Genetic events that limit the efficacy of MEK and RTK inhibitor therapies in a mouse model of KRAS-driven pancreatic cancer.
Mutated KRAS (KRAS*) is a fundamental driver in the majority of pancreatic ductal adenocarcinomas (PDAC). Using an inducible mouse model of KRAS*-driven PDAC, we compared KRAS* genetic extinction with pharmacologic inhibition of MEK1 in tumor spheres and in vivo. KRAS* ablation blocked proliferation and induced apoptosis, whereas MEK1 inhibition exerted cytostatic effects. Proteomic analysis evidenced that MEK1 inhibition was accompanied by a sustained activation of the PI3K-AKT-MTOR pathway and by the activation of AXL, PDGFRa, and HER1-2 receptor tyrosine kinases (RTK) expressed in a large proportion of human PDAC samples analyzed. Although single inhibition of each RTK alone or plus MEK1 inhibitors was ineffective, a combination of inhibitors targeting all three coactivated RTKs and MEK1 was needed to inhibit proliferation and induce apoptosis in both mouse and human low-passage PDAC cultures. Importantly, constitutive AKT activation, which may mimic the fraction of AKT2-amplified PDAC, was able to bypass the induction of apoptosis caused by KRAS* ablation, highlighting a potential inherent resistance mechanism that may inform the clinical application of MEK inhibitor therapy. This study suggests that combinatorial-targeted therapies for pancreatic cancer must be informed by the activation state of each putative driver in a given treatment context. In addition, our work may offer explanative and predictive power in understanding why inhibitors of EGFR signaling fail in PDAC treatment and how drug resistance mechanisms may arise in strategies to directly target KRAS.


Drug treatment of scleroderma.
Scleroderma or systemic sclerosis is a rare condition with many clinical manifestations including Raynaud's phenomenon. As with many other rarely encountered diseases, drug therapy for scleroderma is often empirical with little evidence in the form of randomised controlled trials to aid drug choice. Raynaud's phenomenon has been recognised for well over 100 years. A considerable number of clinical trials in this area have demonstrated unequivocally the use of nifedipine as a gold standard. Large studies have also demonstrated the efficacy of iloprost. However, this drug is not as yet licensed for scleroderma in the UK or elsewhere. This presents an additional problem as information regarding the use and administration of unlicensed drugs is often sparse and post-marketing surveillance to assess safety is not routinely performed. When looking at the other distinct conditions encountered by a patient with scleroderma it becomes evident that trials are often retrospective or limited in patient numbers. Studies investigating the use of methotrexate, antithymocyte globulin and cyclophosphamide in patients with scleroderma have been very small and in some cases not well designed. The major work on penicillamine was a retrospective trial. Again these drugs are not licensed for use in scleroderma. Drug therapy for pulmonary hypertension secondary to scleroderma closely follows that outlined for primary pulmonary hypertension. In the US there is a patient registry for primary pulmonary hypertension that has enabled well designed, large-scale studies to demonstrate the benefits of epoprostenol in severe primary pulmonary hypertension. Hence, research in this area has progressed considerably over the last decade. Clearly, a considerable amount of work is being carried out to elucidate new treatment regimens for scleroderma, however, evaluation of these studies is proving to be a difficult process. Designated hospital centres for scleroderma (there are currently 2 in the UK), better markers of disease activity and methods to measure improvement or deterioration in affected organs, should enable research into aetiology, disease progression and treatment to be carried out on a larger scale resulting, hopefully, in more conclusive answers.


Evaluation of phenytoin dosage regimens based on genotyping of CYP2C subfamily in routinely treated Japanese patients.
Two research groups have reported the effect of genetic polymorphisms of CYP2C9 and CYP2C19 on the pharmacokinetic parameters of phenytoin in Japanese epileptic patients. We measured the plasma phenytoin concentrations at steady-state in 20 routinely treated Japanese patients, and evaluated the usefulness of genotyping the CYP2C subfamily in predicting plasma concentrations and determining the dosage regimens of phenytoin. The plasma phenytoin concentrations predicted by genotypes of the CYP2C subfamily were well correlated with the observed concentrations in some patients, but not in some patients. The pharmacokinetic parameters (Vmax and Km) in individual patients, which were obtained from population estimates according to Bayes' theorem, showed considerable interindividual variability even among patients with the same genotype. In addition, we assessed the effect of plasma protein binding on the residual interindividual variability in the clearance of phenytoin; however, there was no significant correlation between the unbound fraction and the intrinsic metabolic activity (Vmax/Km). These findings suggested that the mechanism responsible for the large variability in the clearance of phenytoin is not completely resolved, and that we should not overestimate the usefulness of genotyping the CYP2C subfamily in determining the dosage regimens of the drug.


The epigenetic control of the Athila family of retrotransposons in Arabidopsis.
Retrotransposons are major constituents of both plant and animal genomes. In the genome of the model plant Arabidopsis thaliana, which is known for its small size and low repeat content, the Athila retrotransposon family occupies over 2.7% of the total genome and is a major building block of the centromere. However, the copy number and location of Athila elements fail to tell the complete story, as recent experiments have demonstrated that Athila is not only literally at the center of each chromosome, but figuratively at the center of Arabidopsis epigenetic regulation. The silencing of Athila retrotransposons has come to the forefront of Arabidopsis small RNA regulation, the control of the centromere core, as well as potentially playing a role in speciation. This review explores what studying one of the largest transposable element families in one of the smallest plant genomes can tell us about the epigenetic regulation of the genome.


Organizational behavior of human umbilical vein endothelial cells.
Culture conditions that favor rapid multiplication of human umbilical vein endothelial cells (HUV-EC) also support long-term serial propagation of the cells. This is routinely achieved when HUV-EC are grown in Medium 199 (M-199) supplemented with fetal bovine serum (FBS) and endothelial cell growth factor (ECGF), on a human fibronectin (HFN) matrix. The HUV-EC can shift from a proliferative to an organized state when the in vitro conditions are changed from those favoring low density proliferation to those supporting high density survival. When ECGF and HFN are omitted, cultures fail to achieve confluence beyond the first or second passage: the preconfluent cultures organize into tubular structures after 4-6 wk. Some tubes become grossly visible and float in the culture medium, remaining tethered to the plastic dish at either end of the tube. On an ultrastructural level, the tubes consist of cells, held together by junctional complexes, arranged so as to form a lumen. The smallest lumens are formed by one cell folding over to form a junction with itself. The cells contain Weibel-Palade bodies and factor VIII-related antigen. The lumens contain granular, fibrillar and amorphous debris. Predigesting the HFN matrix with trypsin (10 min, 37 degrees C) or plasmin significantly accelerates tube formation. Thrombin and plasminogen activator had no apparent effect. Disruption of the largest tubes with trypsin/EDTA permits the cells to revert to a proliferative state if plated on HFN, in M-199, FBS, and ECGF. These observations indicate that culture conditions that do not favor proliferation permit attainment of a state of nonterminal differentiation (organization) by the endothelial cell. Furthermore, proteolytic modification of the HFN matrix may play an important role in endothelial organization.


Role of Erbin in ErbB2-dependent breast tumor growth.
ErbB2 (v-erb-b2 avian erythroblastic leukemia viral oncogene homolog 2), a receptor tyrosine kinase of the ErbB family, is overexpressed in around 25% of breast cancers. In addition to forming a heterodimer with other ErbB receptors in response to ligand stimulation, ErbB2 can be activated in a ligand-independent manner. We report here that Erbin, an ErbB2-interacting protein that was thought to act as an antitumor factor, is specifically expressed in mammary luminal epithelial cells and facilitates ErbB2-dependent proliferation of breast cancer cells and tumorigenesis in MMTV-neu transgenic mice. Disruption of their interaction decreases ErbB2-dependent proliferation, and deletion of the PDZ domain in Erbin hinders ErbB2-dependent tumor development in MMTV-neu mice. Mechanistically, Erbin forms a complex with ErbB2, promotes its interaction with the chaperon protein HSP90, and thus prevents its degradation. Finally, ErbB2 and Erbin expression correlates in human breast tumor tissues. Together, these observations establish Erbin as an ErbB2 regulator for breast tumor formation and progression.


RNA polymerase induces DNA bending at yeast mitochondrial promoters.
Yeast mitochondrial RNA polymerase can bind specifically to promoter-containing DNA fragments in vitro as detected by DNAse I or methidiumpropyl-EDTA. Fe(II) protection assays and gel retardation experiments. Retardation of RNA polymerase-DNA complexes was most pronounced when the promoter was located in the middle of a DNA fragment and was diminished when RNA polymerase was bound near one of the ends. This indicates that upon RNA polymerase-binding the DNA undergoes a conformational change which is most likely a bend. The degree of introduced bending correlated with the efficiency of transcription and promoter-binding in a series of promoter mutants, suggesting that bending is a functional event during promoter utilisation.


Implications of the xylQ gene of TOL plasmid pWW102 for the evolution of aromatic catabolic pathways.
Pseudomonas putida strain O2C2 is able to grow on toluene, m-xylene and p-xylene through benzoate and the corresponding methylbenzoates (toluates). The catabolic genes are encoded on a large TOL plasmid, pWW102, of > 220 kb. The complete catabolic genes were cloned on four large overlapping restriction fragments covering a total of 28 kb of the plasmid, which was carefully mapped by restriction enzyme analysis. The presence of the xyl genes on the cloned DNA was confirmed by assay of representative enzymes of both operons. Virtually all the genes were located on the cloned DNA by hybridization of Southern blots with gene-specific probes from related pathways of other catabolic plasmids. Within the limitations of available restriction sites, the analysis showed that the genes are in two blocks. The major block carries the meta pathway operon xylXYZLTEGFJQKIH with the two regulatory genes xylSR immediately downstream. The upper pathway operon xylUWCMAB(N) is about 2-3 kb downstream of the regulatory genes and transcribed in the same direction as the meta pathway operon. Within each operon the gene order appears to be identical to that found in other TOL plasmids, but the relative location of the operons most closely resembles that found on plasmid pWW53, although there is no evidence of any xyl duplications on pWW102. The nucleotide sequence of the xylQ gene for the acetaldehyde dehydrogenase (acylating; ADA), together with the 3'-end of the upstream xylJ (for 2-oxopent-4-enoate hydratase) and the 5'-end of the downstream xylK (for 4-hydroxy-2-oxovalerate aldolase), was determined. The xylQ gene was ligated into expression vector pTrc99a and high levels of XylQ protein were detected by enzyme assay and by SDS-PAGE. All three genes xylJQK showed a high degree of homology with genes encoding isofunctional proteins from other Pseudomonas meta pathways, the highest being with the naphthalene catabolic genes nahLOM from the plasmid of Pseudomonas sp. NCIB 9816. The implications of the sequence homologies to the evolution of these pathways are discussed.


