal recessive inherited disease. The serum concentration of the protease inhibitor (Pi) alpha1-AT is controlled by a set of codominant allelic genes, constituting the so-called Pi system. Abnormal conditions reported in connection with severe alpha1-AT deficiency of the PiZZ type have been, in the newborn, cholestasis and progressive juvenile cirrhosis, and in adults, panacinar pulmonary emphysema and liver disease. Skin changes have not been described previously in connection with this disease picture. The case is persistent cutaneous vasculitis in a 2-year-old child with alpha1-AT deficiency of the PiZZ type, heterozygosity for the Duarte variant of galactose-1-phosphate uridyl transferase, and neonatal liver disease. A pathogenetic relationship may exist between the biochemical defects and both the skin and liver diseases.


The forgotten dimension of integrated care: barriers to implementing integrated clinical care in English NHS hospitals.
Multimorbid patients who enter English NHS hospitals are frequently subject to care pathways designed to assess, diagnose and treat single medical conditions. Opportunities are thereby lost to offer patients more holistic, person-centred care. Hospital organisations elsewhere are known to use in-hospital, multi-specialty, integrated clinical care (ICC) to overcome this problem. This perspective piece aims to critically discuss barriers to implementing this form of ICC in the English NHS focusing on six key areas: information technologies, the primary-secondary care interface, internal hospital processes, finance, workload, professional roles and behaviours. Integrated care programmes currently underway are largely focused on macro (system) and meso (organisational) levels. A micro (clinical) level ICC, offering highly coordinated multispecialty expertise to multimorbid hospital patients could fill an important gap in the current care pathways.


Miscibility of bioerodible polyphosphazene/poly(lactide-co-glycolide) blends.
We have previously demonstrated the feasibility of blending bioerodible polyphosphazenes with poly(lactide-co-glycolide) (PLGA) to form versatile polymeric materials with altered bioerosion properties. These studies demonstrated the effective neutralization of the acidic degradation products of PLGA by the polyphosphazene hydrolysis products. In the present study, five new polymers of dipeptide polyphosphazenes poly[(ethyl glycinato)x(glycyl-ethyl glycinato)yphosphazene] and novel blends of these polyphosphazenes with poly(lactide-co-glycolide) (PLGA) were synthesized and fabricated. The miscibility was analyzed using differential scanning calorimetry and scanning electron microscopy. Hydrogen bonding within the blends was assessed by attenuated total reflectance infrared spectroscopy. The phosphazene component of the blend contained varying ratios of the glycyl-glycine ethyl ester to the glycine ethyl ester. Poly[(ethyl glycinato)0.5(glycine ethyl glycinato)1.5phosphazene formed completely miscible blends with PLGA (50:50) and PLGA (85:15). This is ascribed to the multiple hydrogen-bonding sites within the side groups of the polyphosphazene. The components of the blend act as plasticizers for each other because a glass transition temperature for each blend was detected at a lower temperature than for each individual polymer. A hydrolysis study showed that unblended solid poly[(ethyl glycinato)0.5(glycyl ethyl glycinato)1.5phosphazene] hydrolyzed in less than 1 week. However, the blends degraded at a slower rate than both parent polymers. This is attributed to the buffering capacity of the polyphosphazene hydrolysis products, which increases the pH of the degradation media from 2.5 to 4, thereby slowing the degradation rate of PLGA.


Sprouty 2 protein, but not Sprouty 4, is an independent prognostic biomarker for human epithelial ovarian cancer.
Sprouty proteins are evolutionary-conserved modulators of receptor tyrosine kinase signaling, deregulation of which has been implicated in the pathophysiology of cancer. In the present study, the expression status of Spry2 and Spry4 proteins and its clinical relevance in human epithelial ovarian cancer (EOC) were investigated retrospectively. We examined the immunohistochemical expression of Spry2 and Spry4 in matched tumor and normal tissue samples from 99 patients. The expression of ERK, p-ERK, Ki67, fibroblast growth factor-2, vascular endothelial growth factor and interleukin-6 and their correlation with Sprouty homologs were also evaluated. Moreover, the correlation between Spry2 and Spry4 and the clinicopathological characteristics were analyzed along with their predictive value for overall survival (OS) and disease-free survival (DFS). Our data indicated significant downregulation of Spry2 and Spry4 in tumor tissues (p < 0.0001). A significant inverse correlation was evident between Spry2 and p-ERK/ERK (p = 0.048), Ki67 (p = 0.011), disease stage (p = 0.013), tumor grade (p = 0.003), recurrence (p < 0.001) and post-treatment ascites (p = 0.001), individually. It was found that Spry2 low-expressing patients had significantly poorer OS (p = 0.002) and DFS (p = 0.004) than those with high expression of Spry2. Multivariate analysis showed that high Spry2 (p = 0.018), low stage (p = 0.049) and no residual tumor (p =0.006) were independent prognostic factors for a better OS. With regard to DFS, high Spry2 (p = 0.044) and low stage (p = 0.046) remained as independent predictors. In conclusion, we report for the first time significant downregulation of Spry2 and Spry4 proteins in human EOC. Spry2 expression was revealed to significantly impact tumor behavior with predictive value as an independent prognostic factor for survival and recurrence.


Blood pressure and risk of breast cancer, overall and by subtypes: a prospective cohort study.
Blood pressure (BP) and breast cancer may share a common pathophysiologic pathway involving chronic inflammation, hormone synthesis and metabolism. Previous studies investigating the association between BP and breast cancer measured BP at a single time point and did not examine associations by breast cancer molecular subtypes. We used data from 22 833 female participants in the Melbourne Collaborative Cohort Study. BP was objectively measured at baseline (1990-1994) and a follow-up visit (2003-2007). Cox regression was used to estimate hazard ratios for baseline BP and temporal changes in BP in relation to risk of breast cancer, overall and by molecular subtypes. We did not observe any associations between BP measured at baseline and breast cancer risk overall (per 5 mmHg SBP, hazard ratio = 1.00, 95% confidence interval: 0.99-1.02), nor by subtype (per 5 mmHg SBP: estrogen-receptor-negative: hazard ratio = 0.99, 0.96-1.03, progesterone-receptor-negative: hazard ratio = 1.01, 0.99-1.04, human epidermal growth factor receptor 2 negative: hazard ratio = 1.00, 0.98-1.01). Temporal changes in BP were not associated with risk of breast cancer (per 5 mmHg change in SBP, hazard ratio = 1.00, 0.97-1.03). Increased DBP over time was associated with higher risk of triple-negative breast cancer (P = 0.04), based on a small number of cases (N = 41). Our study supports previous findings of no association between BP and breast cancer. Similar conclusions were reached when assessing BP over time and when examining specific tumor subtypes.


