RNA interference or small molecule inhibition of Runx1 in the border zone prevents cardiac contractile dysfunction following myocardial infarction.
Myocardial infarction is a major cause of death worldwide. Effective treatments are required to improve recovery of cardiac function following myocardial infarction, with the aim of improving patient outcomes and preventing progression to heart failure. The perfused but hypocontractile region bordering an infarct is functionally distinct from the remote surviving myocardium and is a determinant of adverse remodelling and cardiac contractility. Expression of the transcription factor RUNX1 is increased in the border zone 1-day after myocardial infarction, suggesting potential for targeted therapeutic intervention. This study sought to investigate whether an increase in RUNX1 in the border zone can be therapeutically targeted to preserve contractility following MI. Here we demonstrate that Runx1 drives reductions in cardiomyocyte contractility, calcium handling, mitochondrial density, and expression of genes important for oxidative phosphorylation. Both tamoxifen-inducible Runx1-deficient and essential co-factor Cbfβ-deficient cardiomyocyte-specific mouse models demonstrated that antagonising RUNX1 function preserves the expression of genes important for oxidative phosphorylation following myocardial infarction. Antagonising RUNX1 expression via short-hairpin RNA interference preserved contractile function following myocardial infarction. Equivalent effects were obtained with a small molecule inhibitor (Ro5-3335) that reduces RUNX1 function by blocking its interaction with CBFβ. Our results confirm the translational potential of RUNX1 as a novel therapeutic target in myocardial infarction, with wider opportunities for use across a range of cardiac diseases where RUNX1 drives adverse cardiac remodelling.


Combination gut hormones: prospects and questions for the future of obesity and diabetes therapy.
Obesity represents an important public health challenge for the twenty-first century: globalised, highly prevalent and increasingly common with time, this condition is likely to reverse some of the hard-won gains in mortality accomplished in previous centuries. In the search for safe and effective therapies for obesity and its companion, type 2 diabetes mellitus (T2D), the gut hormone glucagon-like peptide-1 (GLP-1) has emerged as a forerunner and analogues thereof are now widely used in treatment of obesity and T2D, bringing proven benefits in improving glycaemia and weight loss and, notably, cardiovascular outcomes. However, GLP-1 alone is subject to limitations in terms of efficacy, and as a result, investigators are evaluating other gut hormones such as glucose-dependent insulinotropic peptide (GIP), glucagon and peptide YY (PYY) as possible partner hormones that may complement and enhance GLP-1's therapeutic effects. Such combination gut hormone therapies are in pharmaceutical development at present and are likely to make it to market within the next few years. This review examines the physiological basis for combination gut hormone therapy and presents the latest clinical results that underpin the excitement around these treatments. We also pose, however, some hard questions for the field which need to be answered before the full benefit of such treatments can be realised.


Designing passive MRI-safe implantable conducting leads with electrodes.
The presence of implanted electronic devices with conducting leads and electrodes are contraindicated for magnetic resonance imaging (MRI), denying many patients its potential benefits. The prime concern is MRI's radio frequency (RF) fields, which can cause elevated local specific absorption rates (SARs) and potential heat injury. The purpose of this article is to develop and compare a range of passive implantable "MRI-safe" lead designs. Conducting leads incorporating different lengths (3-75 cm), insulation thicknesses (0-105 microm), resistances (100-3000 omega), coiled conductors (inner diameter < or = 1.2 mm), high-impedance (135-2700 omega) RF traps, and single-coiled and triple-coiled coaxial-wound "billabong" leads with reversed coil sections that oppose and reduce the induced current, are investigated both experimentally using local temperature measurements, and by numerical full-wave electromagnetic field analysis of the local SAR, in three different-sized bioanalogous model saline-gel phantoms at 1.5 T MRI and 4 W/kg exposure. In all designs, the maximum computed 1 g average SAR and experimental temperature rise occur at the bare electrodes. Electrode heating increases with lead insulation thickness and peaks for uncoiled leads 25-50 cm long. A reasonable match between computed SAR and the point SAR estimated from thermal sensors obtained by approximating the computation volume to that of the thermal probes. Factors that maximize the impedance of leads with resistive, coiled, RF trap and billabong elements can effectively limit heating below 1-2 degrees, but folded lead configurations can be a concern. The RF trap and billabong designs can both support multiple conductors and electrodes, with billabong prototype leads also heating <1 degrees C when tested for 3 T MRI. Lead insulation and length strongly affect implanted lead safety to RF exposure during MRI. Lead designs employing impedance and reversed winding sections offer hope for the development of passive, MRI-safe, implantable conducting leads for future human use.


Clinical utility of endurance measures for evaluation of treatment in patients with mucopolysaccharidosis VI (Maroteaux-Lamy syndrome).
Increased functional capacity of major organ systems improves the quality of life and contributes to reductions in the morbidity associated with chronic debilitating diseases. Routine endurance tests can be used to gauge the progression of disease and the impact of therapeutic modalities in disorders with multiple organ system involvement such as with Mucopolysaccharidosis type VI (MPS VI). MPS VI is a progressive disorder affecting multiple organs and tissues due to the deficient activity of N-acetylgalactosamine-4-sulfatase leading to the accumulation of glycosaminoglycan (GAG) dermatan sulfate. Since 2005, enzyme replacement therapy (ERT) with human recombinant N-acetylgalactosamine-4-sulfatase (galsulfase) has been an available treatment option for MPS VI. These patients are routinely evaluated for extent of disability, disease progression and the impact of ERT. Evaluations are made by a combination of urinary GAG measurement and submaximal intensity endurance tests such as the 3-minute stair climb (3-MSC), and the 6- and 12-minute walk tests (6-MWT and 12-MWT). This review highlights the clinical validity of endurance measures as inexpensive diagnostic tools for diseases affecting multiple organ systems and evaluating the impact of therapeutic modalities, such as ERT for MPS VI.


Gastric microbiota and carcinogenesis: the role of non-Helicobacter pylori bacteria - A systematic review.
Helicobacter pylori is the strongest risk factor for gastric cancer. However, recent advances in DNA sequencing technology have revealed a complex microbial community in the stomach that could also contribute to the development of gastric cancer. The aim of this study was to present recent scientific evidence regarding the role of non-Helicobacter pylori bacteria in gastric carcinogenesis. A systematic review of original articles published in PubMed in the last ten years related to gastric microbiota and gastric cancer in humans was performed. Thirteen original articles were included. The constitution of gastric microbiota appears to be significantly affected by gastric cancer and premalignant lesions. In fact, differences in gastric microbiota have been documented, depending on Helicobacter pylori status and gastric conditions, such as non-atrophic gastritis, intestinal metaplasia and cancer. Gastric carcinogenesis can be associated with an increase in many bacteria (such as Lactobacillus coleohominis, Klebsiella pneumoniae or Acinetobacter baumannii) as well as decrease in others (such as Porphyromonas spp, Neisseria spp, Prevotella pallens or Streptococcus sinensis). However, there is no conclusive data that confirms if these changes in microbiota are a cause or consequence of the process of carcinogenesis. Even though there is limited evidence in humans, microbiota differences between normal individuals, pre-malignant lesions and gastric cancer could suggest a progressive shift in the constitution of gastric microbiota in carcinogenesis, possibly resulting from a complex cross-talk between gastric microbiota and Helicobacter pylori. However, further studies are needed to elucidate the specific role (if any) of different microorganisms.


Promoting interprofessional student outcomes through the narrative of an opioid use disorder survivor.
The inappropriate use of opioids is a national concern. Experts suggest a multifaceted, collaborative practice approach to reduce mortality rates in complex healthcare issues is effective. Before practice, students require education to address the development of interprofessional (IP) skills. The purpose of this mixed-methods cohort study was to identify changes in student self-perceived value of IP socialization skills and to explore student perceptions of IP engagement in the context of the opioid crisis, before and after a combined IP panel and focus group discussion using a healthcare professional's journey from addiction into recovery. Thirty-three pre-licensure healthcare students in Schools of Counseling, Nursing, Occupational Therapy, Pharmacy, and Physical Therapy assessed their IP experience using the Interprofessional Socialization and Valuing Scale (ISVS). The IP event included interactive discussions with a panel of healthcare providers, a pharmacist in recovery from opioid use disorder, and a local prescription drug awareness and prevention advocate. Significant differences occurred between pre and post ISVS scores in the perceived value of IP collaborative work. Results from the qualitative analysis revealed a need for student-driven self-reflection before the discussions evolved to address the perspectives of future practitioner, the patient, and the healthcare system. Creating a real-time, face-to-face interaction with a panel of healthcare practitioners, an opioid survivor in concert with a local prescription drug prevention advocate may be an effective means toward improving teaching IP value and progressing student outcomes toward IP skill attainment.


Chemical characterization of Rauscher leukaemia virus proteins.
The proteins of Rauscher murine leukaemia virus (R-MuLV) were characterized by amino acid analyses and by determination of their mol. wt. by gel filtration on cross-linked Sepharose 6B in 6M-guanidine hydrochloride (GuHCl). Molecular weights of 56,000, 29,000, 15,000, 10,500 and 7,600 were found for gp70, p30, p15, p12 and p10 respectively. The amino acid compositions of these proteins and of p12E have been determined. The amino acid compositions of the p10 polypeptides of Rauscher-MuLV and Moloney-MuLV are very similar as are those of the p30 polypeptides, whereas the amino acid compositions of the p12 polypeptides differ considerably. P12E contains the highest percentage of hydrophobic amino acid residues. Among the gag-gene coded proteins, p15 contains the highest percentage of hydrophobic amino acid residues while p12 and p10 contain the lowest.