Emergency management of chemical weapons injuries.
The potential for chemical weapons to be used in terrorism is a real possibility. Classes of chemical weapons include nerve agents, vesicants (blister agents), choking agents, incapacitating agents, riot control agents, blood agents, and toxic industrial chemicals. The nerve agents work by blocking the actions of acetylcholinesterase leading to a cholinergic syndrome. Nerve agents include sarin, tabun, VX, cyclosarin, and soman. The vesicants include sulfur mustard and lewisite. The vesicants produce blisters and also damage the upper airways. Choking agents include phosgene and chlorine gas. Choking agents cause pulmonary edema. Incapacitating agents include fentanyl and its derivatives and adamsite. Riot control agents include Mace and pepper spray. Blood agents include cyanide. The mechanism of toxicity for cyanide is blocking oxidative phosphorylation. Toxic industrial chemicals include agents such as formaldehyde, hydrofluoric acid, and ammonia.


The Effect of Combined Ultrasound and Electric Field Stimulation on Wound Healing in Chronic Ulcerations.
Ultrasound and electric stimulation are known therapies for the treatment of chronic ulcerations. Combined modulated ultrasound and electric field stimulation (CUSEFS) have never been studied as a single modality. The authors evaluate the results of CUSEFS (BRH Medical Ltd, Jerusalem, Israel) on a variety of wound types in a number of clinics. This retrospective analysis looked at ulcers treated with CUSEFS in 4 clinics. Wounds were evaluated by an independent assessor and data was evaluated by an independent statistician. Of the 300 wounds treated with the CUSEFS device, only those classified as diabetic foot ulcers (DFUs) or venous leg ulcers (VLUs) were evaluated. A treatment was deemed successful if the wound was 50% closed within 4 weeks. Subjects were then followed to see if their wounds completely closed within 16 weeks. Of the 27 DFUs treated, 59.3% (16) achieved 50% closure within 4 weeks. Of the 38 VLUs treated, 71.1% (27) achieved 50% closure within 4 weeks. It was found that variables such as gender, size of the wound at presentation, and longevity of the wound had no bearing on the outcome. The age of the patient had an effect on the outcome of the VLUs. The wound healing trajectory was supported in that there was a significant difference in the achievement of total closure between those subjects who had a successful trial and those who did not. Combined modulated ultrasound and electric field stimulation has a place as adjunct therapy that aids wound healing and provides an effective noninvasive treatment option.


PKC α regulates netrin-1/UNC5B-mediated survival pathway in bladder cancer.
Netrin-1 and its receptor UNC5B play important roles in angiogenesis, embryonic development, cancer and inflammation. However, their expression patttern and biological roles in bladder cancer have not been well characterized. The present study aims to investigating the clinical significance of PKC α, netrin-1 and UNC5B in bladder cancer as well as their association with malignant biological behavior of cancer cells. Netrin-1 and UNC5B expression was examined in 120 bladder cancer specimens using immunohistochemistry and in 40 fresh cancer tissues by western blot. Immunofluorescence was performed in cancer cell lines. PKC α agonist PMA and PKC siRNA was employed in bladder cancer cells. CCK-8, wound healing assays and flow cytometry analysis were used to examine cell proliferation, migration and cell cycle, respectively. Netrin-1 expression was positively correlated with histological grade, T stage, metastasis and poor prognosis in bladder cancer tissues. Immunofluorescence showed elevated netrin-1 and decreased UNC5B expression in bladder cancer cells compared with normal bladder cell line. Furthermore, cell proliferation, migration and cell cycle progression were promoted with PMA treatment while inhibited by calphostin C. In addition, PMA treatment could induce while calphostin C reduce netrin-1 expression in bladder cancer cells. The present study identified netrin-1/UNC5B, which could be regulated by PKC signaling, was important mediators of bladder cancer progression.


Performance monitoring of self and other in a turn-taking piano duet: A dual-EEG study.
During joint action tasks, expectations for outcomes of one's own and other's actions are collectively monitored. Recent evidence suggests that trait empathy levels may also influence performance monitoring processes. The present study investigated how outcome expectation and empathy interact during a turn-taking piano duet task, using simultaneous electroencephalography (EEG) recording. During the performances, one note in each player's part was altered in pitch to elicit the feedback-related negativity (FRN) and subsequent P3 complex. Pianists memorized and performed pieces containing either a similar or dissimilar sequence as their partner. For additional blocks, pianists also played both sequence types with an audio-only computer partner. The FRN and P3a were larger in response to self than other, while P3b occurred only in response to self, suggesting greater online monitoring of self- compared to other-produced actions during turn-taking joint action. P3a was larger when pianists played a similar sequence as their partner. Finally, as trait empathy level increased, FRN in response to self decreased. This association was absent for FRN in response to other. This may reflect that highly-empathetic musicians during joint performance could use a strategy to suppress exclusive focus on self-monitoring.


Isolation and characterization of spinach photosystem II membrane-associated catalase and polyphenol oxidase.
Photosystem II (PSII) membranes exhibit catalase and polyphenol oxidase (PPO) activities. Mild heat treatment of PSII membranes for 90 min at 30 degrees C releases most of these enzyme activities into the supernatant, accompanied by a 7-fold activation of PPO. In contrast, mild heat treatment of thylakoid membranes does not release significant amounts of either activity, indicating that both enzymes are bound to the luminal surface of the thylakoid membrane. The heat-released PSII membrane-associated catalase and PPO have been purified and characterized. Catalase activity was correlated with a 63 kDa polypeptide which was purified by batch adsorption to anion-exchange beads followed by gel filtration. The PSII membrane-associated catalase is unstable in solution, probably due to irreversible aggregation. The enzyme was characterized in terms of molecular and subunit size, amino-acid composition, UV-visible absorption, heme content, pH optimum, inhibitor sensitivity, and K(m) value for H2O2. Its properties indicate that the PSII membrane-associated catalase is a luminal thylakoid membrane-bound heme enzyme that has not been identified previously. The residual catalase activity of PSII membranes after mild heat treatment is irreversibly inhibited with 3-amino-1,2,4-triazole, a specific inhibitor of heme catalases, without inhibition of O2-evolution activity. This result indicates that little, if any, of the catalase activity from PSII membranes in the dark is catalyzed by the O2-evolving center of PSII. PPO activity was correlated with a 48 kDa polypeptide. However, the 48 kDa polypeptide and another heat-released polypeptide of 72 kDa have the same N-terminal sequence, which is also identical to that of a known 64 kDa protein [Hind, G., Marshak, D. R., & Coughlan, S. J. (1995) Biochemistry 34, 8157-8164]. During heat treatment of PSII membranes and further manipulations it was found that the 72 kDa polypeptide was largely converted into the 48 kDa polypeptide. Thus, the 72 kDa polypeptide appears to be a latent precursor of the active 48 kDa PPO. The PSII membrane-associated PPO was purified by anion-exchange chromatography and was characterized in terms of substrate specificity, pH optimum, inhibitor sensitivity and native molecular weight. The heat-released PPO appears to be identical to the enzyme previously isolated from spinach thylakoid membranes [Golbeck, J. H., & Cammarata, K. V. (1981) Plant Physiol. 67, 977-984].


Safety of intra-aortic balloon pump using glycoprotein IIb/IIIa antagonists.
Anticoagulation with heparin is recommended with intra-aortic balloon pump (IABP) to prevent thrombosis and embolization. However, anticoagulation increases the risk of bleeding, particularly in combination with glycoprotein (GP) IIb/IIIa antagonists. We investigated the safety of using GP IIb/IIIa antagonists without heparin after IABP insertion in patients who underwent primary percutaneous coronary intervention (PCI). Consecutive patients with acute myocardial infarction (AMI), who underwent primary PCI and were treated with GP IIb/IIIa antagonists without concomitant heparin, and in whom IABP was inserted, were followed during hospitalization for thrombotic and hemorrhagic complications. Ninety-seven patients were included in this analysis. Glycoprotein IIb/IIIa antagonist treatment duration was 12-24 h in 89% of patients, and IABP duration was up to 48 h in 97% of patients. Three patients (3.1%) developed vascular complications: 1 had a major limb ischemia (long IABP treatment), 1 had a minor limb ischemia, and 1 had a cerebrovascular event (after prolonged resuscitation). All patients were already on heparin at the time of the thrombotic events. The rates of major and minor bleeding complications were 9% and 15.5%, respectively. The rate of thrombotic complications is relatively low in post-primary PCI patients with IABP treated with GP IIb/IIIa antagonists without concomitant heparin therapy. Such an approach may reduce the risk of hemorrhagic complications, with low risk of thrombotic complications.


The total position-spread tensor: spin partition.
The Total Position Spread (TPS) tensor, defined as the second moment cumulant of the position operator, is a key quantity to describe the mobility of electrons in a molecule or an extended system. In the present investigation, the partition of the TPS tensor according to spin variables is derived and discussed. It is shown that, while the spin-summed TPS gives information on charge mobility, the spin-partitioned TPS tensor becomes a powerful tool that provides information about spin fluctuations. The case of the hydrogen molecule is treated, both analytically, by using a 1s Slater-type orbital, and numerically, at Full Configuration Interaction (FCI) level with a V6Z basis set. It is found that, for very large inter-nuclear distances, the partitioned tensor growths quadratically with the distance in some of the low-lying electronic states. This fact is related to the presence of entanglement in the wave function. Non-dimerized open chains described by a model Hubbard Hamiltonian and linear hydrogen chains Hn (n ≥ 2), composed of equally spaced atoms, are also studied at FCI level. The hydrogen systems show the presence of marked maxima for the spin-summed TPS (corresponding to a high charge mobility) when the inter-nuclear distance is about 2 bohrs. This fact can be associated to the presence of a Mott transition occurring in this region. The spin-partitioned TPS tensor, on the other hand, has a quadratical growth at long distances, a fact that corresponds to the high spin mobility in a magnetic system.