Ruxolitinib Cream 1.5%: A Review in Mild to Moderate Atopic Dermatitis.
Ruxolitinib cream 1.5% (OPZELURA™) is a topical formulation of ruxolitinib, a potent, selective inhibitor of Janus kinase (JAK)1 and JAK2. The targeting of these kinases is associated with therapeutic benefits in patients with atopic dermatitis (AD). In two identically designed, multinational, phase III studies in patients aged ≥ 12 years with mild to moderate AD, ruxolitinib cream 1.5% improved measures of disease severity, pruritus and sleep disturbance relative to vehicle cream when applied twice daily for 8 weeks. Disease severity was controlled for the next 44 weeks when applied as needed to active lesions. Ruxolitinib cream 1.5% was well tolerated in this patient population; its safety profile was similar to that of vehicle cream over the short term, with the types of treatment-emergent adverse events typical of those seen in the vehicle-controlled period over the longer term. Moreover, application site treatment-emergent adverse events indicative of skin tolerability issues (e.g. stinging/burning sensation) were infrequent and no safety findings suggestive of systemic JAK inhibition were identified. Although further longer-term data would be of use, ruxolitinib cream 1.5% provides an alternative to established topical agents (e.g. corticosteroids and calcineurin inhibitors) for the treatment of mild to moderate AD in adults and adolescents.


[Relationship between the intracranial pressure, intracranial blood volume and total cerebral blood flow].
Studies in cats and in neurosurgical patients reveal that intraskull pressure, blood volume and total brain blood flow depend on the same factors, to a different extent though. This is determined by structural--functional organization of the intraskull circulation system, the analysis of which revealed a scheme of functional interrelationships among volumes and pressures of fluid media in the closed skull space. The features of interrelationships are not rigid and can have their own specifics in concrete situations.


Solitary metastasis of breast carcinoma in the optic chiasm.
Optic chiasmatic compression from suprasellar metastatic lesions is well known, but metastasis intrinsic to the optic chiasm has not been reported. A 45-year-old woman, with treated breast carcinoma, presented with headache and chiasmatic syndrome from a large suprasellar tumour. At surgery, an exophytic chiasmatic tumour was encountered, with an appearance similar to a glioma. The pathological appearance was consistent with the primary neoplasm in the breast.


Protein SAP (serum amyloid P-component) in Waldenström's macroglobulinaemia, multiple myeloma and rheumatic diseases.
Serum amyloid P-component (protein SAP) levels in patients with Waldenström's macroglobulinaemia have been determined to be markedly elevated (83 +/- 34 micrograms/ml) compared with healthy adult controls (35 +/- 11 micrograms/ml) and patients with multiple myeloma (39 +/- 17 micrograms/ml). Seropositive rheumatoid arthritis and ankylosing spondylitis patients demonstrated slightly elevated protein SAP levels compared with normals and systemic lupus erythematosus patients, but these values were indistinguishable from those for patients with amyloidosis associated with a rheumatic disease.


The biochemistry of mitosis.
In this article, we will discuss the biochemistry of mitosis in eukaryotic cells. We will focus on conserved principles that, importantly, are adapted to the biology of the organism. It is vital to bear in mind that the structural requirements for division in a rapidly dividing syncytial Drosophila embryo, for example, are markedly different from those in a unicellular yeast cell. Nevertheless, division in both systems is driven by conserved modules of antagonistic protein kinases and phosphatases, underpinned by ubiquitin-mediated proteolysis, which create molecular switches to drive each stage of division forward. These conserved control modules combine with the self-organizing properties of the subcellular architecture to meet the specific needs of the cell. Our discussion will draw on discoveries in several model systems that have been important in the long history of research on mitosis, and we will try to point out those principles that appear to apply to all cells, compared with those in which the biochemistry has been specifically adapted in a particular organism.


Segmentation of Spoken Overlapping Ambiguity Strings in Chinese: An Eye-Tracking Study.
Using the printed-word paradigm with eye tracking, this study conducted three experiments to examine (a) how multiple words in spoken overlapping ambiguity strings (OASs) are activated, (b) how word frequency influences the word segmentation of spoken OASs, and (c) whether the multiple words in spoken OASs are activated competitively or independently. In this study, participants listened to a four-character spoken OAS (ABCD) and were presented with a visual display composed of a semantic associate of the "middle word" (BC; Experiments 1 and 2) or the "left word" (AB; Experiment 3) and two distractors. In Experiment 1, the word frequency of the middle words was manipulated to be higher than that of the neighbor words. In Experiment 2, the word frequency of the middle words was manipulated to be either higher or lower than that of the neighbor words. In Experiment 3, participants listened to either spoken OASs (ABCD) or spoken unambiguous strings (ABEF). In Experiment 1, we observed a significant semantic competition effect; that is, more fixations fell on the semantic competitors than on distractors, suggesting that the semantic information of the middle words in the spoken OASs was activated. In Experiment 2, the semantic competition effect was only observed in the high-frequency condition and was absent in the low-frequency condition. In Experiment 3, the results showed significant semantic competition effects for the left words under both conditions, and the observed effect was similar between the ambiguity condition and the control condition. These findings show that multiple words in spoken OASs are all activated and the activation level is modulated by word frequency. In addition, multiple words in the spoken OASs may be processed independently during spoken comprehension.