Expression and regulation of vascular endothelial growth factor ligands and receptors during menstruation and post-menstrual repair of human endometrium.
Regeneration and growth of the human endometrium after shedding of the functional layer during menstruation depends on an adequate angiogenic response. We analysed the mRNA expression levels of all known vascular endothelial growth factor (VEGF) ligands and receptors in human endometrium collected in the menstrual and proliferative phases of the menstrual cycle. In addition, we evaluated the expression of VEGF-A, VEGF-R2 and NRP-1 at the protein level. Two periods of elevated mRNA expression of ligands and receptors were observed, separated by a distinct drop at cycle days (CDs) 9 and 10. Immunohistochemical staining showed that VEGF and VEGF-R2 were expressed in epithelial, stromal and endothelial cells. NRP-1 was mainly confined to stroma and blood vessels; only in late-proliferative endometrium, epithelial staining was also observed. Except for endothelial VEGF-R2 expression in CDs 6-8, there were no significant differences in the expression of VEGF, VEGF-R2 or NRP-1 in any of the cell compartments. In contrast, VEGF release by cultured human endometrium explants decreased during the proliferative phase. This output was significantly reduced in menstrual and early-proliferative endometrium by estradiol (E2) treatment. Western blot analysis indicated that part of the VEGF-A was trapped in the extracellular matrix (ECM). Changes in VEGF ligands and receptors were associated with elevated expression of the hypoxia markers HIF1alpha and CA-IX in the menstrual and early proliferative phases. HIF1alpha was also detected in late-proliferative phase endometrium. Our findings indicate that VEGF-A exerts its actions mostly during the first half of the proliferative phase. Furthermore, VEGF-A production appears to be triggered by hypoxia in the menstrual phase and subsequently suppressed by estrogen during the late proliferative phase.


Raised object on a planar surface stroked across the fingerpad: responses of cutaneous mechanoreceptors to shape and orientation.
The representations of orientation and shape were studied in the responses of cutaneous mechanoreceptors to an isolated, raised object on a planar surface stroked across the fingerpad. The objects were the top portions of a sphere with a 5-mm radius, and two toroids each with a radius of 5 mm along one axis and differing radii of 1 or 3 mm along the orthogonal axis. The velocity and direction of stroking were fixed while the orientation of the object in the horizontal plane was varied. Each object was stroked along a series of laterally shifted, parallel, linear trajectories over the receptive fields of slowly adapting, type I (SA), and rapidly adapting, type I (RA) mechanoreceptive afferents innervating the fingerpad of the monkey. "Spatial event plots" (SEPs) of the occurrence of action potentials, as a function of the location of each object on the receptive field, were interpreted as the responses of a spatially distributed population of fibers. That portion of the plot evoked by the curved object (the SEPc) provided a representation of the shape and orientation of the two-dimensional outline of the object in the horizontal plane in contact with the skin. For both SAs and RAs, the major vector of the SEPc, obtained by a principal components analysis, was linearly related to the physical orientation of the major axis of each toroid. The spatial distribution of discharge rates [spatial rate surface profiles (SRSs), after plotting mean instantaneous frequency versus spatial locus within the SEPc] represented object shape in a third dimension, normal to the skin surface. The shape of the SA SRSs, well fitted by Gaussian equations, better represented object shape than that of the RA SRSs. A cross-sectional profile along the minor axis [spatial rate profile (SRP)] was approximately triangular for SAs. After normalization for differences in peak height, the falling slopes of the SA SRPs increased, and the base widths decreased with curvature of the object's minor axis. These curvature-related differences in slopes and widths were invariant with changes in object orientation. It is hypothesized that circularity in object shape is coded by the constancy of slopes of SA SRPs between peak and base and that the constancy of differences in the widths and falling slopes evoked by different raised objects encodes, respectively, the differences in their sizes and shapes regardless of differences in their orientation on the skin.


Tumor-associated tissue eosinophilia versus tumor associated blood eosinophilia: A ratio of diagnostic importance in oral squamous cell carcinoma.
Eosinophils are multifunctional granulocytes, which play a pivotal role in health and disease. Tumor Associated Tissue Eosinophilia (TATE) has long been evaluated in the diagnosis and progression of oral squamous cell carcinomas (OSCCs). However, their association with Tumor Associated Blood Eosinophilia (TABE) in OSCCs is still far fetched. We, therefore, attempted to evaluate their individual roles and to achieve a ratio between TATE and TABE in order to signify its usage in objectifying the diagnosis. TATE was evaluated using H and E stain per 10 high power fields in 33 previously diagnosed cases of OSCC which were retrieved from department archives. TABE values were achieved from complete blood hemogram reports of patients. TATE/TABE ratio was calculated. All the parameters were clinicopathologically correlated and statistically evaluated using SPSS. TATE represented higher values in well-differentiated squamous cell carcinoma (WDSCC) and poorly differentiated squamous cell carcinoma (PDSCC) and was least in moderately differentiated squamous cell carcinoma (MDSCC), whereas TABE linearly increased from WDSCC to PDSCC. TNM Stage II cases revealed the highest TATE and lowest TABE. TATE/TABE ratio was the highest in WDSCC. Due to the dual nature of eosinophils in early and late carcinogenesis events, evaluation of only TATE might not be conclusive in determining tumor grade. Hence, in a first of its kind attempt, the TATE/TABE ratio may be suitable to achieve a criterion for the determination of tumor grade and may also help to unfold the underlying biologic events.


An international cross-sectional survey on the Quality and Costs of Primary Care (QUALICO-PC): recruitment and data collection of places delivering primary care across Canada.
Performance reporting in primary health care in Canada is challenging because of the dearth of concise and synthesized information. The paucity of information occurs, in part, because the majority of primary health care in Canada is delivered through a multitude of privately owned small businesses with no mechanism or incentives to provide information about their performance. The purpose of this paper is to report the methods used to recruit family physicians and their patients across 10 provinces to provide self-reported information about primary care and how this information could be used in recruitment and data collection for future large scale pan-Canadian and other cross-country studies. Canada participated in an international large scale study-the QUALICO-PC (Quality and Costs of Primary Care) study. A set of four surveys, designed to collect in-depth information regarding primary care activities was collected from: practices, providers, and patients (experiences and values). Invitations (telephone, electronic or mailed) were sent to family physicians. Eligible participants were sent a package of surveys. Provincial teams kept records on the number of: invitation emails/letters sent, physicians who registered, practices that were sent surveys, and practices returning completed surveys. Response and cooperation rates were calculated. Invitations to participate were sent to approximately 23,000 family physicians across Canada. A total of 792 physicians and 8,332 patients from 772 primary care practices completed the surveys, including 1,160 participants completing a Patient Values survey and 7,172 participants completing a Patient Experience survey. Overall, the response rate was very low ranging from 2% (British Columbia) to 21% (Nova Scotia). However, the participation rate was high, ranging from 72% (Ontario) to 100% (New Brunswick/Prince Edward Island and Newfoundland & Labrador). The difficulties obtaining acceptable response rates by family physicians for survey participation is a universal challenge. This response rate for the QUALICO-PC arm in Canada was similar to rates found in other countries such as Australia and New Zealand. Even though most family physicians operate as self-employed small businesses, they could be supported to routinely submit data through a collective effort and provincial mandate. The groundwork in setting up pan-Canadian collaboration in primary care has been established through this study.


Continuing education needs of health care professionals.
Formal continuing education for health professionals continues to grow around the base of courses, conferences, and general reading. These formats serve the indispensable function of keeping health professionals abreast of the state of medicine. Since most formal continuing education activities are planned for groups, they cannot address the specific information needed in the care of individual patients. Furthermore, the knowledge gained is memory-based, and it is misguided to believe that facts learned in lectures will be remembered accurately enough for patient-care applications. A recent study has demonstrated that physicians often want additional knowledge when they are caring for patients and that access to knowledge is often difficult and time consuming. Advances in computer and telecommunications technology may ultimately permit immediate short answers to specific questions that arise during medical practice. It is time to expand the activities of the National Library of Medicine and the libraries within the Regional Medical Library (RML) network that provide valuable information for health professionals by developing methods to answer specific questions on the spot while health professionals are caring for patients.


Controlling proteins through molecular springs.
We argue that the mechanical control of proteins-the notion of controlling chemical reactions and processes by mechanics-is conceptually interesting. We give a brief review of the main accomplishments so far, leading to our present approach of using DNA molecular springs to exert controlled stresses on proteins. Our focus is on the physical principles that underlie both artificial mechanochemical devices and natural mechanisms of allostery.


Astrocytic junctional adhesion molecule-A regulates T-cell entry past the glia limitans to promote central nervous system autoimmune attack.
Contact-mediated interactions between the astrocytic endfeet and infiltrating immune cells within the perivascular space are underexplored, yet represent potential regulatory check-points against CNS autoimmune disease and disability. Reactive astrocytes upregulate junctional adhesion molecule-A, an immunoglobulin-like cell surface receptor that binds to T cells via its ligand, the integrin, lymphocyte function-associated antigen-1. Here, we tested the role of astrocytic junctional adhesion molecule-A in regulating CNS autoinflammatory disease. In cell co-cultures, we found that junctional adhesion molecule-A-mediated signalling between astrocytes and T cells increases levels of matrix metalloproteinase-2, C-C motif chemokine ligand 2 and granulocyte-macrophage colony-stimulating factor, pro-inflammatory factors driving lymphocyte entry and pathogenicity in multiple sclerosis and experimental autoimmune encephalomyelitis, an animal model of CNS autoimmune disease. In experimental autoimmune encephalomyelitis, mice with astrocyte-specific JAM-A deletion (mGFAP:CreJAM-Afl/fl ) exhibit decreased levels of matrix metalloproteinase-2, reduced ability of T cells to infiltrate the CNS parenchyma from the perivascular spaces and a milder histopathological and clinical course of disease compared with wild-type controls (JAM-Afl/fl ). Treatment of wild-type mice with intraperitoneal injection of soluble junctional adhesion molecule-A blocking peptide decreases the severity of experimental autoimmune encephalomyelitis, highlighting the potential of contact-mediated astrocyte-immune cell signalling as a novel translational target against neuroinflammatory disease.


Posterior Sagittal Approach Provides Optimal Exposure for Urethral Reconstruction in Children With a History of Anorectal Malformations.
To present a unique series of children with previously repaired anorectal malformations (ARM) with subsequent urethral pathology repaired via a posterior sagittal exposure and highlight the associated technical advantages. Using a retrospective review of all procedures performed in our pediatric colorectal and pelvic reconstruction program from January 2020 through December 2022, we compiled a case series of patients with a history of ARM and prior posterior sagittal anorectoplasty (PSARP) who had urethral pathology and concurrent indication for redo-PSARP. Clinical features, operative details, and postoperative outcomes were collected. Six male patients presented at a median age of 4.3 years, all born with an ARM of recto-urinary fistula type, of which 3 were recto-prostatic, 1 recto-bladder-neck, and 2 unknown type. In addition to redo-PSARP, 2 underwent remnant of the original fistula excision and 4 had urethral stricture repair. One required post-operative Heineke-Mikulicz anoplasty. Patients underwent cystoscopy 4-6 weeks post-reconstruction, and none showed urethral stricture requiring treatment. Post-procedurally, 5 patients were able to void urethrally and 1 required additional bladder augmentation/Mitrofanoff. Redo-PSARP completely mobilizes the rectum, thereby providing excellent exposure to the posterior urethra for repair. This approach also allows the option of a rectal flap for augmented urethroplasty as well as harvest of an ischiorectal fat pad for interposition.