Utilization of Boxes for Pesticide Storage in Sri Lanka.
Pesticide self-poisoning is now considered one of the two most common methods of suicide worldwide. Encouraging safe storage of pesticides is one particular approach aimed at reducing pesticide self-poisoning. CropLife Sri Lanka (the local association of pesticide manufacturers), with the aid of the Department of Agriculture, distributed lockable in-house pesticide storage boxes free of charge to a farming community in a rural district of Sri Lanka. Padlocks were not provided with the boxes. These storage boxes were distributed to the farmers without prior education. The authors carried out a cross-sectional follow-up survey to assess the usage of boxes at 7 months after distribution. In an inspection of a sample of 239 box recipients' households, 142 households stored pesticides in the provided box at the time of survey. Among them, only 42 (42/142, 29.65%) households had locked the box; the remaining households (100/142, 70.4%) had not locked the box. A simple hand over of in-house pesticide storage boxes without awareness/education results in poor use of boxes. Additionally, providing in-house storage boxes may encourage farmers to store pesticides in and around houses and, if they are not locked, may lead to unplanned adverse effects.


Ba-induced phase segregation and band gap reduction in mixed-halide inorganic perovskite solar cells.
All-inorganic metal halide perovskites are showing promising development towards efficient long-term stable materials and solar cells. Element doping, especially on the lead site, has been proved to be a useful strategy to obtain the desired film quality and material phase for high efficient and stable inorganic perovskite solar cells. Here we demonstrate a function by adding barium in CsPbI2Br. We find that barium is not incorporated into the perovskite lattice but induces phase segregation, resulting in a change in the iodide/bromide ratio compared with the precursor stoichiometry and consequently a reduction in the band gap energy of the perovskite phase. The device with 20 mol% barium shows a high power conversion efficiency of 14.0% and a great suppression of non-radiative recombination within the inorganic perovskite, yielding a high open-circuit voltage of 1.33 V and an external quantum efficiency of electroluminescence of 10-4.


Overcoming the evening/weekend effects on time delays and outcomes of endovascular stroke therapy: the Calgary Stroke Program experience.
Stentrievers have resulted in faster recanalization times in patients with acute ischemic stroke. Nonetheless, when strokes occur during evenings and weekends, delays are introduced in achieving this goal. We assessed the feasibility of achieving fast and successful endovascular reperfusion in patients with stroke treated during evenings and weekends and whether this has an impact on the outcome. A retrospective review was performed of a longitudinal database of patients with acute anterior ischemic stroke treated with endovascular therapy in a comprehensive stroke center between January 2011 and December 2012. The imaging to reperfusion time was defined as the time from completion of the unenhanced CT scan to the time of angiographic successful reperfusion (TICI 2b-3). This time interval was compared between patients treated during working hours (Monday to Friday 07:00-18:00 h) and those treated in the evening outside these hours and at weekends. The 24-h NIH Stroke Scale score and 90-day favorable outcome score (modified Rankin scale ≤2) were compared between the two groups. In a cohort of 110 patients, 56 (50.9%) were treated on evenings and weekends. The median imaging to reperfusion time in these patients was 111 min compared with 90 min during working hours (p=0.019). The proportion of patients with successful reperfusion (TICI 2b or 3) during the evenings and weekends was 82.1% compared with 76.7% during working hours (p=0.4). The proportion of patients with a 90-day favorable outcome was not significantly different in the two groups (64.3% in those treated during evenings and weekends vs 52.1% in working hours, p=0.2). Some delays were encountered during evenings and weekend hours. Despite that, it was feasible to achieve a relatively short imaging to reperfusion times during these hours, in comparison to existing literature. A target universal time metric is needed to assess the timeliness of endovascular therapy in stroke centers.


Patienthood and participation in the digital era.
The 'digital era' of informatics and knowledge integration has changed the roles and experiences of patients, research participants and health consumers. No longer figured (merely) as passive recipients of healthcare services or as beneficiaries of top-down biomedical information, individuals are increasingly seen as active contributors in healthcare and research. They are positioned into multiple roles that are experienced simultaneously by those who access and co-produce digital content that can easily be transformed into data. This is contextualised by 'big data' technologies that have altered biomedicine, enabling collation and analysis of myriad data from digitised records to personal mobile data. Social media facilitate new formations of communities and knowledge enacted online, while novel kinds of commercial value emerge from digital networks that enable health data commodification. In this paper, we draw from exemplary digital era shifts towards participatory medicine to cast light on the rapprochements between patienthood, participation and consumption, and we explore how these rapprochements are mediated by, and materialise through, the use of participatory digital technologies and big data. We argue that there is a need to use new conceptual tools that account for the multiple roles and experiences of patient-participant-consumers that co-emerge through digital technologies. We must also ethically re-assess the rights and responsibilities of individuals in the digital era, and the implications of digital era changes for the future of biomedicine and healthcare.


Guideline for the classification of the acute emetogenic potential of antineoplastic medication in pediatric cancer patients.
This guideline provides clinicians caring for children with an approach to assessing the acute emetogenic potential of antineoplastic therapies. It was developed by an international, inter-professional panel of clinicians and researchers using AGREE and CAN-ADAPTE methods. The emetogenicity of antineoplastic agents was evaluated and ranked as high, moderate, low, or minimal. The emetogenicity of multiple-agent and multiple-day antineoplastic therapy was also classified. Gaps in the evidence used to underpin the guideline recommendations were identified. The contribution of this guideline to the prevention of antineoplastic-induced nausea and vomiting in individual children about to receive antineoplastic therapy requires prospective evaluation.


Defective recognition and naming of famous people from voice in patients with unilateral temporal lobe tumours.
Twenty-nine patients who underwent surgery for a temporal glioma, either in the left (16 patients) or right (13 patients) hemisphere, were administered standardized tests of unknown voice discrimination (UVD) and of famous voice recognition (VO-REC), which included tasks of familiarity evaluation, semantic identification and naming of famous voices. The UVD consisted of twenty stimuli, in which two audio files were consecutively presented; the subject was requested to judge whether the voices belonged to the same or different persons. In the VO-REC, patients were requested to recognize the voices of 40 very well known people; these voices were intermingled with the voices of 20 unknown people for a familiarity check, followed by identification and naming of persons recognized as familiar. We aimed at verifying the effect of laterality and intra-temporal site of lesion on familiarity assessment, false alarms, identification and naming of familiar people. As for the effect of lesion side, our results showed that patients with right temporal gliomas were significantly more impaired in voices discrimination and produced more false alarms than patients with a left glioma, who, in turn, were significantly more impaired in name retrieval than patients with a right temporal glioma. The high number of false alarms in patients with a right temporal glioma suggests that familiarity judgment was impaired. Regarding the neuroanatomical correlates of these different patterns of impairment, MRI data suggested that: (a) UVD disorders are due to lesions involving the whole right anterior temporal lobe and extending to lateral portions of the temporal and frontal lobes; (b) familiarity judgments (testified by an increased number of false alarms) are impaired in lesions restricted to the right anterior temporal lobe; (c) name retrieval deficits are found only in patients with left temporal lesions. UVD disorders were interpreted, at least in part, as due to an impairment of executive functions, resulting from a disconnection of the right temporal lobe from the frontal lobe control. A partly unexpected finding was that some patients with a right temporal tumour had a normal performance in famous voice recognition and identification, in spite of having severe voice discrimination disturbances. These unexpected results, in agreement with previous observation made in the visual (face) modality, are inconsistent with strictly hierarchical models of voice processing.


Dissuasion in women surgical trainees pursuing cardiothoracic surgery.
The reasons for persistent gender disparity in cardiothoracic surgery (CTS) are multifaceted. The objective of this paper is to understand if and why women surgical trainees are dissuaded from pursuing CTS. A survey was sent to self-identified women participating in Women in Thoracic Surgery speed mentoring. Statistical analysis was performed to determine dissuasion rates. Open-ended responses describing examples of dissuasion were characterized and categorized. Of all participants, 76 % (163/215) reported dissuasion from a CTS career. Third- and fourth-year medical students experienced the highest rate by training (81 %, 48/59) and those interested in Congenital CTS experienced the highest rate based on subspecialty interest (94 %, 17/18). The most cited dissuasion examples included work/life balance, lifestyle with children, and gender. Most women surveyed had been dissuaded from pursuing a career in CTS. Examples of dissuasion provided are heavily associated with traditional gender roles, supporting the presence of continued gender bias in CTS.


Environmental sampling coupled with real-time PCR and genotyping to investigate the source of a Q fever outbreak in a work setting.
A Q fever outbreak was declared in February 2016 in a company that manufactures hoists and chains and therefore with no apparent occupational-associated risk. Coxiella burnetii infection was diagnosed by serology in eight of the 29 workers of the company; seven of them had fever or flu-like signs and five had pneumonia, one requiring hospitalisation. A further case of C. burnetii pneumonia was diagnosed in a local resident. Real-time PCR (RTi-PCR) showed a widespread distribution of C. burnetii DNA in dust samples collected from the plant facilities, thus confirming the exposure of workers to the infection inside the factory. Epidemiological investigations identified a goat flock with high C. burnetii seroprevalence and active shedding which was owned and managed by one of the workers of the company as possible source of infection. Genotyping by multispacer sequence typing (MST) and a 10-loci single-nucleotide polymorphism (SNP) discrimination using RTi-PCR identified the same genotype (MST18 and SNP type 8, respectively) in the farm and the factory. These results confirmed the link between the goat farm and the outbreak and allowed the identification of the source of infection. The circumstances and possible vehicles for the bacteria entering the factory are discussed.


Purinergic activation of Ca2+-permeable TRPV4 channels is essential for mechano-sensitivity in the aldosterone-sensitive distal nephron.
Mechanical forces are known to induce increases of [Ca(2+)](i) in the aldosterone-sensitive distal nephron (ASDN) cells to regulate epithelial transport. At the same time, mechanical stress stimulates ATP release from ASDN cells. In this study, we combined ratiometric Fura-2 based monitoring of [Ca(2+)](i) in freshly isolated split-opened ASDN with targeted deletion of P2Y2 and TRPV4 in mice to probe a role for purinergic signaling in mediating mechano-sensitive responses in ASDN cells. ATP application causes a reproducible transient Ca(2+) peak followed by a sustained plateau. Individual cells of the cortical collecting duct (CCD) and the connecting tubule (CNT) respond to purinergic stimulation with comparative elevations of [Ca(2+)](i). Furthermore, ATP-induced Ca(2+)-responses are nearly identical in both principal (AQP2-positive) and intercalated (AQP2-negative) cells as was confirmed using immunohistochemistry in split-opened ASDN. UTP application produces elevations of [Ca(2+)](i) similar to that observed with ATP suggesting a dominant role of P2Y2-like receptors in generation of [Ca(2+)](i) response. Indeed, genetic deletion of P2Y2 receptors decreases the magnitude of ATP-induced and UTP-induced Ca(2+) responses by more than 70% and 90%, respectively. Both intracellular and extracellular sources of Ca(2+) appeared to contribute to the generation of ATP-induced Ca(2+) response in ASDN cells. Importantly, flow- and hypotonic-induced Ca(2+) elevations are markedly blunted in P2Y2 -/- mice. We further demonstrated that activation of mechano-sensitive TRPV4 channel plays a major role in the sustained [Ca(2+)](i) elevation during purinergic stimulation. Consistent with this, ATP-induced Ca(2+) plateau are dramatically attenuated in TRV4 -/- mice. Inhibition of TRPC channels with 10 µM BTP2 also decreased ATP-induced Ca(2+) plateau whilst to a lower degree than that observed with TRPV4 inhibition/genetic deletion. We conclude that stimulation of purinergic signaling by mechanical stimuli leads to activation of TRPV4 and, to a lesser extent, TRPCs channels, and this is an important component of mechano-sensitive response of the ASDN.