Fibroblast growth factor receptors: multifactorial-contributors to tumor initiation and progression.
Fibroblast growth factor receptors (FGFRs), encoded by four genes (FGFR1, FGFR2, FGFR3, and FGFR4) are tightly associated with many biological processes such as organ development, cell proliferation and migration. Studies over the past decades have validated the pivotal roles FGFRs play in tumorigenesis due to the regulation of diverse tumorigenesis-related processes, including cell survival, proliferation, inflammation, metastasis and angiogenesis. Interestingly, FGFR mutations in somatic cells leading to tumorigenesis and those in germ cells leading to developmental disorders are identical, suggesting that FGFR mutations result in different diseases due to their spatio-temporal expression. Thus, discoveries in developmental biology may also be applicable to cancer. FGFRs regulate the expression and/or the activity of a myriad of molecules (e.g. matrix metalloproteinases (MMPs) and Snail) that are tightly linked to tumorigenesis by four main signaling pathways (RAS-MAPK, PI3K-AKT, PLCγ-PIP2, and STAT), as well as other minor branches. Epigenetic and genetic alteration of FGFR genes, including DNA methylation, histone remodeling, microRNA regulation, single nucleotide polymorphisms (SNPs), gene missense mutations, amplification, and fusion of FGFRs with other genes, which result in gain or loss of FGFR function, have been identified in many types of cancer. In this review, we focus in particular on recent advances in the relationship between FGFR disorders and tumorigenesis.


A new approach for prediction of tumor sensitivity to targeted drugs based on functional data.
The success of targeted anti-cancer drugs are frequently hindered by the lack of knowledge of the individual pathway of the patient and the extreme data requirements on the estimation of the personalized genetic network of the patient's tumor. The prediction of tumor sensitivity to targeted drugs remains a major challenge in the design of optimal therapeutic strategies. The current sensitivity prediction approaches are primarily based on genetic characterizations of the tumor sample. We propose a novel sensitivity prediction approach based on functional perturbation data that incorporates the drug protein interaction information and sensitivities to a training set of drugs with known targets. We illustrate the high prediction accuracy of our framework on synthetic data generated from the Kyoto Encyclopedia of Genes and Genomes (KEGG) and an experimental dataset of four canine osteosarcoma tumor cultures following application of 60 targeted small-molecule drugs. We achieve a low leave one out cross validation error of <10% for the canine osteosarcoma tumor cultures using a drug screen consisting of 60 targeted drugs. The proposed framework provides a unique input-output based methodology to model a cancer pathway and predict the effectiveness of targeted anti-cancer drugs. This framework can be developed as a viable approach for personalized cancer therapy.


Early clinical outcomes of a novel rheolytic directional thrombectomy technique for patients with iliofemoral deep vein thrombosis.
Rheolytic thrombectomy (RT) for acute iliofemoral deep vein thrombosis (DVT) with first-generation techniques is often incomplete and adjunctive conventional catheter-directed thrombolysis (CDT) is required in more than half of patients to achieve venous patency. From the prospective Bern Venous Stent Registry, we investigated rates of primary treatment success, primary patency, and post-thrombotic syndrome (PTS) from 40 consecutive patients (mean age 51 ± 19 years, 45 % women) with acute iliofemoral DVT, treated with a novel directional RT technology and stent placement. Overall, 24 patients were treated for native-vessel iliofemoral DVT (11 with single-session RT, 13 with bail-out RT after failed CDT) and 16 for iliofemoral stent thrombosis. Pulse-spray thrombolysis (r-tPA 10 mg) was performed in 29 (73 %) patients. The mean follow-up duration was 193 ± 132 days (minimum 90 days). Overall, primary treatment success of RT was 95 %; only two patients required adjunctive CDT to restore patency. In 24 patients with native-vessel DVT, six-month primary patency was 92 % (95 %CI 75-99 %), and 23 patients (96 %) were free from the PTS according to the Villalta score. In 16 patients with stent thrombosis, six-month primary patency was 63 % (95 %CI 35-85 %) and 50 % were free from PTS. Except for transient macroscopic haemoglobinuria in all patients, no other side effects were recorded. In patients with iliofemoral DVT of native or stented vessels, RT followed by stent placement appears to be effective and safe. The novel technique enables single-session DVT treatment in the majority of patients without the need for prolonged CDT.


Cell-of-origin determined by both gene expression profiling and immunohistochemistry is the strongest predictor of survival in patients with diffuse large B-cell lymphoma.
The tumor cells in diffuse large B-cell lymphomas (DLBCL) are considered to originate from germinal center derived B-cells (GCB) or activated B-cells (ABC). Gene expression profiling (GEP) is preferably used to determine the cell of origin (COO). However, GEP is not widely applied in clinical practice and consequently, several algorithms based on immunohistochemistry (IHC) have been developed. Our aim was to evaluate the concordance of COO assignment between the Lymph2Cx GEP assay and the IHC-based Hans algorithm, to decide which model is the best survival predictor. Both GEP and IHC were performed in 359 homogenously treated Swedish and Danish DLBCL patients, in a retrospective multicenter cohort. The overall concordance between GEP and IHC algorithm was 72%; GEP classified 85% of cases assigned as GCB by IHC, as GCB, while 58% classified as non-GCB by IHC, were categorized as ABC by GEP. There were significant survival differences (overall survival and progression-free survival) if cases were classified by GEP, whereas if cases were categorized by IHC only progression-free survival differed significantly. Importantly, patients assigned as non-GCB/ABC both by IHC and GEP had the worst prognosis, which was also significant in multivariate analyses. Double expression of MYC and BCL2 was more common in ABC cases and was associated with a dismal outcome. In conclusion, to determine COO both by IHC and GEP is the strongest outcome predictor to identify DLBCL patients with the worst outcome.


Sorafenib N-Oxide Is an Inhibitor of Human Hepatic CYP3A4.
The multi-kinase inhibitor sorafenib (SOR) is clinically important in the treatment of hepatocellular and renal cancers and undergoes CYP3A4-dependent oxidation in liver to the pharmacologically active N-oxide metabolite (SNO). There have been reports that kinase inhibitors such as SOR may precipitate pharmacokinetic interactions with coadministered drugs that compete for CYP3A4-mediated biotransformation, but these occur non-uniformly in patients. Clinical evidence also indicates that SNO accumulates in serum of some patients during prolonged SOR therapy. In this study undertaken in hepatic microsomes from individual donors, we assessed the possibility that SNO might contribute to pharmacokinetic interactions mediated by SOR. Enzyme kinetics of CYP3A4-mediated midazolam 1'-hydroxylation in individual human hepatic microsomes were analyzed by non-linear regression and appropriate replots. Thus, SNO and SOR were linear-mixed inhibitors of microsomal CYP3A4 activity (Kis 15 ± 4 and 33 ± 14 μM, respectively). To assess these findings, further molecular docking studies of SOR and SNO with the 1TQN crystal structure of CYP3A4 were undertaken. SNO elicited a larger number of interactions with key amino acid residues located in substrate recognition sequences of the enzyme. In the optimal docking pose, the N-oxide moiety of SNO was also found to interact directly with the heme moiety of CYP3A4. These findings suggest that SNO could contribute to pharmacokinetic interactions involving SOR, perhaps in individuals who produce high circulating concentrations of the metabolite.