INFLUENZA : III. RAPID ALTERATIONS IN THE RESPIRATORY RATE OF EMBRYONATED EGGS APPARENTLY CAUSED BY INFLUENZA VIRUS TOXIN.
Allantoic fluid from embryonated eggs infected with influenza A virus contains a toxic agent which can be demonstrated and quantitatively measured by its rapid effect on oxygen consumption when it is introduced in new series of fertile eggs. The effects were measured 90 minutes after the injection of the infected fluid, and were seen following both intra-allantoic injection and injection into the yolk sac. This toxin, in concentrations resulting from the injection of 0.5 cc. or less of the infected fluid, has no effect on oxygen consumption. The injection of 0.75 to 2.0 cc. of the fluid strikingly increases the oxygen consumption of the fertile eggs, while the injection of 3.0 cc. markedly depresses respiration. A similar reversal and eventual loss of the effect of the toxin on respiration were noted when the concentration of toxin was progressively diminished by heat inactivation. The toxic agent is slowly inactivated by heating at 56 degrees C., but is effective long after infectivity and hemagglutinating ability have been destroyed. In this respect the agent differs from rickettsial and lymphogranuloma venereum virus toxins. The method described may be of value in studying the physiological effects of other toxic agents.


Protocol for project IMPACT (improving millions hearts for provider and community transformation): a quasi-experimental evaluation of an integrated electronic health record and community health worker intervention study to improve hypertension management among South Asian patients.
The Million Hearts® initiative aims to prevent heart disease and stroke in the United States by mobilizing public and private sectors around a core set of objectives, with particular attention on improving blood pressure control. South Asians in particular have disproportionately high rates of hypertension and face numerous cultural, linguistic, and social barriers to accessing healthcare. Interventions utilizing Health information technology (HIT) and community health worker (CHW)-led patient coaching have each been demonstrated to be effective at advancing Million Hearts® goals, yet few studies have investigated the potential impact of integrating these strategies into a clinical-community linkage initiative. Building upon this initiative, we present the protocol and preliminary results of a research study, Project IMPACT, designed to fill this gap in knowledge. Project IMPACT is a stepped wedge quasi-experimental study designed to test the feasibility, adoption, and impact of integrating CHW-led health coaching with electronic health record (EHR)-based interventions to improve hypertension control among South Asian patients in New York City primary care practices. EHR intervention components include the training and implementation of hypertension-specific registry reports, alerts, and order sets. Fidelity to the EHR intervention is assessed by collecting the type, frequency, and utilization of intervention components for each practice. CHW intervention components consist of health coaching sessions on hypertension and related risk factors for uncontrolled hypertensive patients. The outcome, hypertension control (<140 mmHg systolic blood pressure (BP) and <90 mmHg diastolic BP), is collected at the aggregate- and individual-level for all 16 clinical practices enrolled. Project IMPACT builds upon the evidence base of the effectiveness of CHW and Million Hearts® initiatives and proposes a unique integration of provider-based EHR and community-based CHW interventions. The project informs the effectiveness of these interventions in team-based care approaches, thereby, helping to develop relevant sustainability strategies for improving hypertension control among targeted racial/ethnic minority populations at small primary care practices. This study protocol has been approved and is made available on Clinicaltrials.gov by NCT03159533 as of May 17, 2017.


Central nervous system candidiasis beyond neonates: Lessons from a nationwide study.
Though candidiasis is the most frequent invasive fungal infection, Candida spp. central nervous system (CNS) infections are rare but severe. To further describe clinico-patho-radiological presentations of this entity, we report a retrospective study from January 2005 to December 2018 including patients aged ≥ 28 days with proven or probable CNS candidiasis in France. Twenty-four patients were included. Seventeen patients (70%) had CNS localization secondary to disseminated candidiasis (10 with hematologic malignancies [HM]; the seven other patients had infective endocarditis [IE]). Among patients with HM, seven previously had lumbar puncture for intrathecal chemotherapy, the three others had IE. Among patients with disseminated infection, magnetic resonance imaging (MRI) evidenced meningitis (17%), micro-abscesses (58%), or vascular complications (67%). Seven patients (30%) had isolated CNS involvement related to neurosurgery (n = 2), CARD9 deficiency (n = 2), intravenous drug use, diabetes mellitus, or no identified predisposing condition (n = 1 each). All evaluated patients with isolated CNS involvement had meningitis on cerebrospinal fluid (CSF) and intracranial hypertension. For the latter patients, MRI evidenced meningitis (71%) or abscesses (57%). Among all patients, cerebrospinal fluid (CSF) culture grew Candida spp. in 31% of cases. CSF βDGlucan or mannan Ag were positive in respectively 86% and 80% of cases. Mortality attributed to CNS candidiasis was 42%: 53% in case of disseminated infection (70% for HM) and 14% in case of localized infection. CNS candidiasis are isolated or occur during disseminated infection in patients with HM and lumbar puncture for intrathecal chemotherapy or during IE. Clinical, radiological finding and outcome highly vary according to CNS localized versus disseminated candidiasis. Candida is a yeast and is the most common cause of fungal infections worldwide. Candida central nervous system (CNS) infections are rare, severe, and poorly described. We report a retrospective study from January 2005 to December 2018 including patients aged ≥ 28 days with proven or probable CNS candidiasis in France. Twenty-four patients were included (14 men, median age 51 years). Seventeen patients had CNS localization secondary to disseminated candidiasis from blood to CNS (10 with hematologic malignancies [HM], the seven other patients had infective endocarditis [IE]). Seven patients had isolated CNS involvement related to neurosurgery (n = 2), CARD9 deficiency (n = 2), intravenous drug use (n = 1), diabetes mellitus (n = 1), or no identified risk factor (n = 1).During Candida CNS infections, brain lesions were meningitis abscesses or vascular complications. Cerebrospinal fluid (CSF) culture grew Candida spp. in 31% of cases. Forty-two percent of patients died from infection: 53% in case of disseminated infection (70% for HM) and 14% in case of localized infection.


[Atherosclerosis and inflammation: the role of C-reactive protein].
C-reactive protein (CRP) is an acute phase protein, the serum concentration of which can increase up to a 1000-fold after the onset of a stimulus. It plays a role in the aspecific immune response to bacteria and fungi and the clearance of apoptotic cell material. Inflammation plays an important role in the aetiology and pathogenesis of atherosclerosis and plaque formation. Approximately fifty percent of acute coronary syndromes are the consequence of unstable plaques rupturing, followed by thrombus formation. A characteristic of these unstable plaques is an increase in inflammatory cells (macrophages and T lymphocytes). The serum concentration of CRP might reflect the amount of inflammation within atherosclerotic plaques and thus might provide an indirect measurement of the instability of the plaques. CRP could therefore have a predictive value for the occurrence of plaque rupture. Furthermore, there are indications that CRP itself is active in the inflammatory process. Prospective studies have shown that so-called high-sensitivity CRP (hsCRP) measurements could be used as a tool for determining the risk for acute coronary syndromes. The inflammation-inhibiting characteristics of statins and acetylsalicylic acid (especially the reduction of the hsCRP level) might contribute to reducing the risk of plaque rupture.


Response of canine cutaneous epitheliotropic lymphoma to lomustine (CCNU): a retrospective study of 46 cases (1999-2004).
Epitheliotropic lymphoma (ELSA) is an uncommon cutaneous canine malignancy of T lymphocytes. A consensus regarding the therapeutic standard of care is lacking, warranting evaluation of chemotherapeutic agents traditionally employed against canine nodal lymphoma in the treatment of ELSA. The purpose of this retrospective, multi-institutional study was to evaluate the efficacy of 1-(2-chloroethyl)-3-cyclohexyl-l-nitrosourea (CCNU) in the treatment of ELSA. Forty-six dogs with adequate follow-up and treatment response information. All cases were diagnosed histopathologically. Immunohistochemisty (CD3, CD79a) was performed on 42/46 samples. Presenting skin lesions included generalized scales (25/46), plaques or nodules (22/46), mucocutaneous lesions (14/ 46), and corneal involvement (1/46). Lymph node involvement and Sézary syndrome were documented in 7 and 2 dogs, respectively. The median number of CCNU treatments was 4 (range, 1-11), with a median starting dose of 60 mg/m(2) (range, 30-95). Of the 46 dogs, 15 achieved complete remission, 23 achieved partial remission, 5 had stable disease, and 3 had progressive disease, for an overall response rate of 83%. The median number of treatments to achieve a response was 1 (range, 1-6). The overall median duration of response was 94 days (range, 22-282). Sixteen dose reductions were required because of neutropenia (10/46), thrombocytopenia (1/46), anemia (1/46), increased liver enzyme activity (3/46), or unspecified reasons (1/46). Given the high response rate and well tolerated protocol, prospective studies are warranted to investigate the utility of CCNU alone or in multi-agent protocols for the treatment of ELSA.


Treatment options for PNET liver metastases: a systematic review.
Pancreatic neuroendocrine tumors (PNETs) are rare pancreatic neoplasms. About 40-80% of patients with PNET are metastatic at presentation, usually involving the liver (40-93%). Liver metastasis represents the most significant prognostic factor. The aim of this study is to present an up-to-date review of treatment options for patients with liver metastases from PNETs. A systematic literature search was performed using the PubMed database to identify all pertinent studies published up to May 2018. The literature search evaluated all the therapeutic options for patients with liver metastases of PNETs, including surgical treatment, loco-regional therapies, and pharmacological treatment. All the different treatment options showed particular indications in different presentations of liver metastases of PNET. Surgery remains the only potentially curative therapeutic option in patients with PNETs and resectable liver metastases, even if relapse rates are high. Efficacy of medical treatment has increased with advances in targeted therapies, such as everolimus and sunitinib, and the introduction of radiolabeled somatostatin analogs. Several techniques for loco-regional control of metastases are available, including chemo- or radioembolization. Treatment of patients with PNET metastases should be multidisciplinary and must be personalized according to the features of individual patients and tumors.