Refuge-seeking impairments mirror metabolic recovery following fisheries-related stressors in the Spanish flag snapper (Lutjanus carponotatus) on the Great Barrier Reef.
Fisheries and marine park management strategies for large predatory reef fish can mean that a large proportion of captured fish are released. Despite being released, these fish may experience high mortality while they traverse the water column to locate suitable refuge to avoid predators, all the while recovering from the stress of capture. The predatory reef fish Spanish flag snapper (Lutjanus carponotatus) is frequently released because of a minimum-size or bag limit or by fishers targeting more desirable species. Using L. carponotatus as a model, we tested whether simulated fishing stress (exercise and air exposure) resulted in impairments in reflexes (e.g., response to stimuli) and the ability to identify and use refuge in a laboratory arena and whether any impairments were associated with blood physiology or metabolic recovery. Control fish were consistently responsive to reflex tests and rapidly located and entered refugia in the arena within seconds. Conversely, treatment fish (exhausted and air exposed) were unresponsive to stimuli, took longer to search for refugia, and were more apprehensive to enter the refuge once it was located. Consequently, treatment fish took more than 70 times longer than control fish to enter the coral refuge (26.12 vs. 0.36 min, respectively). The finding that fish exposed to stress were hesitant to use refugia suggests that there was likely cognitive, visual, and/or physiological impairment. Blood lactate, glucose, and hematocrit measures were perturbed at 15 and 30 min after the stressor, relative to controls. However, measurements of oxygen consumption rate revealed that about 50% of metabolic recovery occurred within 30 min after the stressor, coinciding with apparent cognitive/visual/physiological recovery. Recovering the treatment fish in aerated, flow-through chambers for 30 min before introduction to the behavioral arena restored reflexes, and "recovered" fish behaved more similarly to controls. Therefore, we suggest that temporarily holding coral reef fish that have undergone an exhaustive fishing interaction and an air exposure episode should enable significant recovery of cognitive and metabolic attributes that would enable fish to more rapidly locate and utilize refugia to avoid postrelease predation. However, after nonexhaustive fishing interactions (i.e., minimal reflex impairment), it is likely that immediate release would be most beneficial.


The value of laparoscopy in the diagnosis of acute pelvic inflammatory disease.
A total of 40 patients with acute pelvic inflammatory disease (acute PID) were examined over a period of 7 months to determine the diagnostic value of laparoscopic examination in these cases. The most important findings were: the clinical diagnosis of acute PID was confirmed by laparoscopy in 55% of patients; laparoscopy was especially of value in differentiating potentially lethal conditions such as ectopic pregnancy and acute appendicitis from acute PID in 15% of patients; laparoscopically obtained microbiological specimens provide a more accurate means of determining the microbiological aetiology of acute PID than vaginally obtained specimens.


Role of the Multidrug Resistance Efflux Pump MexCD-OprJ in the Pseudomonas aeruginosa Quorum Sensing Response.
Multidrug efflux pumps constitute a category of antibiotic resistance determinants that are a part of the core bacterial genomes. Given their conservation, it is conceivable that they present functions beyond the extrusion of antibiotics currently used for therapy. Pseudomonas aeruginosa stands as a relevant respiratory pathogen, with a high prevalence at hospitals and in cystic fibrosis patients. Part of its success relies on its low susceptibility to antibiotics and on the production of virulence factors, whose expression is regulated in several cases by quorum sensing (QS). We found that overexpression of the MexCD-OprJ multidrug efflux pump shuts down the P. aeruginosa QS response. Our results support that MexCD-OprJ extrudes kynurenine, a precursor of the alkyl-quinolone signal (AQS) molecules. Anthranilate and octanoate, also AQS precursors, do not seem to be extruded by MexCD-OprJ. Kynurenine extrusion is not sufficient to reduce the QS response in a mutant overexpressing this efflux pump. Impaired QS response is mainly due to the extrusion of 4-hydroxy-2-heptylquinoline (HHQ), the precursor of the Pseudomonas Quinolone Signal (PQS), leading to low PQS intracellular levels and reduced production of QS signal molecules. As the consequence, the expression of QS-regulated genes is impaired and the production of QS-regulated virulence factors strongly decreases in a MexCD-OprN P. aeruginosa overexpressing mutant. Previous work showed that MexEF-OprJ, another P. aeruginosa efflux pump, is also able of extruding kynurenine and HHQ. However, opposite to our findings, the QS defect in a MexEF-OprN overproducer is due to kynurenine extrusion. These results indicate that, although efflux pumps can share some substrates, the affinity for each of them can be different. Although the QS response is triggered by population density, information on additional elements able of modulating such response is still scarce. This is particularly important in the case of P. aeruginosa lung chronic infections, a situation in which QS-defective mutants are accumulated. If MexCD-OprJ overexpression alleviates the cost associated to triggering the QS response when un-needed, it could be possible that MexCD-OprJ antibiotic resistant overproducer strains might be selected even in the absence of antibiotic selective pressure, acting as antibiotic resistant cheaters in heterogeneous P. aeruginosa populations.


Incidence of Atrophic Lesions in Stargardt Disease in the Progression of Atrophy Secondary to Stargardt Disease (ProgStar) Study: Report No. 5.
Outcome measures that are sensitive to disease progression are needed as clinical end points for future treatment trials in Stargardt disease. To examine the incidence of atrophic lesions of the retinal pigment epithelium in patients with Stargardt disease as determined by fundus autofluorescence imaging. In this retrospective multicenter cohort study, 217 patients 6 years and older at baseline at tertiary referral centers in Europe, the United States, and the United Kingdom who were harboring disease-causing variants in the adenosine triphosphate (ATP)-binding cassette subfamily A member 4 (ABCA4) gene and who met the following criteria were enrolled: (1) at least 1 well-demarcated area of atrophy with a minimum diameter of 300 µm, with the total area of all atrophic lesions being less than or equal to 12 mm2 in at least 1 eye at the most recent visit, and (2) fundus autofluorescence images for at least 2 visits with a minimum of 6 months between at least 2 visits. Data were collected between August 22, 2013, and December 12, 2014. Data analysis was performed from March 15, 2015, through January 31, 2017. Images were evaluated by staff at a central reading center. Areas of definitely decreased autofluorescence (DDAF) and questionably decreased autofluorescence (QDAF) were outlined and quantified. Lesion-free survival rates were estimated using Kaplan-Meier survival curves. Incidence of atrophic lesions as determined by fundus autofluorescence. The 217 patients (mean [SD] age, 21.8 [13.3] years; 127 female [57.5%]; 148 white [68.2%]) contributed 390 eyes for which the mean (SD) follow-up time was 3.9 (1.6) years (range, 0.7-12.1 years). Among eyes without DDAF at first visit, the median time to develop a DDAF lesion was 4.9 years (95% CI, 4.3-5.6 years). Among eyes without QDAF, the median time to develop a QDAF lesion was 6.3 years (95% CI, 5.6-9.7 years). Eyes with a lesion of DDAF at the first visit were less likely to develop a QDAF lesion compared with eyes without a lesion of DDAF (hazard ratio, 0.19; 95% CI, 0.05-0.70; P = .01). An estimated 50% of the eyes without DDAF at first visit will develop the lesion in less than 5 years, suggesting that incidence of DDAF could serve as an outcome measure for treatment trials.


Influence of various airborne-particle abrasion conditions on bonding between zirconia ceramics and an indirect composite resin material.
Indirect composite resins (ICRs) have been suggested as veneering materials for implant-supported zirconia-based fixed dental prostheses; however, obtaining a durable bond between the zirconia ceramic and the ICR is a challenge. The purpose of this in vitro study was to evaluate the influence of airborne-particle abrasion conditions on the bond strength between 2 kinds of zirconia (yttria-stabilized tetragonal zirconia polycrystal [Y-TZP] and ceria-stabilized tetragonal zirconia/alumina nanocomposite [Ce-TZP/A]) and an ICR. Zirconia disks were prepared by using computer-aided design and computer-aided manufacturing (CAD-CAM) systems. Specimens were airborne-particle abraded with different particle sizes (25, 50, 90, 125 μm) and jet pressures (0.1, 0.2, 0.3, 0.4 MPa). The control group (CO) was not subjected to airborne-particle abrasion. The surface roughness (Ra) of the specimens was measured. Subsequently, the specimens were treated with a primer and bonded with a light-activated composite resin, and the shear bond strength (SBS) was tested. The obtained data were analyzed by using multivariate analysis of variance, the Spearman rank-order correlation, and the Mann-Whitney U test (α=.05). After the SBS test, the interface failure modes were observed by scanning electron microscopy, and X-ray photoelectron spectroscopy (XPS) was used to analyze the chemical changes of the zirconia surface. The Ra values increased significantly (P<.05) after airborne-particle abrasion with a positive correlation with both particle size and jet pressure. The airborne-particle abraded specimens exhibited significantly higher bond strength after thermocycling (P<.05) than the CO. Nevertheless, the bond strength was not significantly different among different airborne-particle abrasion treatments (P>.05). Additionally, Y-TZP had higher mean bond strength values than Ce-TZP/A. The XPS results revealed that after airborne-particle abrasion, the alumina particles mechanically adhered to the zirconia surface. Within the limitations of this in vitro study, airborne-particle abrasion improved the bond strength between zirconia and ICR; however, particle size or jet pressure were not influencing factors.


