Comparison of pneumococcal vaccination response in children with sickle cell disease: HbSS and HbSC.
Sickle cell disease (SCD) children are at increased risk of invasive pneumococcal disease and rely on penicillin prophylaxis and vaccination for infection prevention. Post-vaccination antibody levels in SCD may wane overtime. HbSC are believed to have better immunological response than HbSS. To compare antibody response to 23-valent pneumococcal polysaccharide vaccine (PPSV-23) between HbSS and HbSC. Patients with HbSS (n=33) and HbSC (n=11), aged 7-18 years, were prospectively recruited. Luminex pneumococcal antibody levels were measured for 23-serotypes, after two PPSV-23 doses. Absolute median titer for 20 of the 23 serotypes was higher in HbSC than HbSS and significantly higher for serotypes 22 (3.9 vs. 1.6mcg/ml; p=0.039) and 43 (2.9 vs. 0.8mcg/ml; p=0.007). HbSC mounted a better immune anti-pneumococcal response compared to HbSS (≥1.3mcg/ml) for 18 of 23 serotypes, albeit not significant for any of the serotypes. More HbSC (64%) than HbSS (42%) were good vaccine responders (p=0.303). Two of 21 (10%) good vaccine responders and nine of 23 (39%) poor vaccine responders SCD participants subsequently developed acute chest syndrome or pneumonia (p=0.036). None of the HbSC patients developed ACS after receiving PPSV-23. HbSS poor vaccine responders were at increased future recurrence risk for ACS (p=0.003), pneumonia (p=0.036) or both (p=0.011), compared to good vaccine responders. HbSC possess better pneumococcal vaccine response than HbSS. Poor vaccine response is concerning for future acute pulmonary events. Current vaccination strategy for SCD sub-types are lacking, therefore further study to evaluate utility of vaccine boosters is necessary.


Facilitation, augmentation, and potentiation of synaptic transmission at the superior cervical ganglion of the rabbit.
The effect of repetitive stimulation on synaptic transmission was studied in the isolated superior cervical ganglion of the rabbit under conditions of reduced quantal content. Excitatory postsynaptic potentials (EPSP) were recorded with the sucrose gap technique to obtain estimates of transmitter release. Four components of increased transmitter release, with time constants of decay similar to those observed at the frog neuromuscular junction at 20 degrees C, were found in the ganglion at 34 degrees C: a first component of facilitation, which decayed with a time constant of 59 +/- 14 ms (mean +/- SD); a second component of facilitation, which decayed with a time constant of 388 +/- 97 ms; augmentation, which decayed with a time constant of 7.2 +/- 1 s; and potentiation, which decayed with a time constant of 88 +/- 25 s. The addition of 0.1-0.2 mM Ba2+ to the Locke solution increased the magnitude but not the time constant of decay of augmentation. Ba2+ had little effect on potentiation. The addition of 0.2-0.8 mM Sr2+ to the Locke solution appeared to increase the magnitude of the second component of facilitation. Sr2+ had little effect on augmentation or potentiation. These selective effects of Ba2+ and Sr2+ on the components of increased transmitter release in the rabbit ganglion are similar to the effects of these ions at the frog neuromuscular junction. Although the effects of Ba2+ and Sr2+ are similar in the two preparations, the magnitudes of augmentation and the second component of facilitation after a single impulse were about 6-10 times greater in the rabbit ganglion than at the frog neuromuscular junction. These results suggest that the underlying mechanisms in the nerve terminal that give rise to the components of increased transmitter release in the rabbit ganglion and frog neuromuscular junction are similar but not identical.


Bipolar spectrum psychopathology is associated with altered emotion dynamics across multiple timescales.
Emotion dysregulation is a core feature of bipolar spectrum psychopathology and may confer risk for poor outcomes or progression along the bipolar spectrum. However, previous research on bipolar psychopathology has primarily concentrated on characterizing distinct mood episodes and failed to characterize microlevel dynamics of the experience of emotion. This is the first study to our knowledge to comprehensively examine the extent to which bipolar spectrum psychopathology, as measured by the Hypomanic Personality Scale (HPS), is associated with altered dynamics of positive (PA) and negative affect (NA) across multiple timescales. Young adults (n = 233) oversampled for high HPS scores (>1.5 SD) completed self-report questionnaires and 14 days of experience sampling questionnaires assessing high- and low-arousal NA and PA. Four emotion dynamics (reactivity, variability, instability, inertia) were computed from each participant's time series. As predicted, HPS scores were positively associated with variability and instability of high-arousal NA and PA both within and between days (over and above mean levels of emotions, depression, and neuroticism). Further, HPS scores were associated with large fluctuations in low- but not high-arousal NA and moderated stress reactivity. Specifically, high scorers on the HPS were more likely to report feeling like their emotions were out of control (but not high-intensity NA) when experiencing stress. Contrary to expectation, HPS scores were unassociated with inertia of high-arousal PA. Findings indicated that microlevel emotion dynamics are disrupted across multiple timescales in those high in bipolar spectrum psychopathology. Examining emotion dynamics should enhance understanding of risk for bipolar disorders and facilitate development of mood-monitoring interventions. (PsycInfo Database Record (c) 2022 APA, all rights reserved).