The curvilinear relationship between state neuroticism and momentary task performance.
A daily diary and two experience sampling studies were carried out to investigate curvilinearity of the within-person relationship between state neuroticism and task performance, as well as the moderating effects of within-person variation in momentary job demands (i.e., work pressure and task complexity). In one, results showed that under high work pressure, the state neuroticism-task performance relationship was best described by an exponentially decreasing curve, whereas an inverted U-shaped curve was found for tasks low in work pressure, while in another study, a similar trend was visible for task complexity. In the final study, the state neuroticism-momentary task performance relationship was a linear one, and this relationship was moderated by momentary task complexity. Together, results from all three studies showed that it is important to take into account the moderating effects of momentary job demands because within-person variation in job demands affects the way in which state neuroticism relates to momentary levels of task performance. Specifically, we found that experiencing low levels of state neuroticism may be most beneficial in high demanding tasks, whereas more moderate levels of state neuroticism are optimal under low momentary job demands.


Gibberellic Acid Initiates ER Stress and Activation of Differentiation in Cultured Human Immortalized Keratinocytes HaCaT and Epidermoid Carcinoma Cells A431.
Diterpenoid plant hormone gibberellic acid (GA) plays an important role in regulation of plant growth and development and is commonly used in agriculture for activation of plant growth and food production. It is known that many plant-derived compounds have miscellaneous biological effects on animals and humans, influencing specific cellular functions and metabolic pathways. However, the effect of GA on animal and human cells remains controversial. We investigated the effect of GA on cultured human cell lines of epidermoid origin-immortalized non-tumorigenic keratinocytes HaCaT and carcinoma A431 cells. We found that at a non-toxic dose, GA upregulated the expression of genes associated with the ER stress response-CHOP, sXBP1, GRP87 in both cell lines, and ATF4 predominantly in A431 cells. We also showed that GA was more effective in upregulating the production of ER stress marker GRP78, autophagy marker LC3B-II, and differentiation markers involucrin and filaggrin in A431 cells than in HaCaT. We conclude that GA induces mild ER stress in both cell lines, followed by the activation of differentiation via upregulation of autophagy. However, in comparison with immortalized keratinocytes HaCaT, GA is more effective in inducing differentiation of carcinoma A431 cells, probably due to the inherently lower differentiation status of A431 cells. The activation of differentiation in poorly differentiated and highly malignant A431 cells by GA may lower the level of malignancy of these cells and decrease their tumorigenic potential.


Colorimetric sensing of alpha-amino acids and its application for the "label-free" detection of protease.
A new indirect approach to explore sensitive colorimetric sensors toward alpha-amino acids is proposed: the pink solution of 1 and copper ions changed to colorless immediately upon the addition of alpha-amino acids. As the hydrolysis of bovine serum albumin (BSA) with the aid of trypsin produces alpha-amino acids, the complex of 1/Cu(2+)/BSA could act as a label-free, sensitive, selective sensor toward trypsin. The detection process could be visually observed by naked eyes.


Digital LAMP in a sample self-digitization (SD) chip.
This paper describes the realization of digital loop-mediated DNA amplification (dLAMP) in a sample self-digitization (SD) chip. Digital DNA amplification has become an attractive technique to quantify absolute concentrations of DNA in a sample. While digital polymerase chain reaction is still the most widespread implementation, its use in resource-limited settings is impeded by the need for thermal cycling and robust temperature control. In such situations, isothermal protocols that can amplify DNA or RNA without thermal cycling are of great interest. Here, we accomplished the successful amplification of single DNA molecules in a stationary droplet array using isothermal digital loop-mediated DNA amplification. Unlike most (if not all) existing methods for sample discretization, our design allows for automated, loss-less digitization of sample volumes on-chip. We demonstrated accurate quantification of relative and absolute DNA concentrations with sample volumes of less than 2 μl. We assessed the homogeneity of droplet size during sample self-digitization in our device, and verified that the size variation was small enough such that straightforward counting of LAMP-active droplets sufficed for data analysis. We anticipate that the simplicity and robustness of our SD chip make it attractive as an inexpensive and easy-to-operate device for DNA amplification, for example in point-of-care settings.


Awareness and Self Care Practices of Elderly Men Regarding Prostate Diseases in Karachi, Pakistan.
The prostate gland is a male sexual organ which has a number of diseases associated with it, such as prostatitis, benign prostatic hyperplasia (BPH), and prostatic cancer (PC). BPH is the most common neoplasm, and it causes significant urinary symptoms in adult males. According to the World Health Organization (WHO) report of 2014, out of all the cancers, PC had the fifth highest incidence in males throughout Pakistan. The purpose of this study was to determine the awareness of elderly men of Karachi regarding prostate diseases (PDs) and their attitude towards screening practices. From September to December 2018, a cross-sectional study was performed among 450 men of Karachi older than 50 years of age. Frequencies and percentages were evaluated for categorical variables using Statistical Package for Social Sciences (SPSS), version 22 (IBM SPSS Statistics, Armonk, NY). Chi-square test was used to determine if there was any significant difference. A p-value of < 0.05 was considered significant. A total of 350 respondents answered the questionnaire. The mean age of the respondents was 61 years. Almost half of the population had heard about the prostate but 64% did not know any PDs, whereas 48% were aware of the increased risk of PDs in the elderly. Almost 48% of the respondents believed that age was the main cause of disorders involving the prostate. Even though the knowledge was lacking, people had an overall positive attitude. Most respondents (66%) had the attitude that all adult men must undergo prostate screening. The majority of respondents (85%) had not undergone screening of the prostate as the huge group of participants (86%) had not been advised to do it. Upon statistical testing, having heard about the prostate and undergoing prostate screening in the past (p = 0.008 and 0.024, respectively) was significantly associated with age. Having prior experience with prostate screening was also associated significantly with marital status (p < 0.001). Respondents have inadequate knowledge about PC but a good attitude about undergoing prostate examination. It is absolutely crucial to increase information on the risks of PDs, particularly PC, and the benefits of early detection.


Transient-time correlation function applied to mixed shear and elongational flows.
The transient-time correlation function (TTCF) method is used to calculate the nonlinear response of a homogeneous atomic fluid close to equilibrium. The TTCF response of the pressure tensor subjected to a time-independent planar mixed flow of shear and elongation is compared to directly averaged non-equilibrium molecular dynamics (NEMD) simulations. We discuss the consequence of noise in simulations with a small rate of deformation. The generalized viscosity for planar mixed flow is also calculated with TTCF. We find that for small rates of deformation, TTCF is far more efficient than direct averages of NEMD simulations. Therefore, TTCF can be applied to fluids with deformation rates which are much smaller than those commonly used in NEMD simulations. Ultimately, TTCF applied to molecular systems is amenable to direct comparison between NEMD simulations and experiments and so in principle can be used to study the rheology of polymer melts in industrial processes.


Incidentally detected retroperitoneal paraganglioma in a 10-year-old French bulldog.
This article reports a case of a 10-year-old French bulldog initially seen for reluctance to move and episodes of pain. A magnetic resonance imaging study was undertaken in order to rule out a herniated disc. A large, retroperitoneal mass was visualized and cytological analysis suggested a neoplastic proliferation. The mass appeared to compress the caudal vena cava when viewed by abdominal CT scan. The mass was surgically removed. A nephrectomy was also carried out and aortic bleeding identified after dissection of adhesions. Despite these complications, the dog did well after the procedures. Postoperative checkups were normal. Histological and immunohistochemical analyses of the mass were compatible with a retroperitoneal paraganglioma. Key clinical message: This type of tumor is poorly described in the veterinary literature. As the behavior of this tumor type is not yet fully understood, each new description adds to our knowledge and should help in diagnosing and treating it more effectively in the future.


Real time data acquisition: recommendations for the Medical Information Bus (MIB).
Care of the acutely ill patient requires rapid acquisition, recording and communications of data. In the modern hospital it is not unusual for a patient to be connected to several monitoring and recording devices simultaneously. Each of these devices is typically made by a different manufacturer who may specialize in one sort of measurement, for example, pulse oximetry. Most of the modern monitoring and recording devices are micro-processor based and have communication capabilities. Unfortunately, there is no operable standard communication technology available from all devices. In addition different clinical staff (physicians, nurses, or respiratory therapists) may be responsible for collecting data. As a result there is a need to develop methods, standards, and strategies for timely and automatic collection of data from these monitoring and recording devices. We report on more than 5 years of clinical experience of automated ICU data collection using a prototype of the Medical Information Bus (MIB).


UBE2O reduces the effectiveness of interferon-α via degradation of IFIT3 in hepatocellular carcinoma.
Interferon (IFN) exerts its effects through interferon-stimulated genes (ISGs), but its efficacy is limited by interferon resistance, which can be caused by the ubiquitination of key proteins. UBE2O was initially identified as a promising therapeutic target based on data from the TCGA and iUUCD 2.0 databases. Through the inhibition of UBE2O, interferon α/β signaling and overall interferon signaling were activated. Integrating data from proteomic, mass spectrometry, and survival analyses led to the identification of IFIT3, a mediator of interferon signaling, as a ubiquitination substrate of UBE2O. The results of in vitro and in vivo experiments demonstrated that the knockdown of UBE2O can enhance the efficacy of interferon-α by upregulating IFIT3 expression. K236 was identified as a ubiquitination site in IFIT3, and the results of rescue experiments confirmed that the effect of UBE2O on interferon-α sensitivity is dependent on IFIT3 activity. ATO treatment inhibited UBE2O and increased IFIT3 expression, thereby increasing the effectiveness of interferon-α. In conclusion, these findings suggest that UBE2O worsens the therapeutic effect of interferon-α by targeting IFIT3 for ubiquitination and degradation.