Effect of community-based interventions targeting female sex workers along the HIV care cascade in sub-Saharan Africa: a systematic review and meta-analysis.
Female sex workers are extremely vulnerable and highly susceptible to being infected with human immunodeficiency virus. As a result, community-based targeted interventions have been recommended as one of the models of care to improve access to HIV services and continued engagement in care. We conducted a systematic review to (1) assess the effect of FSW-targeted community interventions on the improvement of HIV services access along the treatment cascade and (2) describe community-based interventions that positively affect continuation in HIV care across the HIV treatment cascade for FSWs in sub-Saharan Africa. We defined the 5 steps that make up the HIV care cascade and categorized them as outcomes, namely, HIV testing and diagnosis, linkage to care, receipt of ART, and achievement of viral suppression. We conducted a systematic search of randomized controlled trials, cohort, and cross-sectional studies done in sub-Saharan African countries and published from 2004 to 2020. The period was selected based on the time span within which ART was scaled up through widespread roll-out of comprehensive HIV programs in sub-Saharan Africa. We reviewed studies with data on the implementation of community interventions for any of the HIV care cascade stage. The data were analyzed using random effects meta-analysis where possible, and for the rest of the studies, data were synthesized using summary statistics. The significant impact of the community interventions was observed on HIV testing, HIV diagnosis, and ART use. However, for HIV testing and ART use, the improvement was not sustained for the entire period of implementation. There were minimal interventions that had impact on HIV diagnosis, with only one community service delivery model showing significance. Generally, the interventions that had reasonable impact are those that implemented targeted and comprehensive package of HIV services provided at one location, and with unique strategies specific to each cascade stage. The evidence brought forward from this review shows that the effect of community-based interventions varies across the different stages of HIV care cascade. A broad package of interventions including a combination of behavioral, biomedical, and structural, designed with specific strategies, unique to each cascade stage appears to be more effective, although information on long-term treatment outcomes and the extent to which FSWs remain engaged in care is sparse. There is need to conduct a further research to deepen the assessment of the effectiveness of community-based interventions on HIV care cascade for FSWs. This will enhance identification of evidence-based optimal interventions that will guide effective allocation of scarce resources for strategies that would have a significant impact on HIV service delivery. PROSPERO CRD42020157623.


CDK11 Facilitates Centromeric Transcription to Maintain Centromeric Cohesion During mitosis.
Actively-transcribing RNA polymerase (RNAP)II is remained on centromeres to maintain centromeric cohesion during mitosis although it is largely released from chromosome arms. This pool of RNAPII plays an important role in centromere functions. However, the mechanism of RNAPII retention on mitotic centromeres is poorly understood. We here demonstrate that Cdk11 is involved in RNAPII regulation on mitotic centromeres. Consistently, we show that Cdk11 knockdown induces centromeric cohesion defects and decreases Bub1 on kinetochores, but the centromeric cohesion defects are partially attributed to Bub1. Furthermore, Cdk11 knockdown and the expression of its kinase-dead version significantly reduce both RNAPII and elongating RNAPII (pSer2) levels on centromeres and decrease centromeric transcription. Importantly, the overexpression of centromeric α-satellite RNAs fully rescues Cdk11-knockdown defects. These results suggest that the maintenance of centromeric cohesion requires Cdk11-facilitated centromeric transcription. Mechanistically, Cdk11 localizes on centromeres where it binds and phosphorylates RNAPII to promote transcription. Remarkably, mitosis-specific degradation of G2/M Cdk11-p58 recapitulates Cdk11-knockdown defects. Altogether, our findings establish Cdk11 as an important regulator of centromeric transcription and as part of the mechanism for retaining RNAPII on centromeres during mitosis.


The Bacillus subtilis RNase P holoenzyme contains two RNase P RNA and two RNase P protein subunits.
Ribonuclease P (RNase P) catalyzes the 5' maturation of precursor tRNA transcripts and, in bacteria, is composed of a catalytic RNA and a protein. We investigated the oligomerization state and the shape of the RNA alone and the holoenzyme of Bacillus subtilis RNase P in the absence of substrate by synchrotron small-angle X-ray scattering and affinity retention. The B. subtilis RNase P RNA alone is a monomer; however, the scattering profile changes upon the addition of monovalent ions, possibly suggesting different interdomain angles. To our surprise, the X-ray scattering data combined with the affinity retention results indicate that the holoenzyme contains two RNase P RNA and two RNase P protein molecules. We propose a structural model of the holoenzyme with a symmetrical arrangement of the two RNA subunits, consistent with the X-ray scattering results. This (P RNA)2(P protein)2 complex likely binds substrate differently than the conventional (P RNA)1(P protein)1 complex; therefore, the function of the B. subtilis RNase P holoenzyme may be more diverse than previously thought. These revisions to our knowledge of the RNase P holoenzyme suggest a more versatile role for proteins in ribonucleoprotein complexes.


Postoperative C-reactive protein kinetics predict postoperative complications in patients treated with cytoreductive surgery and hyperthermic intraperitoneal chemotherapy for peritoneal carcinomatosis.
Relatively high morbidity rates are reported after cytoreductive surgery (CRS) with hyperthermic intraperitoneal chemotherapy (HIPEC). However, early predictors of complications after CRS plus HIPEC have not been identified. The aim of this study was to evaluate the predictive role of early postoperative serum C-reactive protein (CRP) level (Day 2-4) for the detection of post-operative complications. We performed a retrospective study including 94 patients treated with complete CRS (R1) and HIPEC for PC from various primary origins (2011-2016). Post-operative complications were recorded. The values for postoperative inflammatory markers (white blood cells [WBC] and platelet counts, CRP) were compared between the different groups. CRP on post-operative days 2-4 was significantly higher in patients with than without complications (124 mg/L vs 46 mg/L; p < 0.0001) and higher in those with more major complications (162 mg/L vs 80 mg/L; p < 0.0012). WBC and platelet counts showed no difference within 5 days postoperatively. CRP levels, and kinetics mainly, between post-operative day 2 and 4, are decisive predictive markers of early and late post-operative complications after CRS plus HIPEC. The presence of post-operative complications should be suspected in patients with a high CRP mean, and a plateau level (days 2-4).