Characterization of the stable maintenance properties of the par region of broad-host-range plasmid RK2.
A 3.2-kb fragment encoding five genes, parCBA/DE, in two divergently transcribed operons promotes stable maintenance of the replicon of the broad-host-range plasmid RK2 in a vector-independent manner in Escherichia coli. The parDE operon has been shown to contribute to stabilization through the postsegregational killing of plasmid-free daughter cells, while the parCBA operon encodes a resolvase, ParA, that mediates the resolution of plasmid multimers through site-specific recombination. To date, evidence indicates that multimer resolution alone does not play a significant role in RK2 stable maintenance by the parCBA operon in E. coli. It has been proposed, instead, that the parCBA region encodes an additional stability mechanism, a partition system, that ensures that each daughter cell receives a plasmid copy at cell division. However, studies carried out to date have not directly determined the plasmid stabilization activity of the parCBA operon alone. An assessment was made of the relative contributions of postsegregational killing (parDE) and the putative partitioning system (parCBA) to the stabilization of mini-RK2 replicons in E. coli. Mini-RK2 replicons carrying either the entire 3.2-kb (parCBA/DE) fragment or the 2.3-kb parCBA region alone were found to be stably maintained in two E. coli strains tested. The stabilization found is not due to resolution of multimers. The stabilizing effectiveness of parCBA was substantially reduced when the plasmid copy number was lowered, as in the case of E. coli cells carrying a temperature-sensitive mini-RK2 replicon grown at a nonpermissive temperature. The presence of the entire 3.2-kb region effectively stabilized the replicon, however, under both low- and high-copy-number-conditions. In those instances of decreased plasmid copy number, the postsegregational killing activity, encoded by parDE, either as part of the 3.2-kb fragment or alone played the major role in the stabilization of mini-RK2 replicons within the growing bacterial population. Our findings indicate that the parCBA operon functions to stabilize by a mechanism other than cell killing and resolution of plasmid multimers, while the parDE operon functions solely to stabilize plasmids by cell killing. The relative contribution of each system to stabilization depends on plasmid copy number and the particular E. coli host.


Molecular cloning of an oncogene from a human hepatocellular carcinoma.
A transforming DNA, named lca (for liver cancer), was obtained from a primary human hepatocellular carcinoma (HCC) in transformation assays using NIH 3T3 cells and a calcium phosphate coprecipitation method. High molecular weight DNA obtained from the HCC tissue was employed for this purpose. This transforming DNA had a linkage to the Alu sequence and was cloned in lambda phage for further studies. Restriction enzyme analyses showed that the minimal size of the lca transforming DNA is about 10 kilobase pairs and that its cleavage profiles are different from those of any one of the previously reported human transforming genes or retroviral oncogenes. No cross-hybridization was observed between these genes and the lca DNA. Southern blot analyses of DNAs from flow-sorted human chromosomes and human-mouse somatic cell hybrids indicated that the lca DNA is located on human chromosome 2. An independently obtained transforming DNA from another HCC exhibited identical restriction enzyme cleavage profiles. Thus, lca DNA is likely to represent a commonly encountered transforming DNA in HCC.


Exercise testing in the evaluation of patients at high risk for complications from lung resection.
Exercise testing was performed on 37 patients with resectable lung lesions who were deemed inoperable because of any of the following risk factors: (1) FEV1 less than or equal to 40 percent of predicted; (2) radionuclide calculated postlobectomy FEV1 less than or equal to 33 percent of predicted; or (3) arterial PCO2 greater than or equal to 45 mm Hg. The patients who reached a peak level of oxygen consumption during exercise (VO2Peak) of greater than or equal to 15 ml/kg/min were offered surgical treatment. Patients with a VO2Peak of less than 15 ml/kg/min were referred for nonsurgical management and excluded from the study. Eight patients underwent lung resection. Their pulmonary function revealed a severe obstructive lung defect with a group mean predicted FEV1 of 40 +/- 6 percent, an FEV1/FVC ratio of 47 +/- 10, a radionuclide calculated postlobectomy FEV1 of 31 +/- 4 percent, and a mean arterial PCO2 of 44 +/- 6 mm Hg. No relationship was found between each patient's exercise performance and spirometric function. Six of the patients had an uncomplicated postoperative course. Two patients had complications but no patient died as a result of surgery or postoperative complications. All patients were discharged from the hospital within 22 days (mean = 9.8 days). We conclude that exercise testing is a useful complement to conventional cardiopulmonary evaluation used in selecting patients for lung resection.


Empiric Antibacterial Therapy and Community-onset Bacterial Coinfection in Patients Hospitalized With Coronavirus Disease 2019 (COVID-19): A Multi-hospital Cohort Study.
Antibacterials may be initiated out of concern for bacterial coinfection in coronavirus disease 2019 (COVID-19). We determined prevalence and predictors of empiric antibacterial therapy and community-onset bacterial coinfections in hospitalized patients with COVID-19. A randomly sampled cohort of 1705 patients hospitalized with COVID-19 in 38 Michigan hospitals between 3/13/2020 and 6/18/2020. Data were collected on early (within 2 days of hospitalization) empiric antibacterial therapy and community-onset bacterial coinfections (positive microbiologic test ≤3 days). Poisson generalized estimating equation models were used to assess predictors. Of 1705 patients with COVID-19, 56.6% were prescribed early empiric antibacterial therapy; 3.5% (59/1705) had a confirmed community-onset bacterial infection. Across hospitals, early empiric antibacterial use varied from 27% to 84%. Patients were more likely to receive early empiric antibacterial therapy if they were older (adjusted rate ratio [ARR]: 1.04 [1.00-1.08] per 10 years); had a lower body mass index (ARR: 0.99 [0.99-1.00] per kg/m2), more severe illness (eg, severe sepsis; ARR: 1.16 [1.07-1.27]), a lobar infiltrate (ARR: 1.21 [1.04-1.42]); or were admitted to a for-profit hospital (ARR: 1.30 [1.15-1.47]). Over time, COVID-19 test turnaround time (returned ≤1 day in March [54.2%, 461/850] vs April [85.2%, 628/737], P < .001) and empiric antibacterial use (ARR: 0.71 [0.63-0.81] April vs March) decreased. The prevalence of confirmed community-onset bacterial coinfections was low. Despite this, half of patients received early empiric antibacterial therapy. Antibacterial use varied widely by hospital. Reducing COVID-19 test turnaround time and supporting stewardship could improve antibacterial use.


Treating posttraumatic stress disorder and alcohol use disorder comorbidity: Current pharmacological therapies and the future of MDMA-integrated psychotherapy.
Posttraumatic stress disorder (PTSD) and alcohol use disorder (AUD) frequently co-occur in patients who have experienced trauma. This comorbidity leads to a vicious cycle where PTSD symptoms beget heavy drinking and vice versa. There are no FDA-approved medications to treat PTSD-AUD; therefore, individuals suffering from this comorbidity are treated with medication approved to treat the disorders separately or with off-label pharmacological interventions. However, these medications are limited in their efficacy for treating PTSD-AUD comorbidity. Emerging research on the nonclassical psychedelic drug 3,4-methylenedioxymethamphetamine (MDMA) suggests that it may be an effective drug used in conjunction with psychotherapy. The following reviews the current research for clinical pharmacotherapies, as well as MDMA-integrative psychotherapy as they pertain to PTSD and AUD in isolation and co-occurrence. Future directions for the role of psychedelic-integrative therapy for the treatment of this comorbidity are discussed.


Comparing stepping-in-place and gait ability in adults with and without hemiplegia.
To determine and compare select temporal-distance measures of stepping-in-place with gait ability in 2 age-matched groups. Repeated measures, matched research design. Gait laboratory and hospital outpatient unit. Convenience sample recruited from within the community and the outpatient unit of a local rehabilitation hospital included 30 healthy adults (age range, 58.1 +/- 10.8yr) and 30 age-matched adults with hemiplegia (age range, 58.6 +/- 10.3yr), secondary to a cerebrovascular accident. Subjects were videotaped in the sagittal plane performing stepping-in-place and while walking. Select temporal-distance measures obtained by manual calculations from the video recordings were determined for 3 20-second trials of each activity. Single limb support duration (SLSD) of the lower extremities (LEs) and step frequency during stepping-in-place and during gait. A significant difference was found between the step frequency of each activity for the adults with hemiplegia (p <.05), but not for the healthy adults. A significant difference was also found between SLSD of the same LE across activities for each group (p <.05). SLSD of each LE during each individual activity, stepping-in-place, or gait, was not significantly different for the healthy adults, indicating LE symmetry; but it was significantly different for the adults with hemiplegia (p <.05), indicating LE asymmetry. Stepping-in-place incorporates reciprocal, rhythmic LE movement patterns similar to gait. And, although SLSD of the LEs was different between the activities in both groups, each group showed similar LE movement patterns during each individual activity. In addition, step frequency was consistent between the activities for the healthy adults. These results seem to indicate that the reciprocal, rhythmic LE movement patterns, which are invoked during gait, may also be invoked during stepping-in-place. However, further research is needed to enhance the data related to stepping-in-place and gait ability in clinical populations.


Aetiology of sympathetic ophthalmitis.
The aetiology of sympathetic ophthalmitis is still unknown. Recent investigations on patients and experimental studies on allergic uveitis in guinea-pigs suggest that sympathetic ophthalmitis may be due to delayed hypersensitivity to one of the retinal antigens associated with photoreceptor membranes (called the retinal 's' antigen). It is postulated that a penetrating injury causes a reversal of normal tolerance by introducing an adjuvant effect from bacterial or viral contamination along with the release of the intraocular antigen. The antigen then gains access to the regional lymphatics by way of the penetrating wound. A specific cell-mediated immune response is then initiated followed by the onset of sympathetic ophthalmitis.


Effects of Ni(2+) on aluminum hydroxide scale formation and transformation on a simulated drinking water distribution system.
Observations of aluminum containing sediments/scales formed within the distribution pipes have been reported for several decades. In this study, the effect of Ni(2+) on the formation and transformation processes of aluminum hydroxide sediment in a simulated drinking water distribution system were investigated using X-ray diffraction spectrum (XRD), Fourier transform infrared spectrum (FT-IR), scanning electron microscope (SEM), and thermodynamic calculation methods. It was determined that the existence of Ni(2+) had notable effects on the formation of bayerite. In the system without Ni(2+) addition, there was no X-ray diffraction signal observed after 400 d of aging. The presence of Ni(2+), however, even when present in small amounts (Ni/Al=1:100) the formation of bayerite would occur in as little as 3d at pH 8.5. As the molar ratio of Ni/Al increase from 1:100 to 1:10, the amount of bayerite formed on the pipeline increased further; meanwhile, the specific area of the pipe scale decreased from 160 to 122 m(2)g(-1). In the system with Ni/Al molar ratio at 1:3, the diffraction spectrum strength of bayerite became weaker, and disappeared when Ni/Al molar ratios increased above 1:1. At these highs Ni/Al molar ratios, Ni5Al4O11⋅18H2O was determined to be the major component of the pipe scale. Further study indicated that the presence of Ni(2+) promoted the formation of bayerite and Ni5Al4O11⋅18H2O under basic conditions. At lower pH (6.5) however, the existence of Ni(2+) had little effect on the formation of bayerite and Ni5Al4O11⋅18H2O, rather the adsorption of amorphous Al(OH)3 for Ni(2+) promoted the formation of crystal Ni(OH)2.