Correlations between genotype and pharmacological, histological, functional, and clinical phenotypes in malignant hyperthermia susceptibility.
Malignant hyperthermia susceptibility (MHS) is a subclinical pharmacogenetic disorder caused by an impairment of skeletal muscle calcium homeostasis in response to triggering agents. While in vitro contracture testing (IVCT) is the gold standard for defining MHS, molecular analysis is increasingly used to diagnosis MHS. Mutations associated with MHS have been reported in two genes: RYR1 and CACNA1S. Mutations in RYR1 are also responsible for central core disease (CCD), a myopathy that can be associated with a positive IVCT response. We report here the results of correlation studies performed with molecular, pharmacological, histological, and functional data obtained in 175 families (referred to as confirmed (129) or potential (46) MHS families). Extensive molecular analysis allowed us to identify a variant in 60% of the confirmed MHS families, and resulted in the characterization of 11 new variants in the RYR1 gene. Most mutations clustered to MH1 and MH2 domains of RYR1. Functional analysis allowed us to assign a causative role for seven MHS mutations that we propose to add to the panel of MHS mutations used for genetic testing. The use of genetic data to determine MHS status led to a 99.5% sensitivity for IVCT. IVCT-positive/mutation-negative diagnoses were analyzed not only in terms of specificity for IVCT, but also to assess the presence of a second MHS trait in families, and the genetic heterogeneity of the disease. Histological analyses revealed the presence of cores in more than 20% of muscle biopsies originating from 242 genotyped and tested MHS patients who did not present with clinical symptoms. This indicates that these patients must be considered as MHS patients with cores, and are clearly differentiated from CCD patients who have been tested positive for MHS.


Motor task difficulty and brain activity: investigation of goal-directed reciprocal aiming using positron emission tomography.
Differences in the kinematics and pattern of relative regional cerebral blood flow (rCBF) during goal-directed arm aiming were investigated with the use of a Fitts continuous aiming paradigm with three difficulty conditions (index of difficulty, ID) and two aiming types (transport vs. targeting) in six healthy right-handed young participants with the use of video-based movement trajectory analysis and positron emission tomography. Movement time and kinematic characteristics were analyzed together with the magnitude of cerebral blood flow to identify areas of brain activity proportionate to task and movement variables. Significant differences in rCBF between task conditions were determined by analysis of variance with planned comparisons of means with the use of group mean weighted linear contrasts. Data were first analyzed for the group. Then individual subject differences for the movement versus no movement and task difficulty comparisons were related to each individual subjects' anatomy by magnetic resonance imaging. Significant differences in rCBF during reciprocal aiming compared with no-movement conditions were found in a mosaic of well-known cortical and subcortical areas associated with the planning and execution of goal-directed movements. These included cortical areas in the left sensorimotor, dorsal premotor, and ventral premotor cortices, caudal supplementary motor area (SMA) proper, and parietal cortex, and subcortical areas in the left putamen, globus pallidus, red nucleus, thalamus, and anterior cerebellum. As aiming task difficulty (ID) increased, rCBF increased in areas associated with the planning of more complex movements requiring greater visuomotor processing. These included bilateral occipital, left inferior parietal, and left dorsal cingulate cortices--caudal SMA proper and right dorsal premotor area. These same areas showed significant increases or decreases, respectively, when contrast means were compared with the use of movement time or relative acceleration time, respectively, as the weighting factor. Analysis of individual subject differences revealed a correspondence between the spatial extent of rCBF changes as a function of task ID and the individuals' movement times. As task ID decreased, significant increases in rCBF were evident in the right anterior cerebellum, left middle occipital gyrus, and right ventral premotor area. Functionally, these areas are associated with aiming conditions in which the motor execution demands are high (i.e., coordination of rapid reversals) and precise trajectory planning is minimal. These same areas showed significant increases or decreases, respectively, when contrast means were compared with the use of movement time or relative acceleration time, respectively, as the weighting factor. A functional dissociation resulted from the weighted linear contrasts between larger (limb transport) or smaller (endpoint targeting) type amplitude/target width aiming conditions. Areas with significantly greater rCBF for targeting were the left motor cortex, left intraparietal sulcus, and left caudate. In contrast, those areas with greater rCBF associated with limb transport included bilateral occipital lingual gyri and the right anterior cerebellum. Various theoretical explanations for the speed/accuracy tradeoffs of rapid aiming movements have been proposed since the original information theory hypothesis of Fitts. This is the first report to relate the predictable variations in motor control under changing task constraints with the functional anatomy of these rapid goal-directed aiming movements. Differences in unimanual aiming task difficulty lead to dissociable activation of cortical-subcortical networks. Further, these data suggest that when more precise targeting is required, independent of task difficulty, a cortical-subcortical loop composed of the contralateral motor cortex, intraparietal sulcus, and caudate is activated. This is consistent with the role of motor cortex


Stable production of recombinant SARS-CoV-2 receptor-binding domain in mammalian cells with co-expression of a fluorescent reporter and its validation as antigenic target for COVID-19 serology testing.
SARS-CoV-2 receptor binding domain (RBD) recognizes the angiotensin converting enzyme 2 (ACE2) receptor in host cells that enables infection. Due to its antigenic specificity, RBD production is important for development of serological assays. Here we have established a system for stable RBD production in HEK 293T mammalian cells that simultaneously express the recombinant fluorescent protein dTomato, which enables kinetic monitoring of RBD expression by fluorescence microscopy. In addition, we have validated the use of this recombinant RBD in an ELISA assay for the detection of anti-RBD antibodies in serum samples of COVID-19 convalescent patients. Recombinant RBD generated using this approach can be useful for generation of antibody-based therapeutics against SARS-CoV-2, as well serological assays aimed to test antibody responses to this relevant virus.


Diagnostic Accuracy of Cell Block Preparations and Clinical Features Affecting It in Vitreoretinal Lymphoma.
Purpose: The purpose of this study was to examine the diagnostic accuracy of the cell block (CB) method and clinical features affecting it in patients with vitreoretinal lymphoma (VRL). Methods: This study enrolled 38 eyes in 33 VRL patients, and 7 eyes in 7 patients with idiopathic uveitis who underwent diagnostic vitrectomy. Medical records including the results of CB cytology, interleukin (IL)-10/-6 concentrations, and immunoglobulin heavy chain gene (IgH) rearrangement were retrospectively searched. Results: Patients with VRL comprised 16 women and 17 men, and the age of onset ranged from 44 to 85 years (mean: 70 years). CB preparations detected large malignant cells in 35 eyes (92%), whereas the other 3 VRL eyes were negative. Two of the latter three eyes showed subretinal infiltrates, which existed in 7 of 35 CB-positive eyes. Intravitreal IL-10 and -6 concentrations were 1866 ± 4088 pg/mL and 98 ± 139 pg/mL, respectively, and the rate of IL-10/-6 >1 was 86.9%. The presence of IgH monoclonality was 63.2%. In patients with uveitis, CB specimens revealed no atypical but small inflammatory cells. IL-6 concentration was 311.1 ± 240 pg/mL, whereas IL-10 was undetectable in six eyes, and the IL-negative rate was 85.7%. Six eyes (85.7%) with uveitis showed no IgH monoclonality. Conclusions: Diagnostic accuracy of CB preparations in VRL could achieve an equivalent outcome to IL ratio calculation and IgH monoclonality detection. The appearance of subretinal infiltrates may diminish the CB positivity.


Autonomic and brain responses associated with empathy deficits in autism spectrum disorder.
Accumulating evidence suggests that autonomic signals and their cortical representations are closely linked to emotional processes, and that related abnormalities could lead to social deficits. Although socio-emotional impairments are a defining feature of autism spectrum disorder (ASD), empirical evidence directly supporting the link between autonomic, cortical, and socio-emotional abnormalities in ASD is still lacking. In this study, we examined autonomic arousal indexed by skin conductance responses (SCR), concurrent cortical responses measured by functional magnetic resonance imaging, and effective brain connectivity estimated by dynamic causal modeling in seventeen unmedicated high-functioning adults with ASD and seventeen matched controls while they performed an empathy-for-pain task. Compared to controls, adults with ASD showed enhanced SCR related to empathetic pain, along with increased neural activity in the anterior insular cortex, although their behavioral empathetic pain discriminability was reduced and overall SCR was decreased. ASD individuals also showed enhanced correlation between SCR and neural activities in the anterior insular cortex. Importantly, significant group differences in effective brain connectivity were limited to greater reduction in the negative intrinsic connectivity of the anterior insular cortex in the ASD group, indicating a failure in attenuating anterior insular responses to empathetic pain. These results suggest that aberrant interoceptive precision, as indexed by abnormalities in autonomic activity and its central representations, may underlie empathy deficits in ASD.


Long-term follow-up of patients with severe rheumatic tricuspid stenosis.
Tricuspid stenosis is a part of the chronically rheumatic heart. Although rare, when tricuspid stenosis does occur, it occurs in the setting of coexistent mitral and aortic valve disease. The natural course of patients with severe tricuspid stenosis is not well defined. The aim of this study is to present close follow-up of patients with chronic rheumatic heart disease and severe tricuspid stenosis. We retrospectively studied 13 patients (11 women and 2 men) with severe tricuspid stenosis who were followed closely for 6 to 31 years. The mean tricuspid pressure gradient ranged from 3 to 9 mm Hg. Twelve patients underwent surgery for mitral and/or aortic valve lesions without complications. Concomitant tricuspid valve surgery was performed on six patients: two De Vega procedures, two Kay plications, and two implantations of Carpentier rings. All these also had leaflet commissurotomy. After surgery, the mean tricuspid gradient decreased in three patients, did not change in two, and increased in one. All 13 patients were treated with diuretics, digoxin, warfarin, and spirinolactone or ACE inhibitors. On their last follow-up visit, every patient had increased jugular venous pressure. Hepatomegaly was found in 6 of 13, leg edema in 4 of 13, and ascites in 1 of 13. Most tricuspid stenos patients are women with severe mitral and aortic valve disease. After successful repair of the mitral or aortic valve, and regardless of the type of tricuspid valve surgery, severe tricuspid stenosis was found to be very well tolerated by all the patients over many years of follow-up.


Hormonal, metabolic, and cardiovascular responses to static exercise in humans: influence of epidural anesthesia.
To determine the role of reflex neural mechanisms for hormonal, metabolic, heart rate (HR), and blood pressure (MABP) changes during static exercise, seven health young males performed 10-min periods of two-legged static knee extension both during control and during epidural anesthesia. Comparisons were made at identical absolute (29 Nm) and relative [15% maximal voluntary contraction (MVC)] force. Afferent nerve blockade was verified by hypesthesia below T10-T12 and attenuated postexercise ischemic pressor response. Leg strength was reduced to 67 +/- 5% of control. At same relative force, increases in MABP and HR occurred more rapidly without than with epidural anesthesia (P less than 0.05). This difference was diminished during identical absolute force. Changes in plasma concentrations of catecholamines followed the pattern of HR and MABP responses, with differences between epidural and control experiments being most pronounced early in the work period. Plasma beta-endorphin was elevated only after control exercise. No response at 15% MVC was found for growth hormone, adrenocorticotropic hormone, insulin, glucagon, cortisol, glycerol, free fatty acids, or glucose (P greater than 0.05). In conclusion, during static exercise with large muscle groups and moderate relative force, modest changes in plasma hormones and metabolites take place. Furthermore, afferent nervous feedback from contracting muscles is important in regulation of blood pressure, heart rate, and catecholamine responses during static exercise in humans.