Risk of hepatitis B for travelers: is vaccination for all travelers really necessary?
Behavioral studies in travelers suggest that 33% to 76% of all travelers to hepatitis B virus (HBV)-endemic countries are at risk for HBV infection. We study the incidence and risk factors for HBV infection in travelers. Retrospective analysis of the characteristics and risk factors of all reported acute HBV patients in Amsterdam, the Netherlands, from January 1, 1992, until December 31, 2003. The estimated incidence in travelers from Amsterdam to HBV-endemic countries is 4.5/100,000 travelers. Two thirds of these patients were immigrants who lived in Amsterdam and who had visited their friends and relatives in their country of origin. In 12 years, only three Dutch short-term tourists contracted HBV while traveling, all by heterosexual contacts. Dutch tourists who travel to HBV-endemic countries run a very low risk of contracting HBV. Vaccination of short-term Dutch tourists is not necessary. Immigrants run a higher risk irrespective of travel or duration of travel. This group should be advised vaccination.


CALIPER: A deformable image registration algorithm for large geometric changes during radiotherapy for locally advanced non-small cell lung cancer.
Locally advanced non-small cell lung cancer (NSCLC) patients may experience dramatic changes in anatomy during radiotherapy and could benefit from adaptive radiotherapy (ART). Deformable image registration (DIR) is necessary to accurately accumulate dose during plan adaptation, but current algorithms perform poorly in the presence of large geometric changes, namely atelectasis resolution. The goal of this work was to develop a DIR framework, named Consistent Anatomy in Lung Parametric imagE Registration (CALIPER), to handle large geometric changes in the thorax. Registrations were performed on pairs of baseline and mid-treatment CT datasets of NSCLC patients presenting with atelectasis at the start of treatment. Pairs were classified based on atelectasis volume change as either full, partial, or no resolution. The evaluated registration algorithms consisted of several combinations of a hybrid intensity- and feature-based similarity cost function to investigate the ability to simultaneously match healthy lung parenchyma and adjacent atelectasis. These components of the cost function included a mass-preserving intensity cost in the lung parenchyma, use of filters to enhance vascular structures in the lung parenchyma, manually delineated lung lobes as labels, and several intensity cost functions to model atelectasis change. Registration error was quantified with landmark-based target registration error and post-registration alignment of atelectatic lobes. The registrations using both lobe labels and vasculature enhancement in addition to intensity of the CT images were found to have the highest accuracy. Of these registrations, the mean (SD) of mean landmark error across patients was 2.50 (1.16) mm, 2.80 (0.70) mm, and 2.04 (0.13) mm for no change, partial resolution, and full atelectasis resolution, respectively. The mean (SD) atelectatic lobe Dice similarity coefficient was 0.91 (0.08), 0.90 (0.08), and 0.89 (0.04), respectively, for the same groups. Registration accuracy was comparable to healthy lung registrations of current state-of-the-art algorithms reported in literature. The CALIPER algorithm developed in this work achieves accurate image registration for challenging cases involving large geometric and topological changes in NSCLC patients, a requirement for enabling ART in this patient group.


Synthesis of ZnO sol-gel thin-films CMOS-Compatible.
Zinc oxide (ZnO) is a II-VI group semiconductor with a wide direct bandgap and is an important material for various fields of industry and high-technological applications. The effects of thickness, annealing process in N2 and air, optical properties, and morphology of ZnO thin-films are studied. A low-cost sol-gel spin-coating technique is used in this study for the simple synthesis of eco-friendly ZnO multilayer films deposited on (100)-oriented silicon substrates ranging from 150 to 600 nm by adjusting the spin coating rate. The ZnO sol-gel thin-films using precursor solutions of molarity 0.75 M exhibit an average optical transparency above 98%, with an optical band gap energy of 3.42 eV. The c-axis (002) orientation of the ZnO thin-films annealed at 400 °C were mainly influenced by the thickness of the multilayer, which is of interest for piezoelectric applications. These results demonstrate that a low-temperature method can be used to produce an eco-friendly, cost-effective ZnO sol-gel that is compatible with a complementary metal-oxide-semiconductor (CMOS) and integrated-circuits (IC).


Preoperative CT in symptomatic abdominal aortic aneurysms: accuracy and efficacy.
Of 80 patients who underwent operations for abdominal aortic aneurysm at the Gainesville Veterans Administration Medical Center, 23 had a preoperative CT scan. Twenty patients in this group were symptomatic. In determining the presence of rupture, there was only one false-negative examination and no false-positives for a sensitivity of 0.9 and a specificity of 1.0. Nine of the 20 symptomatic patients had a rupture confirmed at laparotomy, and these patients had a 22 per cent mortality. Unruptured symptomatic patients operated upon after an expeditious preparation (usually about 36 hr), including optimization of cardiac output and mechanical bowel cleansing, had a mortality of 30 per cent primarily for postoperative myocardial infarction and left ventricular failure. The high operative mortality previously reported for emergently repaired unruptured symptomatic abdominal aortic aneurysms (18%) was not diminished by limited preoperative preparation.


[Treatment of chromoblastomycosis and phaeohyphomycosis].
Cases of chromoblastomycosis are frequent in certain parts of the world, especially in some developing countries. Clinical manifestations of chromoblastomycosis are typical. To a certain extent, pathogens causing chromoblastomycosis overlap with those causing phaeohyphomycosis. Although cases of phaeohyphomycosis are not very common, they may end fatally. Therefore early management of these life-threatening infections is rather important. Targeted antifungal therapy and surgery are effective in combating these infections. Recently, several triazole antifungals such as posaconazole and isavuconazole have been available to treat even the most severe cases. Prevention of the infection should be aimed at reducing the risk of subcutaneous trauma, particularly in persons in contact with potential sources of infection such as wood materials important from endemic areas.