Attitudes and beliefs of the French public about schizophrenia and major depression: results from a vignette-based population survey.
In their study 'Mental Health in the General Population: Images and Realities' Jean-Luc Roelandt et al. found a huge divide between the French public's conceptualizations of insanity and depression. The study aims to examine whether such differences can be replicated using modern operationalized diagnostic criteria for schizophrenia and major depressive disorder. In 2012, an online survey was conducted using a representative sample drawn from the adult French population (N = 1600). After presentation of a case-vignette depicting a person with either schizophrenia or major depressive disorder a fully structured interview was carried out. Despite some similarities marked differences between both disorders emerge regarding beliefs and attitudes. While respondents presented with the schizophrenia vignette more frequently defined symptoms as the expression of an illness with a stronger biological component and a less favorable prognosis, demanding psychiatric treatment, respondents presented with the depression vignette considered the occurrence of symptoms more frequently as the consequence of current psychosocial stress, benefitting not only from established but also from alternative treatments. People with schizophrenia were more frequently perceived as unpredictable and dangerous, there was a stronger need to separate one-self from them, they were more frequently met with fear and less frequently reacted to with pro-social feelings, and they also faced more rejection. The French public draws a clear line between schizophrenia and major depressive disorder. This applies equally to beliefs about both disorders and to attitudes towards the persons afflicted. There is a need for interventions trying to reduce existing misconceptions in order to improve the care of patients.


Low serum vitamin D in North Indian multi-drug resistant pulmonary tuberculosis patients: the role of diet and sunlight.
Background: Tuberculosis (TB) and malnutrition are major global health problems, with multidrug-resistant (MDR) TB complicating international efforts. The role of vitamin D in susceptibility to and as an adjunctive treatment for TB is being studied extensively, although no study has included MDR-TB patients in context to dietary profile with vitamin D levels and sunlight exposure.Objective: This study aimed to estimate vitamin D serum levels and examine their association with dietary intake of vitamin D and sun exposure in patients with MDR-TB.Methods: North Indian participants were enrolled in three groups: MDR-TB, drug-susceptible pulmonary TB (DS-PTB), and healthy controls. All consenting participants underwent the estimation of macro- and micronutrient intake and sunlight exposure using structured questionnaires. Serum biochemistry, including 25-hydroxyvitamin D and calcium levels, was measured, and the correlation between variables was determined.Results: 747 participants were enrolled. Significant differences among the three groups were found in mean serum 25-hydroxyvitamin D levels, body mass index, macronutrient intake, dietary vitamin D and calcium content, and sun exposure index (SEI). All except sun exposure (SEI was highest in DS-PTB patients) were found to follow the trend: MDR-TB < DS-PTB < healthy controls. The mean serum vitamin D levels of all groups were deficient and correlated positively with dietary intake and SEI.Conclusion: In this study's we found significant association of serum vitamin D concentrations, dietary intake and sunlight exposure in MDR-TB, DS-PTB patients and healthy controls. Dietary intake may be more important than sun exposure in determining serum levels. However, the significance of this finding is uncertain. Further studies are required to confirm the association, direction, and potential for vitamin D supplementation to treat or prevent MDR-TB infection.


Polyomavirus and simian virus 40 large T antigens bind to common DNA sequences.
The large T antigens of polyomavirus and simian virus 40 (SV40) recognize and bind to specific, noncoding DNA sequences which are located between the beginning of the early and late transcription units in their respective genomes. Each large T antigen binds to multiple sites within this intergenic DNA stretch. Polyomavirus large T antigen binds to at least two sites within its DNA, and SV40 large T antigen binds to three sites within SV40 DNA. Comparison of the DNA sequences which comprise the binding sites in polyomavirus DNA or those which make up the binding sites in SV40 DNA has led to recognition of a common sequence, -GAGGC-, which is repeated within each large-T-antigen-binding site. We tested the hypothesis that repeats of this pentanucleotide form the recognition-binding site for polyomavirus and SV40 large T antigen. This was accomplished by measuring the binding of each large T antigen to both polyomavirus and SV40 DNA and to synthetic DNA substrates which did or did not contain repeats of the -GAGGC- sequence. Polyomavirus large T antigen bound to specific fragments of SV40 DNA, and SV40 large T antigen bound with specificity to polyomavirus DNA. In each case, the DNA fragments bound by the heterologous large T antigen were the same as those bound by the homologous large T antigen. Moreover, polyomavirus and SV40 large T antigen only bound to synthetic DNA substrates which contained repeats of the pentameric sequence. This synthetic DNA also competed effectively with native polyomavirus or SV40 DNA as a substrate in binding reactions with one or the other large T antigen. These results led us to conclude that repeats of the -GAGGC- sequence form the recognition-binding site for both polyomavirus and SV40 large T antigen.


[Clinical picture and course of hereditary extrapyramidal diseases in children].
The report contains a description of the clinical development of hepato-cerebral dystrophy in 11 children and of deformans muscular dystrophy in 7 children. The authors indicate to expressed visceral disorders in patients with hepato-cerebral dystrophy and to positive results in the treatment by thiol preparations. The paper also contains an observation with an inheritance of deformans muscular dystonia of a dominant type. Due to a clinical polymorphism of hepato-cerebral dystrophy and deformans muscular dystrophy in children a possibility of a wide phenocopy of this pathology should be taken into consideration.


Diethylhexyl phthalate (DEHP) regulates the proliferation and chemosensitivity of esophageal squamous cell carcinoma cells via regulation of PTEN.
As one of the most prevalent and deadly cancers worldwide, esophageal squamous cell carcinoma (ESCC) can be directly exposed to endocrine-disrupting chemical (EDC). As a potential EDC, diethylhexyl phthalate (DEHP) can trigger the development of various cancers, while the potential effect of DEHP on the ESCC progression was not clear. Our present study revealed that DEHP can trigger the proliferation of ESCC cells and decrease the cisplatin (CDDP) and fluorouracil (5-FU) sensitivity. Mechanistical studies indicated that DEHP can decrease the transcription of PTEN, a well-characterized tumor suppressor, in ESCC cells. Over expression of PTEN can reverse DEHP-regulated ESCC cell proliferation and chemosensitivity. Further, DEHP can increase the expression of HES-1, which can bind with the promoter of PTEN to inhibit its transcription. Collectively, DEHP can increase proliferation while decrease chemosensitivity of ESCC cells via regulation of HES-1/PTEN axis. Further, daily expression of DEHP may be a potent risk factor for ESCC development.


Why some stems are red: cauline anthocyanins shield photosystem II against high light stress.
Red-stemmed plants are extremely common, yet the functions of cauline anthocyanins are largely unknown. The possibility that photoabatement by anthocyanins in the periderm reduces the propensity for photoinhibition in cortical chlorenchyma was tested for Cornus stolonifera. Anthocyanins were induced in green stems exposed to full sunlight. PSII quantum yields (capital EF, Cyrillic(PSII)) and photochemical quenching coefficients were depressed less in red than in green stems, both under a light ramp and after prolonged exposures to saturating white light. These differences were primarily attributable to the attenuation of PAR, especially green/yellow light, by anthocyanins. However, the red internodes also had less chlorophyll and higher carotenoid:chlorophyll ratios than the green, and when the anthocyanic periderm was removed, small differences in the capital EF, Cyrillic(PSII) of the underlying chlorenchyma were retained. Thus, light screening by cauline anthocyanins is important, but is only part of a set of protective acclimations to high irradiance. Hourly measurements of capital EF, Cyrillic(PSII) on established trees under natural daylight indicated a possible advantage of red versus green stems under sub-saturating diffuse, but not direct sunlight. To judge the wider applicability of the hypothesis, responses to high light were compared for red and green stems across five further unrelated species. There was a strong, linear, interspecific correlation between photoprotective advantage and anthocyanin concentration differences among red and green internodes. The photoprotective effect appears to be a widespread phenomenon.


Very preterm/very low birthweight infants' attachment: infant and maternal characteristics.
To investigate whether there are differences in attachment security and disorganisation between very preterm or very low birthweight (VP/VLBW) (<32 weeks gestation or <1500 g birthweight) and full-term infants (37-42 weeks gestation) and whether the pathways to disorganised attachment differ between VP/VLBW and full-term infants. The sample with complete longitudinal data consisted of 71 VP/VLBW and 105 full-term children and their mothers matched for twin status, maternal age, income and maternal education. Infant attachment was assessed with the Strange Situation Assessment at 18 months of age. Maternal sensitivity in the VP/VLBW and full-term samples was rated by neonatal nurses and community midwives in the neonatal period, respectively, and mother-infant interaction was observed at 3 months. Infant difficultness was assessed by maternal report at 3 months and infant's developmental status was assessed with the Bayley Scales (BSID-II). Most VP/VLBW (61%) and full-term (72%) children were found to be securely attached. However, more VP/VLBW (32%) than full-term children (17%) had disorganised attachment. Longitudinal path analysis found that maternal sensitivity was predictive of attachment disorganisation in full-term children. In contrast, infant's distressing cry and infant's developmental delay, but not maternal sensitivity, were predictive of disorganised attachment in VP/VLBW children. A third of VP/VLBW children showed disorganised attachment. Underlying neurodevelopmental problems associated with VP/VLBW birth appear to be a common pathway to a range of social relationship problems in this group. Clinicians should be aware that disorganised attachment and relationship problems in VP/VLBW infants are frequent despite sensitive parenting.


Does Traumatic Brain Injury Lead to Criminality? A Whole-Population Retrospective Cohort Study Using Linked Data.
Traumatic brain injury (TBI) may be a risk factor for criminal behaviour however multiple factors potentially confound the association. Record linkage and Cox proportional hazards regression analyses were used to examine the association between hospital-recorded TBI (n = 7,694) and subsequent first criminal conviction in a retrospective cohort matched 1:3 with 22,905 unaffected community controls and full-sibling controls (n = 2,397). Aboriginality, substance abuse, social disadvantage, and mental illness were included in analyses as potential confounders. In multivariable models, relative to general population controls, TBI was associated with any conviction (males: Hazard Ratio (HR) = 1.58 (95% CI 1.46 to 1.72); females: HR = 1.52 (95% CI 1.28 to 1.81)); and similar Hazard Ratios were obtained for the sibling analyses in males (HR = 1.68 (95% CI 1.31-2.18)) and females (HR 1.27 (95% CI 0.71-2.29)). TBI was also associated with violent convictions relative to the general population, (males: HR = 1.65 (95% CI 1.42 to 1.92); females HR = 1.73 (95% CI 1.21 to 2.47)), and in analyses with sibling controls in men (HR = 1.89 (95% CI 1.20-3.00)), but not in women (HR 0.73, 95% CI 0.29-1.81)). The results support a modest causal link between TBI and criminality after comprehensive adjustment for confounding. Reducing the rate of TBI, a major public health imperative, might have benefits in terms of crime reduction.