[Pain and genetics].
Genetic factors can explain a significant amount of the variance in the perception of pain, sensitivity to painful stimuli and development of chronic pain. Twin studies, association studies and linkage analysis have located DNA sequences and SNPs that may be involved in the regulation of pain. Individual genes have an influence on the reaction to experimental painful stimuli, and certain genes are probably involved in painful clinical conditions. Optimal pain control and counselling of patients may be achievable through research into the genetic mechanisms involved in pain.


Facial resurfacing of the male patient.
Cosmetic facial plastic procedures, surgical and nonsurgical alike, continue to increase in number. Recent statistics from the American Society of Aesthetic Plastic Surgery indicate that approximately 78% of the nearly 8.3 million cosmetic procedures performed in the United States each year are nonsurgical. Similar statistics have been demonstrated by the American Academy of Facial Plastic and Reconstructive Surgery who report that over the past 5 years there has been a 47% increase in nonsurgical procedures compared with a 19% increase in surgical procedures. The demographic of those seeking cosmetic procedures is dramatically changing also. Although cosmetic surgery was once predominantly sought by females, more and more male patients are now seeking treatment.


Studies on the mechanism and kinetics of the 2-oxoglutarate dehydrogenase system from pig heart.
1. The kinetic properties of the 2-oxoglutarate dehydrogenase system were investigated. To this end, initial-velocity studies were carried out by the method of Fromm [(1967) Biochim. Biophys. Acta 139, 221-230]. Reciprocal plots of the results did not agree with those expected for the Hexa Uni Ping Pong mechanism previously proposed for the system. 2. The measured initial velocities were fitted to initial-rate equations corresponding to several possible mechanisms by using a computer optimization technique. Statistical analyses performed on the results of the optimization studies indicated that one mechanism was a significantly better fit to the experimental data than the other mechanisms tested. This mechanism is one in which there is a random order of binding of NAD+ and CoA and release of succinyl-CoA, although the binding of 2-oxoglutarate and release of CO2 is still given a Ping Pong mechanism, which precedes the binding of the other substrates. These conclusions were supported by NADH-inhibition studies. 3. The usefulness of the method of fitting initial-rate data to rate equations and the applicability of the proposed enzymic mechanism to the enzyme complex are discussed.


[Unusual radiological findings after surgically treated constrictive pericarditis].
The radiological findings in three patients who had had surgery for constrictive pericarditis are reported: 1. acute myocardial dilatation after pericardectomy for constrictive pericarditis, with good restitution of ventricular function; 2. abnormal ventricular appearances after pericardial resection during childhood; 3. diastolic prolapse of the cardiac apex after fenestration of the pericardium.


Microtubules as platforms for probing liquid-liquid phase separation in cells - application to RNA-binding proteins.
Liquid-liquid phase separation enables compartmentalization of biomolecules in cells, notably RNA and associated proteins in the nucleus. Besides having critical functions in RNA processing, there is a major interest in deciphering the molecular mechanisms of compartmentalization orchestrated by RNA-binding proteins such as TDP-43 (also known as TARDBP) and FUS because of their link to neuron diseases. However, tools for probing compartmentalization in cells are lacking. Here, we developed a method to analyze the mixing and demixing of two different phases in a cellular context. The principle is the following: RNA-binding proteins are confined on microtubules and quantitative parameters defining their spatial segregation are measured along the microtubule network. Through this approach, we found that four mRNA-binding proteins, HuR (also known as ELAVL1), G3BP1, TDP-43 and FUS form mRNA-rich liquid-like compartments on microtubules. TDP-43 is partly miscible with FUS but immiscible with either HuR or G3BP1. We also demonstrate that mRNA is essential to capture the mixing and demixing behavior of mRNA-binding proteins in cells. Taken together, we show that microtubules can be used as platforms to understand the mechanisms underlying liquid-liquid phase separation and their deregulation in human diseases.


[Diagnostic value of exercise tomoscintigraphy with thallium 201 in patients with complete left branch block].
Eighteen patients with rate-dependent (n = 5) or chronic (n = 13) left bundle branch block underwent thallium 201 exercise SPECT and selective coronary arteriography. 15 patients showed significant septal or anteroseptal perfusion defects on the exercise scintigrams, but in only 4 of them did the coronary disease involve the left anterior descending artery (LAD) (n = 3) or the left main coronary artery (n = 1). Among patients with normal scintigrams, one had right coronary artery stenosis. Test performance in detecting individual coronary artery stenosis greater than 70 p. 100 was: sensitivity 80 p. 100 (4/5) and specificity 15 p. 100. In patients with left bundle branch block, T1 201 SPECT was indeterminate for LAD disease due to reversible septal perfusion defect. We conclude that the usefulness of stress thallium 201 SPECT in patients with left bundle branch block is very limited.


Carotid inter-adventitial diameter is more strongly related to plaque score than lumen diameter: An automated tool for stroke analysis.
To compare the strength of correlation between automatically measured carotid lumen diameter (LD) and interadventitial diameter (IAD) with plaque score (PS). Retrospective study on a database of 404 common carotid artery B-mode sonographic images from 202 diabetic patients. LD and IAD were computed automatically using an advanced computerized edge detection method and compared with two distinct manual measurements. PS was computed by adding the maximal thickness in millimeters of plaques in segments taken from the internal carotid artery, bulb, and common carotid artery on both sides. The coefficient of correlation was 0.19 (p < 0.007) between LD and PS, and 0.25 (p < 0.0006) between IAD and PS. After excluding 10 outliers, coefficient of correlation was 0.25 (p < 0.0001) between LD and PS, and 0.38 (p < 0.0001) between IAD and PS. The precision of merit of automated versus the two manual measurements was 96.6% and 97.2% for LD, and 97.7% and 98.1%, for IAD, respectively. Our automated measurement system gave satisfying results in comparison with manual measurements. Carotid IAD was more strongly correlated to PS than carotid LD in this population sample of Japanese diabetic patients.


Modulation of the structure, catalytic activity, and fidelity of African swine fever virus DNA polymerase X by a reversible disulfide switch.
African swine fever virus polymerase X (pol X) is the smallest DNA polymerase known (174 amino acids), and its tertiary structure resembles the C-terminal half of prototypical X-family pol beta, which includes a catalytic dNTP-binding site (palm domain) and a finger domain. This structural similarity and the presence of viral genes coding for other base excision repair proteins suggest that pol X functions in a manner similar to pol beta, but inconsistencies concerning pol X catalysis have been reported. We examined the structural and functional properties of two forms of pol X using spectroscopic and kinetic analysis. Using (1)H-(15)N correlated NMR, we unambiguously demonstrated the slow interconversion of pol X between a reduced (pol X(red)) and an oxidized form (pol X(ox)), confirmed by mass spectrometry. Steady-state kinetic analysis revealed that pol X(ox), with a disulfide bond between Cys-81 and Cys-86, has approximately 10-fold lower fidelity than pol X(red) during dNTP insertion opposite a template G. The disulfide linkage is located between two beta-strands in the palm domain, near the putative dNTP-binding site. Structural alignment of pol X with a pol beta ternary structure suggests that the disulfide switch may modulate fidelity by altering the ability of the palm domain to align and stabilize the primer terminus and catalytic metal ion for deprotonation of the 3'-OH group and subsequent phosphoryl transfer. Thus, DNA polymerase fidelity is altered by the redox state of the enzyme and its related conformational changes.


Dystrophin-related muscular dystrophies.
The gene for the locus involved in Duchenne and Becker muscular dystrophies has been cloned and subject to intense analysis. The protein product of the locus is called dystrophin, and it has been shown to be associated with the muscle fiber membrane. The new knowledge of the molecular genetics of these disorders is being applied rapidly in clinical practice. Carrier detection and prenatal diagnosis have been revolutionized by the use of probes for the gene. These probes are also being employed to clarify cases where conventional clinical examination results in equivocal diagnoses. It is suggested that the disorders characterized by dystrophin abnormalities should be called dystrophin-related muscular dystrophies (DRMD). There are mouse and dog models for DRMD and these are being used to explore therapeutic strategies for treating DRMD patients.


Cyclic AMP controls mTOR through regulation of the dynamic interaction between Rheb and phosphodiesterase 4D.
The mammalian target of rapamycin complex 1 (mTORC1) is a molecular hub that regulates protein synthesis in response to a number of extracellular stimuli. Cyclic AMP (cAMP) is considered to be an important second messenger that controls mTOR; however, the signaling components of this pathway have not yet been elucidated. Here, we identify cAMP phosphodiesterase 4D (PDE4D) as a binding partner of Rheb that acts as a cAMP-specific negative regulator of mTORC1. Under basal conditions, PDE4D binds Rheb in a noncatalytic manner that does not require its cAMP-hydrolyzing activity and thereby inhibits the ability of Rheb to activate mTORC1. However, elevated cAMP levels disrupt the interaction of PDE4D with Rheb and increase the interaction between Rheb and mTOR. This enhanced Rheb-mTOR interaction induces the activation of mTORC1 and cap-dependent translation, a cellular function of mTORC1. Taken together, our results suggest a novel regulatory mechanism for mTORC1 in which the cAMP-determined dynamic interaction between Rheb and PDE4D provides a key, unique regulatory event. We also propose a new role for PDE4 as a molecular transducer for cAMP signaling.


Hydroxyl radicals and DNA double-strand breaks in X-irradiated E. coli.
We have used glycerol to study the relationship between hydroxyl radicals, one of the primary radiolytic products, and the production of DNA double-strand breaks in selected E. coli strains. Our results suggest that when bacteria are irradiated at doses up to about 120 Gray, hydroxyl radicals produce DNA lesions, but not double-strand breaks.