Use of in vivo 13C nuclear magnetic resonance spectroscopy to elucidate L-arabinose metabolism in yeasts.
Candida arabinofermentans PYCC 5603(T) and Pichia guilliermondii PYCC 3012 were shown to grow well on L-arabinose, albeit exhibiting distinct features that justify an in-depth comparative study of their respective pentose catabolism. Carbon-13 labeling experiments coupled with in vivo nuclear magnetic resonance (NMR) spectroscopy were used to investigate L-arabinose metabolism in these yeasts, thereby complementing recently reported physiological and enzymatic data. The label supplied in L-[2-(13)C]arabinose to nongrowing cells, under aerobic conditions, was found on C-1 and C-2 of arabitol and ribitol, on C-2 of xylitol, and on C-1, C-2, and C-3 of trehalose. The detection of labeled arabitol and xylitol constitutes additional evidence for the operation in yeast of the redox catabolic pathway, which is widespread among filamentous fungi. Furthermore, labeling at position C-1 of trehalose and arabitol demonstrates that glucose-6-phosphate is recycled through the oxidative pentose phosphate pathway (PPP). This result was interpreted as a metabolic strategy to regenerate NADPH, the cofactor essential for sustaining l-arabinose catabolism at the level of L-arabinose reductase and L-xylulose reductase. Moreover, the observed synthesis of D-arabitol and ribitol provides a route with which to supply NAD(+) under oxygen-limiting conditions. In P. guilliermondii PYCC 3012, the strong accumulation of L-arabitol (intracellular concentration of up to 0.4 M) during aerobic L-arabinose metabolism indicates the existence of a bottleneck at the level of L-arabitol 4-dehydrogenase. This report provides the first experimental evidence for a link between L-arabinose metabolism in fungi and the oxidative branch of the PPP and suggests rational guidelines for the design of strategies for the production of new and efficient L-arabinose-fermenting yeasts.


Sulfonamide resistance of propionibacteria: nutrition and transport.
Three variations of a synthetic growth medium were used to study the folic acid and p-aminobenzoic acid (PABA) requirements of Propionibacterium. P. shermanii, P. freudenreichii, P. thoenii, and P. arabinosum synthesize folic acid and do not require PABA or folic acid. P. pentosaceum, P. jensenii, and P. rubrum are stimulated by folic acid or PABA, but do not show an absolute requirement. P. peterssonii shows a requirement for either PABA or folic acid. The addition of 300 mug of sulfadiazine per ml did not inhibit growth of propionibacteria in the synthetic medium, synthetic medium plus PABA, or synthetic medium plus folic acid. P. freudenreichii was not inhibited even when 500 mug of sulfadiazine per ml was added to the synthetic medium, nor did it degrade sulfadiazine significantly. Trimethoprim totally inhibited the growth of Propionibacterium. Radioactive sulfadiazine was transported by sulfadiazine-sensitive Escherichia coli but not by P. freudenreichii, indicating that the sulfadiazine resistance of propionibacteria could be mainly due to their inability to transport sulfonamides.


Histone 3 lysine 9 trimethylation is differentially associated with isocitrate dehydrogenase mutations in oligodendrogliomas and high-grade astrocytomas.
Trimethylation of histone 3 lysine 9 (H3K9me3) is a marker of repressed transcription. Cells transfected with mutant isocitrate dehydrogenase (IDH) show increased methylation of histone lysine residues, including H3K9me3, because of inhibition of histone demethylases by 2-hydroxyglutarate. Here, we evaluated H3K9me3 and its association with IDH mutations in 284 gliomas. Trimethylation of H3K9 was significantly associated with IDH mutations in oligodendrogliomas. Moreover, 72% of World Health Organization grade II and 65% of grade III oligodendrogliomas showed combined H3K9me3 positivity and 1p19q codeletion. In astrocytic tumors, H3K9me3 positivity was found in all grades of tumors; it showed a significant relationship with IDH mutational status in grade II astrocytomas but not in grade III astrocytomas or glioblastomas. Finally, H3K9me3-positive grade II oligodendrogliomas, but not other tumor subtypes, showed improved overall survival compared with H3K9me3-negative cases. These results suggest that repressive trimethylation of H3K9 in gliomas may occur in a context-dependent manner and is associated with IDH mutations in oligodendrogliomas but may be differently regulated in high-grade astrocytic tumors. Furthermore, H3K9me3 may define a subset of grade II oligodendrogliomas with better overall survival. Our results suggest variable roles for IDH mutations in the pathogenesis of oligodendrogliomas versus astrocytic tumors.


Nuclear factor-kappaB (NF-kappaB) p65 interacts with Stat5b in growth plate chondrocytes and mediates the effects of growth hormone on chondrogenesis and on the expression of insulin-like growth factor-1 and bone morphogenetic protein-2.
Growth hormone (GH) stimulates growth plate chondrogenesis and longitudinal bone growth with its stimulatory effects primarily mediated by insulin-like growth factor-1 (IGF-1) both systemically and locally in the growth plate. It has been shown that the transcription factor Stat5b mediates the GH promoting effect on IGF-1 expression and on chondrogenesis, yet it is not known whether other signaling molecules are activated by GH in growth plate chondrocytes. We have previously demonstrated that nuclear factor-κB p65 is a transcription factor expressed in growth plate chondrocytes where it facilitates chondrogenesis. We have also shown that fibroblasts isolated from a patient with growth failure and a heterozygous mutation of inhibitor-κBα (IκB; component of the nuclear factor-κB (NF-κB) signaling pathway) exhibit GH insensitivity. In this study, we cultured rat metatarsal bones in the presence of GH and/or pyrrolidine dithiocarbamate (PDTC), a known NF-κB inhibitor. The GH-mediated stimulation of metatarsal longitudinal growth and growth plate chondrogenesis was neutralized by PDTC. In cultured chondrocytes isolated from rat metatarsal growth plates, GH induced NF-κB-DNA binding and chondrocyte proliferation and differentiation and prevented chondrocyte apoptosis. The inhibition of NF-κB p65 expression and activity (by NF-κB p65 siRNA and PDTC, respectively) in chondrocytes reversed the GH-mediated effects on chondrocyte proliferation, differentiation, and apoptosis. Lastly, the inhibition of Stat5b expression in chondrocytes prevented the GH promoting effects on NF-κB-DNA binding, whereas the inhibition of NF-κB p65 expression or activity prevented the GH-dependent activation of IGF-1 and bone morphogenetic protein-2 expression.