Working from Home during the COVID-19 Pandemic and Its Effects on Diet, Sedentary Lifestyle, and Stress.
Many companies switched to working from home (WFH) after the COVID-19 pandemic. This paper aimed to examine the changes in dietary behavior, body weight, sedentary lifestyle, and stress in individuals who practice WFH. A cross-sectional, web-based questionnaire was administered between March and May 2021 and included socio-demographic characteristics, anthropometric measurements, WFH arrangement, changes in diet, sedentary lifestyle, and stress status. A total of 328 individuals (260 women, 68 men), aged 31.3 ± 8.3 years with a BMI of 24.9 ± 4.6 kg/m2, participated in the study. The questionnaire revealed that the daily working time increased with WFH. The majority of the individuals (59.1%) gained weight. The average daily sedentary time and the Perceived Stress Scale score increased significantly. The daily sedentary time and Non-Healthy Diet Index scores were higher in individuals who gained weight (p < 0.05). A multinominal regression model revealed that increased body weight was less likely in individuals with underweight and normal BMI classifications. Normal BMI, stable work shifts, and no physical activity were positive predictors for gaining weight. These results suggest that WFH may have significant negative effects on physical and mental status of individuals.


CNS infection with clostridium septicum.
We present an unusual case of Clostridium septicum brain infection in a 72-yr-old woman who had no underlying malignant disease. The infection spread from a localized sit to the CNS causing gas formation. The patient died rapidly.


The epigonal organ and mature pole of the testis in the recreationally fished blue shark (Prionace glauca): histochemico-functional correlates.
The exact role of the immune system in normal spermatogenesis is poorly understood. The attachment, however, of the lymphomyeloid epigonal organ specifically to the testis's mature pole in many shark species is a curious finding. Unlike the histology of the lymphomyeloid tissues of many other elasmobranchs, the epigonal organ leukocytes of wild-caught blue shark (Prionace glauca), besides exhibiting extensive nuclear heterogeneity, contain some of the largest known granules ever seen in vertebrate white blood cells. It was previously shown that the blue shark epigonal organ remains unremarkable and functionally unchanged despite cestode parasites embedded into its surface, suggesting that it might have other functions in addition to microbial defense. We show here that Prionace epigonal leukocytes shed their granule-laden cytoplasm into the cyst resorption zone (RZ) of the testis, i.e. the region separating the spermatogenic tissue from the epigonal organ, as they begin to migrate into the RZ. Using the immunoreactivity of the conserved transcription factor (proliferating cell nuclear antigen) as marker, it is shown that the granule-lacking leukocytes exclusively infiltrated spermatozoal cysts leftover after the wave of wide-spread multinuclear cell death in summer-breeding males in a seasonally dependent manner. By contrast, Prionace caught 2 months later showed fully recovered testes containing numerous completely intact spermatozoal cysts. Conversely, degenerating immature spermatids were gradually phagocytized by their accompanying Sertoli cells, and leukocytes did not infiltrate such cysts. The autoimmune response described here resembles in every aspect the testicular autoimmune response induced experimentally in a teleost fish. These observations suggest functional adaptation of shark leukocytes in response to specific changes in the testicular microenvironment.


Treatment of hemicrania continua: case series and literature review.
Hemicrania Continua (HC) is a primary, disabling headache characterized by a continuous unilateral pain and responsive to indomethacin. There are symptoms common to the trigeminal-autonomic cephalalgias and migraine that complicate the diagnosis. This review aims to describe HC in a case series and review the best available evidence on alternative therapies. A systematic review of medical records and diaries of pain of 1,600 patients treated between January 1992 and January 2011 in a headache outpatient clinic. Ten patients with a possible diagnosis of hemicrania continua were selected; seven were diagnosed with HC according to the II International Classification of Headache Disorders. None of the patients had received the correct diagnosis before being treated at the outpatient clinic and the average time for treatment was 12 years. Prophylactic treatment was effective in 66.6% of cases with amitriptyline, 20% with gabapentin and 10% with topiramate. HC should be considered among the diagnostic hypotheses of patients with continuous headache, with no change in neurological examination and additional tests, regardless the age of onset. The standard treatment with indomethacin (100-150mg.day(-1)) has significant risks associated with both short and long term use and may not be a good choice for continuous use. Recent studies point out possible alternatives: gabapentin, topiramate, cyclooxygenase-2 inhibitors, piroxicam, beta-cyclodextrin, amitriptyline, melatonin. Other drugs were described in different reports as efficient, but most of them were considered inefficient in other HC cases.


Cost-effectiveness of FDG-PET in staging non-small cell lung cancer: the PLUS study.
Currently, up to 50% of the operations in early-stage non-small cell lung cancer (NSCLC) are futile owing to the presence of locally advanced tumour or distant metastases. More accurate pre-operative staging is required in order to reduce the number of futile operations. The cost-effectiveness of fluorine-18 fluorodeoxyglucose positron emission tomography ((18)FDG-PET) added to the conventional diagnostic work-up was studied in the PLUS study. Prior to invasive staging and/or thoracotomy, 188 patients with (suspected) NSCLC were randomly assigned to conventional work-up (CWU) and whole-body PET or to CWU alone. CWU was based on prevailing guidelines. Pre-operative staging was followed by 1 year of follow-up. Outcomes are expressed in the percentage of correctly staged patients and the associated costs. The cost price of PET varied between <euro>736 and <euro>1,588 depending on the (hospital) setting and the procurement of (18)FDG commercially or from on-site production. In the CWU group, 41% of the patients underwent a futile thoracotomy, whereas in the PET group 21% of the thoracotomies were considered futile ( P=0.003). The average costs per patient in the CWU group were <euro>9,573 and in the PET group, <euro>8,284. The major cost driver was the number of hospital days related to recovery from surgery. Sensitivity analysis on the cost and accuracy of PET showed that the results were robust, i.e. in favour of the PET group. The addition of PET to CWU prevented futile surgery in one out of five patients with suspected NSCLC. Despite the additional PET costs, the total costs were lower in the PET group, mainly due to a reduction in the number of futile operations. The additional use of PET in the staging of patients with NSCLC is feasible, safe and cost saving from a clinical and from an economic perspective.


Visible-Light-Induced Transition-Metal-Free Redox-Neutral Carboxylation of Remote Benzylic C(sp3)-H Bonds via 1,5-Hydrogen Atom Transfer.
The direct carboxylation of the benzylic C-H bonds under mild conditions is of great importance and is quite challenging. Herein, we report an approach for the carboxylation of remote benzylic C(sp3)-H bonds by integrating the redox-neutral visible-light photoredox catalysis and the nitrogen-centered 1,5-hydrogen atom transfer. The chemical transformation progresses via consecutive single electron transfer, 1,5-hydrogen atom transfer, formation of benzylic carbanion, and nucleophilic attack on the CO2 steps, thereby enabling access to the desired carboxylation products with moderate to high yields. We also endeavor to recover the CO2 groups generated in situ intramolecularly to achieve carboxylation under a nitrogen atmosphere, resulting in moderate yields of corresponding carboxylation.


A Review of the Relationships among the Key Determinants Affecting the Mental Health Disorders of the People in Greater Mekong Subregion Countries.
ASEAN integration aims to transform the GMS into a single market with free flows of products, services, and skilled labor, as well as investment openness, which will ultimately force regional economic growth. Therefore, this integration is likely to bring about a big change to this area in the new era; it can subsequently cause many problems as well, including mental health issues of the people in this region. The characteristic differences among the GMS member countries in terms of trade and investment, so-cial and cultural values, medical information and technology, and the living and working environment have become major problems affecting mental health disorders, which are usually identified as depression, stress, and substance abuse. This review paper is a literature review of the relationship of the determinants affecting GMS mental disorders conducted using the following strategies: 1) collecting data from previous qualitative and quantitative research studies, com-paratively analyzing the literature, articles, published papers, and reports relevant to the existing policies on economic, environmental, and healthcare issues obtained from the GMS; and 2) exchanging information from the institutions involved, including reports and papers regarding the determinants affecting mental health disorders of the people in the GMS, which were used to generate the synthesis of the existing knowledge of the mental health and to provide recommenda-tion programs for the GMS people. Based on the reviewed literature there are four key factors affecting mental health, especially mental health in GMS populations: 1) the living and work environments; 2) trade and investment; 3) technology and medical information; and 4) social and cultural values. The study found that the increasing number of mental health dis-orders is a big burden for national healthcare spending. Financial issues have become a major key to the wide prevalence of mental disorders in the GMS. Health issues related to mental health disorders are also caused by the environment and other related factors and therefore a stable and a well-balanced environment is an indicator of healthy mental status. In addition, the environment is a way to pursue both physical and mental health because green spaces serve as a mood freshener and can al-leviate anxiety, stress, and depression. Globalization and urbanization should follow sustainable development instructions and concerns about the population's health, especially regarding mental health. These key determinants affect the people's life, especially in terms of mental health thus leading to mental health disorders.


Designing vaccines to neutralize effective toxin delivery by enterotoxigenic Escherichia coli.
Enterotoxigenic Escherichia coli (ETEC) are a leading cause of diarrheal illness in developing countries. Despite the discovery of these pathogens as a cause of cholera-like diarrhea over 40 years ago, and decades of vaccine development effort, there remains no broadly protective ETEC vaccine. The discovery of new virulence proteins and an improved appreciation of the complexity of the molecular events required for effective toxin delivery may provide additional avenues to pursue in development of an effective vaccine to prevent severe diarrhea caused by these important pathogens.


Medicine or meddling? use of arthrography in rheumatology.
In the wardrobe of diagnostic procedures for the arthritic patient, the arthrogram is like a tuxedo. It produces striking images in black-and-white, it can be slightly uncomfortable, and there are times when it can be just the right thing. However, like the tuxedo, the arthrogram should be reserved for infrequent special occasions. Although arthrography can show changes which are characteristic of arthritis, it can seldom differentiate one type of synovitis from another. It may be useful to determine whether or not a synovial disorder is present, but this will not be necessary for the great majority of patients. Its most important uses are in the evaluation of masses in and around joints, and of the pseudothrombophlebitis syndrome. In selected cases, it may help to elucidate the stage and mechanism of disease.