[Work of nurses in hyperbaric oxygenation].
The work of nursing personnel with patients receiving treatment with hyperbaric oxygenation is intended mainly to prepare the patients and provide care and psychological support. Hyperbaric oxygenation as a therapeutic method was included in Cuba's Health System in 1986. Hyperbaric oxygenation is applied in different diseases, both alone and as supportive treatment for clinical or surgical therapy and it is based on the significant increased oxygen dissolved in the plasma when gas pressure is increased to a proper dosage using hyperbaric chambers. Nursing personnel plays a very important role in providing care to patients and the team is in charge of the security measures and techniques. Hyperbaric oxygenation has proved to be effective for the treatment of anaerobic sepsis, intoxication due to carbon monoxide, peritonitis, gastroduodenal ulcers, liver diseases, osteomyelitis, as a support for grafting and transplants and other diseases.


Antibiotics prior to age 2 years have limited association with preschool growth trajectory.
Prior studies of early antibiotic use and growth have shown mixed results, primarily on cross-sectional outcomes. This study examined the effect of oral antibiotics before age 24 months on growth trajectory at age 2-5 years. We captured oral antibiotic prescriptions and anthropometrics from electronic health records through PCORnet, for children with ≥1 height and weight at 0-12 months of age, ≥1 at 12-30 months, and ≥2 between 25 and 72 months. Prescriptions were grouped into episodes by time and by antimicrobial spectrum. Longitudinal rate regression was used to assess differences in growth rate from 25 to 72 months of age. Models were adjusted for sex, race/ethnicity, steroid use, diagnosed asthma, complex chronic conditions, and infections. 430,376 children from 29 health U.S. systems were included, with 58% receiving antibiotics before 24 months. Exposure to any antibiotic was associated with an average 0.7% (95% CI 0.5, 0.9, p < 0.0001) greater rate of weight gain, corresponding to 0.05 kg additional weight. The estimated effect was slightly greater for narrow-spectrum (0.8% [0.6, 1.1]) than broad-spectrum (0.6% [0.3, 0.8], p < 0.0001) drugs. There was a small dose response relationship between the number of antibiotic episodes and weight gain. Oral antibiotic use prior to 24 months of age was associated with very small changes in average growth rate at ages 2-5 years. The small effect size is unlikely to affect individual prescribing decisions, though it may reflect a biologic effect that can combine with others.


Emotion regulation and executive functions in adolescents with skin picking disorder.
This study aimed to investigate emotion regulation difficulties and executive functions of adolescent outpatients with skin picking disorder (SPD). Ninety six adolescents with SPD and ninety healthy controls were included in the study. All patients were diagnosed with SPD as per the diagnostic criteria of DSM-5. A battery of tests were implemented to evaluate emotional regulation strategies (i.e. acceptance,), as well as associations between those strategies and executive functions, and clinical variables (anxiety, depressive symptoms, impulsivity and illness characteristics). The SPD group had significantly higher scores in inhibition (t = 2.982, p = 0.030), emotional control (t = 2.461, p = 0.016), and planning-organization (t = 2.139, p = 0.038) Multiple linear regression model explained a considerable amount of variance of executive functions in the patient group (Adjusted R2=66.4%). In the patient group, age at illness-onset and the severity of inhibiton were significantly associated with the disruptions in emotional control functions (For age at illness-onset, β= -0.45, t=-3.0, p = 0.012 and for BRIEF Inhibition scores, β = 0.31, t = 2.8, p = 0.008). The results of this study suggest that those with SPD have more emotion regulation problems and poorer executive function skills compared to those without SPD. Deficits in emotional control were associated with inhibition process and age-onset of the illness.


Graphene Aerogels for In Situ Synthesis of Conductive Poly(para-phenylenediamine) Polymers, and Their Sensor Application.
In this study, macroporous graphene aerogels (GAs) were synthesized by chemical reduction of graphene oxide sheets and were used as a support material for in situ synthesis of conductive poly(para-phenylenediamine) (p(p-PDA)). The in situ synthesis of p(p-PDA) in GA was carried out by using a simple oxidation polymerization technique. Moreover, the prepared conductive p(p-PDA) polymers in the networks of GAs were doped with various types of acids such as hydrochloric acid (HCl), nitric acid (HNO3), sulfuric acid (H2SO4), phosphoric acid (H3PO4), respectively. The prepared GA and different acid-doped forms as GA/p(p-PDA) composites were characterized by FT-IR, TGA, and conductivity measurements. The observed FT-IR peaks at 1574 cm-1, and 1491 cm-1, for stretching deformations of quinone and benzene, respectively, confirmed the in situ synthesis of P(p-PDA) polymers within GAs. The conductivity of GAs with 2.17 × 10-4 ± 3.15 × 10-5 S·cm-1 has experienced an approximately 250-fold increase to 5.16 × 10-2 ± 2.72 × 10-3 S·cm-1 after in situ synthesis of p(p-PDA) polymers and with HCl doping. Conductivity values for different types of acid-doped GA/p(p-PDA) composites were compared with the bare p(p-PDA) and their undoped forms. Moreover, the changes in the conductivity of GA and GA/p(p-PDA) composites upon CO2 gas exposure were compared and their sensory potential in terms of response and sensitivity, along with reusability in CO2 detection, were evaluated.


Characterization of human and rat glucagon-like peptide-1 receptors in the neurointermediate lobe: lack of coupling to either stimulation or inhibition of adenylyl cyclase.
Glucagon-like peptide-1 (GLP-1) has been shown to bind to the posterior pituitary in the rat. We examined GLP-1 binding sites in human postmortem and rat pituitaries. Dense [125I]GLP-1 binding was seen in both human and rat posterior pituitary. In rat neurointermediate lobe membranes the binding site showed a Kd of 0.2 +/- 0.01 nM and a binding capacity of 600 +/- 33 fmol/mg protein (n = 3). In human pituitary membranes the binding site showed a Kd of 0.82 +/-0.05 nM and a binding capacity of 680 +/- 93 fmol/mg protein (n = 3). Chemical cross-linking showed a relative mol wt for the receptor-ligand complex of 73,100 +/- 1,400 (n = 3) in man and 59,300 +/- 900 (n = 3) in rat. GLP-1 (1 microM) failed to increase cAMP levels measured in rat neurointermediate lobes, whereas pituitary adenylate cyclase-activating polypeptide (100 nM) increased cAMP from a basal level of 14 +/-1 to 80 +/- 4 pmol/neurointermediate lobe 15 min (n = 5; P < 0.01). GLP-1 (up to 1 microM) did not affect the pituitary adenylate cyclase-activating polypeptide-stimulated cAMP levels. GLP-1 (up to 1 microM) also did not stimulate release of vasopressin or oxytocin from isolated rat neurointermediate lobes. The posterior pituitary shows the highest density of GLP-1-binding sites yet seen, but their function and signal transduction mechanism remain unknown.


Pituitary surgery as alternative to dopamine agonists treatment for microprolactinomas: a cohort study.
Microprolactinomas are currently treated with dopamine agonists. Outcome information on microprolactinoma patients treated by surgery is limited. This study reports the first large series of consecutive non-invasive microprolactinoma patients treated by pituitary surgery and evaluates the efficiency and safety of this treatment. Follow-up of a cohort of consecutive patients treated by surgery. Between January 2008 and October 2020, 114 adult patients with pure microprolactinomas were operated on in a single tertiary expert neurosurgical department, using an endoscopic endonasal transsphenoidal approach. Eligible patients presented with a microprolactinoma with no obvious cavernous invasion on MRI. Prolactin was assayed before and after surgery. Disease-free survival was modeled using Kaplan-Meier representation. A cox regression model was used to predict remission. Median follow-up was 18.2 months (range: 2.8-155). In this cohort, 14/114 (12%) patients were not cured by surgery, including ten early surgical failures and four late relapses occurring 37.4 months (33-41.8) after surgery. From Kaplan-Meier estimates, 1-year and 5-year disease free survival was 90.9% (95% CI: 85.6-96.4%) and 81% (95% CI: 71.2-92.1%) respectively. The preoperative prolactinemia was the only significant preoperative predictive factor for remission (P < 0.05). No severe complication was reported, with no anterior pituitary deficiency after surgery, one diabetes insipidus, and one postoperative cerebrospinal fluid leakage properly treated by muscle plasty. In well-selected microprolactinoma patients, pituitary surgery performed by an expert neurosurgical team is a valid first-line alternative treatment to dopamine agonists.


Orthopedic infections: A prospective study of 378 clean procedures.
Six hundred twenty orthopedic surgery patients were evaluated in a prospective study of postoperative infection. The wound infection rate among the 378 elective clean procedures was 5.8 per cent (3.2 per cent major plus 2.6 per cent minor infections). Staphylococcus aureus was the single most common pathogen recovered in both major and minor infections. Gram-negative rods predominated in major infections, but were rarely found in minor infections. In the clean procedure group, infection rates increased with age and duration of operation. Preoperative consideration should be given to all A "profile sheet" or checklist of several such factors is presented for this purpose.


Real-time machine-learning-driven control system of a deformable mirror for achieving aberration-free X-ray wavefronts.
A neural-network machine learning model is developed to control a bimorph adaptive mirror to achieve and preserve aberration-free coherent X-ray wavefronts at synchrotron radiation and free electron laser beamlines. The controller is trained on a mirror actuator response directly measured at a beamline with a real-time single-shot wavefront sensor, which uses a coded mask and wavelet-transform analysis. The system has been successfully tested on a bimorph deformable mirror at the 28-ID IDEA beamline of the Advanced Photon Source at Argonne National Laboratory. It achieved a response time of a few seconds and maintained desired wavefront shapes (e.g., a spherical wavefront) with sub-wavelength accuracy at 20 keV of X-ray energy. This result is significantly better than what can be obtained using a linear model of the mirror's response. The developed system has not been tailored to a specific mirror and can be applied, in principle, to different kinds of bending mechanisms and actuators.