The intestine plays a substantial role in human vitamin B6 metabolism: a Caco-2 cell model.
Vitamin B6 is present in various forms (vitamers) in the diet that need to be metabolized to pyridoxal phosphate (PLP), the active cofactor form of vitamin B6. In literature, the liver has been reported to be the major site for this conversion, whereas the exact role of the intestine remains to be elucidated. To gain insight into the role of the intestine in human vitamin B6 metabolism. Expression of the enzymes pyridoxal kinase (PK), pyridox(am)ine phosphate oxidase (PNPO) and PLP-phosphatase was determined in Caco-2 cells and in lysates of human intestine. Vitamin B6 uptake, conversion and excretion were studied in polarized Caco-2 cell monolayers. B6 vitamer concentrations (pyridoxine (PN), pyridoxal (PL), PLP, pyridoxamine (PM), pyridoxamine phosphate (PMP)) and pyridoxic acid (PA) were quantified by ultra performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) using stable isotope-labeled internal standards. The enzymatic system involved in vitamin B6 metabolism (PK, PNPO and PLP-phosphatase) is fully expressed in Caco-2 cells as well as in human intestine. We show uptake of PN, PM and PL by Caco-2 cells, conversion of PN and PM into PL and excretion of all three unphosphorylated B6 vitamers. We demonstrate, in a Caco-2 cell model, that the intestine plays a substantial role in human vitamin B6 metabolism.


Panchromatic quantum-dot-sensitized solar cells based on a parallel tandem structure.
A tandem-structure sensitized solar cell, comprising different inorganic semiconductor quantum dots (QDs) as sensitizers in two different compartments, has been designed for the first time with the aim of extending the light-absorption range of current technologies. In this system, the CdS/CdSe co-sensitized quantum-dot solar cell (QDSC) is in the upper part, whereas the PbS/CdS co-sensitized QDSC is in the lower part; these are connected in parallel with each other. In the middle of the tandem solar cell, a Cu2 S mesh counter electrode is employed. By optimizing the electrode thickness and QD-deposition time, short-circuit photocurrent density values of as high as 25.12 mA cm(-2) have been achieved; this value is nearly equal to the sum of the two constituent QD-sensitized devices and gives rise to a solar power-conversion efficiency of 5.06 %.


Pro- and Antitumorigenic Capacity of Immunoproteasomes in Shaping the Tumor Microenvironment.
Apart from the constitutive proteasome, the immunoproteasome that comprises the three proteolytic subunits LMP2, MECL-1, and LMP7 is expressed in most immune cells. In this study, we describe opposing roles for immunoproteasomes in regulating the tumor microenvironment (TME). During chronic inflammation, immunoproteasomes modulated the expression of protumorigenic cytokines and chemokines and enhanced infiltration of innate immune cells, thus triggering the onset of colitis-associated carcinogenesis (CAC) in wild-type mice. Consequently, immunoproteasome-deficient animals (LMP2/MECL-1/LMP7-null mice) were almost completely resistant to CAC development. In patients with ulcerative colitis with high risk for CAC, immunoproteasome-induced protumorigenic mediators were upregulated. In melanoma tumors, the role of immunoproteasomes is relatively unknown. We found that high expression of immunoproteasomes in human melanoma was associated with better prognosis. Similarly, our data revealed that the immunoproteasome has antitumorigenic activity in a mouse model of melanoma. The antitumor immunity against melanoma was compromised in immunoproteasome-deficient mice because of the impaired activity of CD8+ CTLs, CD4+ Th1 cells, and antigen-presenting cells. These findings show that immunoproteasomes may exert opposing roles with either pro- or antitumoral properties in a context-dependent manner.


Efficacy of a bioreactor filled with porcine hepatocytes immobilized on nonwoven fabric for ex vivo direct hemoperfusion treatment of liver failure in pigs.
We developed a new bioreactor for a bioartificial liver filled with porcine hepatocytes immobilized on polyester nonwoven fabric (NWF) and in our previous study showed that this NWF bioreactor has promising in vitro efficiency. In the present study, we investigated the efficacy of the NWF bioreactor in a direct hemoperfusion experiment conducted to treat pigs with liver failure. Porcine hepatocytes were isolated from the whole liver of a Sangen strain pig. They were immobilized in a 200 ml column containing NWF via perfusion in a closed circuit for 24 h to prepare a NWF bioreactor. The following day an operative liver failure model was produced by creating a portocaval shunt and ligating the entire hepatoduodenal ligament in the porta hepatis. Perfusion treatment was initiated 4 h after operative induction of liver failure and continued for about 1 h. The pigs which underwent perfusion treatment showed significant improvements in survival and blood data, including ammonia, total bile acid, glucose, and prothrombin time, attributed to significant improvements in the post- as compared to the prebioreactor levels in the perfused blood of the treated pigs. These beneficial effects of the NWF bioreactor were based on its excellent composition which allows the accommodation of adequate numbers of hepatocytes and direct contact between hepatocytes and perfused blood.


Navigating uncertainty, employment and women's safety during COVID-19: Reflections of sexual assault resistance educators.
COVID-19 affects women in ways unique to the impacts of structural inequalities related to gender, sexuality, disability, race and socioeconomic status. In this article, we reflect on our own experiences of the pandemic, as feminist students, workers and sexual assault resistance educators located in a Canadian post-secondary setting. Situating ourselves within feminist responses to sexual violence prevention, as facilitators of the Enhanced Assess, Acknowledge, and Act (EAAA) sexual assault resistance education programme for university women, we reflect on the impacts of the COVID-19 pandemic on our work as EAAA facilitators in our Canadian university. We explore the theoretical possibilities that critical disability theory and queer theory present to the EAAA programme, and argue that incorporating concepts from these frameworks will complement the goals of the EAAA programme and improve inclusivity of queer, trans and disabled participants. We conclude with a look into the future by anticipating the impacts of COVID-19 on our future work.