Isoproterenol Promotes Rapid Ryanodine Receptor Movement to Bridging Integrator 1 (BIN1)-Organized Dyads.
The key pathophysiology of human acquired heart failure is impaired calcium transient, which is initiated at dyads consisting of ryanodine receptors (RyRs) at sarcoplasmic reticulum apposing CaV1.2 channels at t-tubules. Sympathetic tone regulates myocardial calcium transients through β-adrenergic receptor (β-AR)-mediated phosphorylation of dyadic proteins. Phosphorylated RyRs (P-RyR) have increased calcium sensitivity and open probability, amplifying calcium transient at a cost of receptor instability. Given that bridging integrator 1 (BIN1) organizes t-tubule microfolds and facilitates CaV1.2 delivery, we explored whether β-AR-regulated RyRs are also affected by BIN1. Isolated adult mouse hearts or cardiomyocytes were perfused for 5 minutes with the β-AR agonist isoproterenol (1 µmol/L) or the blockers CGP+ICI (baseline). Using biochemistry and superresolution fluorescent imaging, we identified that BIN1 clusters P-RyR and CaV1.2. Acute β-AR activation increases coimmunoprecipitation between P-RyR and cardiac spliced BIN1+13+17 (with exons 13 and 17). Isoproterenol redistributes BIN1 to t-tubules, recruiting P-RyRs and improving the calcium transient. In cardiac-specific Bin1 heterozygote mice, isoproterenol fails to concentrate BIN1 to t-tubules, impairing P-RyR recruitment. The resultant accumulation of uncoupled P-RyRs increases the incidence of spontaneous calcium release. In human hearts with end-stage ischemic cardiomyopathy, we find that BIN1 is also 50% reduced, with diminished P-RyR association with BIN1. On β-AR activation, reorganization of BIN1-induced microdomains recruits P-RyR into dyads, increasing the calcium transient while preserving electric stability. When BIN1 is reduced as in human acquired heart failure, acute stress impairs microdomain formation, limiting contractility and promoting arrhythmias.


Impact of Graft Weight Change During Perfusion on Hepatocellular Carcinoma Recurrence After Living Donor Liver Transplantation.
Inadequate liver volume and weight is a major source of morbidity and mortality after adult living donor liver transplantation (LDLT). The purpose of our study was to investigate HCC recurrence, graft failure, and patient survival according to change in right liver graft weight after histidine-tryptophan-ketoglutarate (HTK) solution perfusion in LDLT. Two hundred twenty-eight patients underwent LDLT between 2013 and 2017. We calculated the change in graft weight by subtracting pre-perfusion graft weight from post-perfusion graft weight. Patients with increased graft weight were defined as the positive group, and patients with decreased graft weight were defined as the negative group. After excluding patients who did not meet study criteria, 148 patients underwent right or extended right hepatectomy. The negative group included 89 patients (60.1%), and the positive group included 59 patients (39.9%). Median graft weight change was -28 g (range; -132-0 g) in the negative group and 21 g (range; 1-63 g) in the positive group (P<0.001). Median hospitalization time was longer for the positive group than the negative group (27 days vs. 23 days; P=0.048). There were no statistical differences in tumor characteristics, postoperative complications, early allograft dysfunction, or acute rejection between the two groups. Disease-free survival, death-censored graft survival, and patient survival were lower in the positive group than the negative group. Additionally, the positive group showed strong association with HCC recurrence, death-censored graft survival, and patient survival in multivariate analysis. This study suggests that positive graft weight change during HTK solution perfusion indicates poor prognosis in LDLT.


Remote at-home wearable-based gait assessments in Progressive Supranuclear Palsy compared to Parkinson's Disease.
Wearable sensors can differentiate Progressive Supranuclear Palsy (PSP) from Parkinson's Disease (PD) in laboratory settings but have not been tested in remote settings. To compare gait and balance in PSP and PD remotely using wearable-based assessments. Participants with probable PSP or probable/clinically established PD with reliable caregivers, still able to ambulate 10 feet unassisted, were recruited, enrolled, and consented remotely and instructed by video conference to operate a study-specific tablet solution (BioDigit Home ™) and to wear three inertial sensors (LEGSys™, BioSensics LLC, Newton, MA USA) while performing the Timed Up and Go, 5 × sit-to-stand, and 2-min walk tests. PSPRS and MDS-UPDRS scores were collected virtually or during routine clinical visits. Between November, 2021- November, 2022, 27 participants were screened of whom 3 were excluded because of technological difficulties. Eleven PSP and 12 PD participants enrolled, of whom 10 from each group had complete analyzable data. Demographics were well-matched (PSP mean age = 67.6 ± 1.3 years, 40% female; PD mean age = 70.3 ± 1.8 years, 40% female) while disease duration was significantly shorter in PSP (PSP 14 ± 3.5 months vs PD 87.9 ± 16.9 months). Gait parameters showed significant group differences with effect sizes ranging from d = 1.0 to 2.27. Gait speed was significantly slower in PSP: 0.45 ± 0.06 m/s vs. 0.79 ± 0.06 m/s in PD (d = 1.78, p < 0.001). Our study demonstrates the feasibility of measuring gait in PSP and PD remotely using wearable sensors. The study provides insight into digital biomarkers for both neurodegenerative diseases. ClinicalTrials.gov Identifier: NCT04753320, first posted Febuary 15, 2021.


Use of a guideline based questionnaire to audit hospital care of acute asthma.
To design an audit questionnaire and pilot its use by an audit assistant to monitor inpatient management of acute asthma and to compare the care given by chest physicians and general physicians. Retrospective review by a chest physician and audit assistant of a random sample of 76 case records of patients by a criterion based questionnaire developed from hospital guidelines on management of acute asthma. One district general hospital. 76 adult patients with acute asthma: 38 admitted with a relevant primary diagnosis between April 1988 and March 1989 and a further 38 admitted through the accident and emergency department between April 1989 and March 1990. Conformity with recognised standards for assessment and management of acute asthma before and after the audit and by chest physicians and general physicians. Age and sex did not differ significantly between the different groups of patients. Overall, deviations from the guidelines occurred in recording measures of severity of asthma, emergency treatment with beta 2 agonists (60/76, 79%) and steroids (43/76, 57%), and prescription of antibiotics in accordance with at least one criterion of the guidelines (29/45, 64%). Chest physicians were more rigorous than general physicians in recording severity measures, especially serum potassium concentration (chi 2 = 3.6, df = 1, p = 0.06), emergency steroid treatment within the correct period (chi 2 = 3.9, df = 1, p = 0.05), and referral for follow up at an outpatient chest clinic. Recording of arterial blood gas tensions improved significantly between the 1988-9 and 1989-90 samples (chi 2 = 7.0, df = 1, p = 0.08). The questionnaire proved easy to use for both doctor and audit assistant. The audit improved few standards of care and emphasises the need for further reinforcement and feedback.


The association of short segment Barrett's esophagus with intestinal metaplasia in stomach.
The aims of this study were to investigate the presence of short segment Barrett's esophagus in people found to have tongue-like columnar mucosal protrusions in the distal esophagus and to determine the relationship between short segment Barrert's esophagus and Helicobacter pylori, gastritis and intestinal metaplasia observed in other parts of the stomach. The study included 50 patients (32 male, 18 female). Two biopsy specimens were taken from the antrum, at least 2 cm away from the pylorus, from the incisura angularis, corpus and cardia and four biopsy specimens were taken from tongue-like columnar protrusions (<3 cm long) above the gastroesophageal junction. Tissue samples were stained with hematoxyline-eosine, HID-Alcian blue pH 2.5 and modified Giemsa. Of the 50 subjects who were found to have tongue-like columnar protrusions above the gastroesophageal junction, short segment Barrett's esophagus was detected in nine (18%). Whereas all short segment Barretti's esophagus cases were associated with chronic gastritis, Helicobacter pylori was found to be positive in five (55.5%) of them and there was intestinal metaplasia in other parts of the stomach (antrum in two patients, incisura angularis in three, antrum and cardia in one) in six (66.6%) cases. In 41 patients without short segment Barrett's esophagus 33 (80%) had chronic gastritis, 27 (66%) had Helicobacter pylori infection and eight had intestinal metaplasia in different locations (there in antrum, four in incisura angularis, one in the antrum and cardia) of the stomach. An association between short segment Barrett's esophagus and intestinal metaplasia was found in different parts of the stomach. The link between intestinal metaplasia in the stomach and these metaplastic changes in the tubular esophagus requires evalation in larger and more comprehensive studies.


["Fenaf"--a new histochemical stain].
The authors have synthesized a new dye which by its histochemical properties is analogous to the imported aldehyde-fuchsin but much cheaper. The production of this dye under the trade name "Fenaf" is organized at Shostka's factory of chemicals. The dye reveals neurosecretion, thyrothrophocytes of the adenohypophysis, tissue mast cells and other structures that are stained with aldehyde-fuchsin.


Response of serum carboxylated and undercarboxylated osteocalcin to risedronate monotherapy and combined therapy with vitamin K(2) in corticosteroid-treated patients: a pilot study.
The aim of this study was to investigate the responses of serum osteocalcin (OC), undercarboxylated osteocalcin (ucOC) and N-terminal telopeptide of type I collagen (NTx) to corticosteroids, and to examine the effects of risedronate therapy with or without vitamin K(2) supplementation on bone metabolic markers in corticosteroid-treated patients. Sixteen patients on corticosteroid therapy for neuromuscular disorders were assigned randomly to 2 groups (A: risedronate monotherapy, n=8; B: combined risedronate and vitamin K(2) therapy, n=8) and treated for 1 year. Another 6 patients who received intravenous steroid pulse therapy were assigned to group C for investigation of the effects of corticosteroids on OC and ucOC 1 month after pulse therapy. Serial measurements revealed that significant decreases of OC, ucOC and NTx persisted with a similar time course profile during 1 year of treatment in groups A and B, and between-group analysis failed to demonstrate any additional effects of vitamin K(2) on risedronate therapy. Intravenous steroid pulse therapy induced a transient depression of OC and ucOC within 1 week in group C. These results indicate that serum concentrations of OC and ucOC become consistently low during corticosteroid administration despite risedronate therapy with or without vitamin K(2) supplementation, and the serum ucOC level may not be a reliable indicator of vitamin K status under corticosteroid administration.