A distinct source and differentiation history for Kolumbo submarine volcano, Santorini volcanic field, Aegean arc.
This study reports the first detailed geochemical characterization of Kolumbo submarine volcano in order to investigate the role of source heterogeneity in controlling geochemical variability within the Santorini volcanic field in the central Aegean arc. Kolumbo, situated 15 km to the northeast of Santorini, last erupted in 1650 AD and is thus closely associated with the Santorini volcanic system in space and time. Samples taken by remotely-operated vehicle that were analyzed for major element, trace element and Sr-Nd-Hf-Pb isotope composition include the 1650 AD and underlying K2 rhyolitic, enclave-bearing pumices that are nearly identical in composition (73 wt.% SiO2, 4.2 wt.% K2O). Lava bodies exposed in the crater and enclaves are basalts to andesites (52-60 wt.% SiO2). Biotite and amphibole are common phenocryst phases, in contrast with the typically anhydrous mineral assemblages of Santorini. The strong geochemical signature of amphibole fractionation and the assimilation of lower crustal basement in the petrogenesis of the Kolumbo magmas indicates that Kolumbo and Santorini underwent different crustal differentiation histories and that their crustal magmatic systems are unrelated. Moreover, the Kolumbo samples are derived from a distinct, more enriched mantle source that is characterized by high Nb/Yb (>3) and low 206Pb/204Pb (<18.82) that has not been recognized in the Santorini volcanic products. The strong dissimilarity in both petrogenesis and inferred mantle sources between Kolumbo and Santorini suggests that pronounced source variations can be manifested in arc magmas that are closely associated in space and time within a single volcanic field.


Expression of an (Engineered) 4,6-α-Glucanotransferase in Potato Results in Changes in Starch Characteristics.
Starch structure strongly influences starch physicochemical properties, determining the end uses of starch in various applications. To produce starches with novel structure and exploit the mechanism of starch granule formation, an (engineered) 4, 6-α-glucanotransferase (GTFB) from Lactobacillus reuteri 121 was introduced into two potato genetic backgrounds: amylose-containing line Kardal and amylose-free mutant amf. The resulting starches showed severe changes in granule morphology regardless of genetic backgrounds. Modified starches from amf background exhibited a significant increase in granule size and starch phosphate content relative to the control, while starches from Kardal background displayed a higher digestibility, but did not show changes in granule size and phosphate content. Transcriptome analysis revealed the existence of a mechanism to restore the regular packing of double helices in starch granules, which possibly resulted in the removal of novel glucose chains potentially introduced by the (engineered) GTFB. This amendment mechanics would also explain the difficulties to detect alterations in starch fine structure in the transgenic lines.


Alterations of glucose metabolism during perfusion of rat lung with paraquat.
Isolated perfused rat lungs were used to investigate effects of paraquat on lung glucose metabolism. Lungs were ventilated with 5% CO2 in air and perfused with Krebs-Ringer bicarbonate buffer, pH 7.4, containing albumin and 5.5 mM radiolabeled D-glucose. Control lung glucose utilization, estimated from rate of 3H2O production from [5-3H]glucose, was 44 mumol/h-g dry wt. Pentose cycle activity, based on 14CO2 specific yields at the end of perfusions with [1-14C]- and [6-14C]glucose, was 14% of glucose utilization. During perfusion with 1.5 mM paraquat, glucose utilization increased 28%, 14CO2 production via the pentose cycle increased 182% (P less than 0.005), CO2 production via mitochondrial metabolism increased 39% (P less than 0.02), and the rate of lactate production increased 28% (P less than 0.05). Pyruvate production and the lactate-to-pyruvate ratio were not significantly altered. The data indicate that interaction of paraquat with the lung results in increased turnover of cytoplasmic NADPH and increased mitochondrial metabolism, but no significant change in cytoplasmic redox state. The findings are compatible with intracellular enzymatic reduction of paraquat by an NADPH-requiring reductase.


Intraoperative conversion during video-assisted thoracoscopy does not constitute a treatment failure†.
Intraoperative conversion may be required during video-assisted thoracoscopic surgery (VATS) for lung cancer. We evaluated the morbidity and mortality rates associated with VATS for anatomical pulmonary resection with conversion to thoracotomy and compared this technique with full VATS and an open thoracotomic approach. We performed a retrospective, single-centre study between January 2011 and January 2017 and included 610 consecutive patients having undergone either VATS (with or without intraoperative conversion) or open thoracotomy for anatomical pulmonary resection. Pneumonectomies and angioplastic/bronchoplastic/chest wall resections were excluded. After propensity score adjustment, we assessed the 90-day mortality and determined whether the surgical approach was a risk factor for mortality. Of the 610 patients, 253 patients underwent full VATS, 56 patients underwent VATS + conversion and 301 patients underwent up-front open thoracotomy. Relative to the open thoracotomy group, the VATS + conversion group had a higher incidence of cardiac or respiratory comorbidities and was more likely to have an early-stage tumour. Following adjustment, the 90-day postoperative mortality rate was 5.4% (n = 3/56) in the VATS + conversion group and 3.7% (n = 11/301) in the open thoracotomy group (P = 0.58). Likewise, the morbidity rate was similar in these 2 groups. In a multivariable analysis, the surgical approach was not a risk factor for postoperative mortality. Following anatomical resection for lung cancer, VATS with conversion and open thoracotomy were associated with similar early postoperative morbidity and mortality rates. When in doubt, VATS should be preferred to thoracotomy; it potentially provides the patient with benefits of a fully VATS-based resection but is not disadvantageous when intraoperative conversion is required.


Hypoxia-mediated stabilization of HIF1A in prostatic intraepithelial neoplasia promotes cell plasticity and malignant progression.
Prostate cancer (PCa) is a leading cause of cancer-related deaths. The slow evolution of precancerous lesions to malignant tumors provides a broad time frame for preventing PCa. To characterize prostatic intraepithelial neoplasia (PIN) progression, we conducted longitudinal studies on Pten(i)pe-/- mice that recapitulate prostate carcinogenesis in humans. We found that early PINs are hypoxic and that hypoxia-inducible factor 1 alpha (HIF1A) signaling is activated in luminal cells, thus enhancing malignant progression. Luminal HIF1A dampens immune surveillance and drives luminal plasticity, leading to the emergence of cells that overexpress Transglutaminase 2 (TGM2) and have impaired androgen signaling. Elevated TGM2 levels in patients with PCa are associated with shortened progression-free survival after prostatectomy. Last, we show that pharmacologically inhibiting HIF1A impairs cell proliferation and induces apoptosis in PINs. Therefore, our study demonstrates that HIF1A is a target for PCa prevention and that TGM2 is a promising prognostic biomarker of early relapse after prostatectomy.


Recent progress in engineering alpha/beta hydrolase-fold family members.
The members of the alpha/beta hydrolase-fold family represent a functionally versatile group of enzymes with many important applications in biocatalysis. Given the technical significance of alpha/beta hydrolases in processes ranging from the kinetic resolution of enantiomeric precursors for pharmaceutical compounds to bulk products such as laundry detergent, optimizing and tailoring enzymes for these applications presents an ongoing challenge to chemists, biochemists, and engineers alike. A review of the recent literature on alpha/beta hydrolase engineering suggests that the early successes of "random processes" such as directed evolution are now being slowly replaced by more hypothesis-driven, focused library approaches. These developments reflect a better understanding of the enzymes' structure-function relationship and improved computational resources, which allow for more sophisticated search and prediction algorithms, as well as, in a very practical sense, the realization that bigger is not always better.


Intravenous glycoprotein IIb/IIIa inhibition in non-ST segment elevation acute coronary syndromes.
Over recent years, substantial clinical trial evidence regarding glycoprotein IIb/IIIa inhibition for the medical management of non-ST segment elevation acute coronary syndromes has been compiled. Despite being recently advocated for the management of coronary instability within widely accepted guidelines, its use among patients presenting with acute coronary syndromes remains somewhat contentious. Within randomized placebo-controlled trials, uniform efficacy with the glycoprotein IIb/IIIa inhibitors has not been shown, whereas a disturbing excess in adverse events is evident within some trials. Currently, the basis for this heterogeneity of clinical evidence has not been adequately explained. However, evolving insights from clinical trials and basic research have further refined our understanding of glycoprotein IIb/IIIa antagonist therapy and the potential effects beyond the inhibition of the fibrinogen receptor. Likewise, appreciation of the pharmacokinetic characteristics of these agents provides putative explanations for the diverse findings of the randomized trials. Reexamination of the clinical trial data in light of this recent evidence provides a basis for interpreting the marginal results of glycoprotein IIb/IIIa inhibition in acute coronary syndromes. Consideration of these factors may facilitate the optimal clinical application of this class of agents to the management of coronary instability.


Cloning and sequence analysis of a cDNA clone coding for the mouse GM2 activator protein.
A cDNA (1.1 kb) containing the complete coding sequence for the mouse GM2 activator protein was isolated from a mouse macrophage library using a cDNA for the human protein as a probe. There was a single ATG located 12 bp from the 5' end of the cDNA clone followed by an open reading frame of 579 bp. Northern blot analysis of mouse macrophage RNA showed that there was a single band with a mobility corresponding to a size of 2.3 kb. We deduce from this that the mouse mRNA, in common with the mRNA for the human GM2 activator protein, has a long 3' untranslated sequence of approx. 1.7 kb. Alignment of the mouse and human deduced amino acid sequences showed 68% identity overall and 75% identity for the sequence on the C-terminal side of the first 31 residues, which in the human GM2 activator protein contains the signal peptide. Hydropathicity plots showed great similarity between the mouse and human sequences even in regions of low sequence similarity. There is a single N-glycosylation site in the mouse GM2 activator protein sequence (Asn151-Phe-Thr) which differs in its location from the single site reported in the human GM2 activator protein sequence (Asn63-Val-Thr).


Machine learning for magnetic phase diagrams and inverse scattering problems.
Machine learning promises to deliver powerful new approaches to neutron scattering from magnetic materials. Large scale simulations provide the means to realise this with approaches including spin-wave, Landau Lifshitz, and Monte Carlo methods. These approaches are shown to be effective at simulating magnetic structures and dynamics in a wide range of materials. Using large numbers of simulations the effectiveness of machine learning approaches are assessed. Principal component analysis and nonlinear autoencoders are considered with the latter found to provide a high degree of compression and to be highly suited to neutron scattering problems. Agglomerative heirarchical clustering in the latent space is shown to be effective at extracting phase diagrams of behavior and features in an automated way that aid understanding and interpretation. The autoencoders are also well suited to optimizing model parameters and were found to be highly advantageous over conventional fitting approaches including being tolerant of artifacts in untreated data. The potential of machine learning to automate complex data analysis tasks including the inversion of neutron scattering data into models and the processing of large volumes of multidimensional data is assessed. Directions for future developments are considered and machine learning argued to have high potential for impact on neutron science generally.