Management of tricuspid valve regurgitation: Position statement of the European Society of Cardiology Working Groups of Cardiovascular Surgery and Valvular Heart Disease.
Tricuspid regurgitation (TR) is a very frequent manifestation of valvular heart disease. It may be due to the primary involvement of the valve or secondary to pulmonary hypertension or to the left-sided heart valve disease (most commonly rheumatic and involving the mitral valve). The pathophysiology of secondary TR is complex and is intrinsically connected to the anatomy and function of the right ventricle. A systematic multimodality approach to diagnosis and assessment (based not only on the severity of the TR but also on the assessment of annular size, RV function and degree of pulmonary hypertension) is, therefore, essential. Once considered non-important, treatment of secondary TR is currently viewed as an essential concomitant procedure at the time of mitral (and, less frequently, aortic valve) surgery. Although the indications for surgical management of severe TR are now generally accepted (Class I), controversy persists concerning the role of intervention for moderate TR. However, there is a trend for intervention in this setting, especially at the time of surgery for left-sided heart valve disease and/or in patients with significant tricuspid annular dilatation (Class IIa). Currently, surgery remains the best approach for the interventional treatment of TR. Percutaneous tricuspid valve intervention (both repair and replacement) is still in its infancy but may become a reliable option in future, especially for high-risk patients with isolated primary TR or with secondary TR related to advanced left-sided heart valve disease.


Role of plasmids in the virulence of enteric bacteria.
Plasmids have been shown to play an important role in the pathogenecity of most enterobacteria. Their involvement in various enterobacteria was discovered at different times and there is resemblance in the type of toxins produced by a number of enterobacteria and in the genes responsible for the production of the toxins and invasiveness. This indicates a spread of a factor from one bacterial strain to another, thus enabling the recipient to demonstrate the characteristic coded for. This factor may be the plasmid or chromosomal portion that codes for the characteristic.


Neonatal Survival After Serial Amnioinfusions for Bilateral Renal Agenesis: The Renal Anhydramnios Fetal Therapy Trial.
Early anhydramnios during pregnancy, resulting from fetal bilateral renal agenesis, causes lethal pulmonary hypoplasia in neonates. Restoring amniotic fluid via serial amnioinfusions may promote lung development, enabling survival. To assess neonatal outcomes of serial amnioinfusions initiated before 26 weeks' gestation to mitigate lethal pulmonary hypoplasia. Prospective, nonrandomized clinical trial conducted at 9 US fetal therapy centers between December 2018 and July 2022. Outcomes are reported for 21 maternal-fetal pairs with confirmed anhydramnios due to isolated fetal bilateral renal agenesis without other identified congenital anomalies. Enrolled participants initiated ultrasound-guided percutaneous amnioinfusions of isotonic fluid before 26 weeks' gestation, with frequency of infusions individualized to maintain normal amniotic fluid levels for gestational age. The primary end point was postnatal infant survival to 14 days of life or longer with dialysis access placement. The trial was stopped early based on an interim analysis of 18 maternal-fetal pairs given concern about neonatal morbidity and mortality beyond the primary end point despite demonstration of the efficacy of the intervention. There were 17 live births (94%), with a median gestational age at delivery of 32 weeks, 4 days (IQR, 32-34 weeks). All participants delivered prior to 37 weeks' gestation. The primary outcome was achieved in 14 (82%) of 17 live-born infants (95% CI, 44%-99%). Factors associated with survival to the primary outcome included a higher number of amnioinfusions (P = .01), gestational age greater than 32 weeks (P = .005), and higher birth weight (P = .03). Only 6 (35%) of the 17 neonates born alive survived to hospital discharge while receiving peritoneal dialysis at a median age of 24 weeks of life (range, 12-32 weeks). Serial amnioinfusions mitigated lethal pulmonary hypoplasia but were associated with preterm delivery. The lower rate of survival to discharge highlights the additional mortality burden independent of lung function. Additional long-term data are needed to fully characterize the outcomes in surviving neonates and assess the morbidity and mortality burden. ClinicalTrials.gov Identifier: NCT03101891.


[18 O-exchange reactions catalyzed by subfragment 1 of myosin molecule].
18 O-exchange properties of enzymically active proteolytic fragment of myosin molecule--subfragment 1 were studied. It was shown that 18O-exchange activity of subfragment 1 is similar to that of parental myosin and its other proteolytic fragment--heavy meromyosin. The experimental data suggest that the 18O-exchange activity is an integral property of myosin and is not determined by its contaminations.


Resonant soft X-ray scattering reveals cellulose microfibril spacing in plant primary cell walls.
Cellulose microfibrils are crucial for many of the remarkable mechanical properties of primary cell walls. Nevertheless, many structural features of cellulose microfibril organization in cell walls are not yet fully described. Microscopy techniques provide direct visualization of cell wall organization, and quantification of some aspects of wall microstructure is possible through image processing. Complementary to microscopy techniques, scattering yields structural information in reciprocal space over large sample areas. Using the onion epidermal wall as a model system, we introduce resonant soft X-ray scattering (RSoXS) to directly quantify the average interfibril spacing. Tuning the X-ray energy to the calcium L-edge enhances the contrast between cellulose and pectin due to the localization of calcium ions to homogalacturonan in the pectin matrix. As a consequence, RSoXS profiles reveal an average center-to-center distance between cellulose microfibrils or microfibril bundles of about 20 nm.


Neural correlates of memories of abandonment in women with and without borderline personality disorder.
Borderline personality disorder (BPD) is a common psychiatric disorder that is often linked to early stressors. One particularly salient feature of the disorder is fear of abandonment. This pilot study was conducted to measure neural correlates of memories of abandonment in women with and without BPD. Twenty women with a history of childhood sexual abuse underwent measurement of brain blood flow with positron emission tomography imaging while they listened to scripts describing neutral and personal abandonment events. Brain blood flow during exposure to abandonment and neutral scripts was compared among women with and without BPD. Memories of abandonment were associated with greater increases in blood flow in bilateral dorsolateral prefrontal cortex (middle frontal gyrus, Brodmann's areas 9 and 10) as well as right cuneus (area 19) in women with BPD than in women without BPD. Abandonment memories were associated with greater decreases in right anterior cingulate (areas 24 and 32) in women with BPD than in women without BPD. These findings implicate dysfunction of dorsolateral and medial prefrontal cortex including anterior cingulate, left temporal cortex, and visual association cortex in memories of abandonment in women with BPD. These brain areas may mediate symptoms of BPD.