Evaluation of bacterial coinfections and susceptible antibiotic profiles in hospitalized COVID-19 patients in Koya district, Iraq.
Bacterial coinfection among intensive care unit (ICU) COVID-19 patients is not widely studied in Iraq. Hence, the current study was performed to determine the prevalence of secondary bacterial infection and susceptible profile in ICU patients with COVID-19 infections. The study was conducted from November 2021 to April 2022, in Mad Center/ Shahid Doctor Khalid Hospital/Koya district. The midstream urine (MSU), sputum, and throat swab (TS) were obtained. Age, gender, clinical characteristics, bacterial identities, and antibiotic sensitivity profiles were collected for 200 COVID-19 patients. The standard biochemical tests confirmed the bacterial isolates. Antibiotic susceptibility was implemented by using the disk diffusion method. Out of 200 ICU patients, 87 (43.5%) of them had bacterial coinfection. The most predominant bacteria were isolated Acinetobacter baumannii (25.3%), Escherichia coli (18.3%), Pseudomonas aeruginosa (16%), Klebsiella pneumonia (11.5%), followed by Staphylococcus aureus (4.6%), and Enterococcus spp. (3.5%). Gram-negative bacteria showed a high level of sensitivity to Ertapenem (90.7%) and Piperacillin/Tazobactam (84.9%). Gram-positive isolates showed high sensitivity to Teicoplanin (77.2%) and Rifampicin (71%). The susceptibility rate of the isolated bacteria is moderate; this indicates that early diagnosis of coinfections and more accurate use of antibiotics are necessary to mitigate the severity of COVID-19.


Screening, diagnosis and management of diabetic sensorimotor polyneuropathy in clinical practice: International expert consensus recommendations.
Diabetic sensorimotor polyneuropathy (DSPN) affects around one third of people with diabetes and accounts for considerable morbidity, increased risk of mortality, reduced quality of life, and increased health care costs resulting particularly from neuropathic pain and foot ulcers. Painful DSPN is encountered in 13-26% of diabetes patients, while up to 50% of patients with DSPN may be asymptomatic. Unfortunately, DSPN still remains inadequately diagnosed and treated. Herein we provide international expert consensus recommendations and algorithms for screening, diagnosis, and treatment of DSPN in clinical practice derived from a Delphi process. Typical neuropathic symptoms include pain, paresthesias, and numbness particularly in the feet and calves. Clinical diagnosis of DSPN is based on neuropathic symptoms and signs (deficits). Management of DSPN includes three cornerstones: (1) lifestyle modification, optimal diabetes treatment aimed at near-normoglycemia, and multifactorial cardiovascular risk intervention, (2) pathogenetically oriented pharmacotherapy (e.g. α-lipoic acid and benfotiamine), and (3) symptomatic treatment of neuropathic pain including analgesic pharmacotherapy (antidepressants, anticonvulsants, opioids, capsaicin 8% patch and combinations, if required) and non-pharmacological options. Considering the individual risk profile, pain management should not only aim at pain relief, but also allow for improvement in quality of sleep, functionality, and general quality of life.


Studies on formulation and in vitro evaluation of floating matrix tablets of domperidone.
Floating matrix tablets of domperidone were developed to prolong gastric residence time and thereby increased drug bioavailability. Domperidone was chosen as a model drug because it is poorly absorbed from the lower gastrointestinal tract. The tablets were prepared by wet granulation technique, using polymers such as hydroxypropylmethylcellulose K4M, carbopol 934P, and sodium alginate, either alone or in combination, and other standard excipients. Tablets were evaluated for physical characteristics viz. hardness, % friability, floating capacity, weight variation and content uniformity. Further, tablets were evaluated for in vitro release characteristics for 24 h. In vitro release mechanism was evaluated by linear regression analysis. Floating matrix tablets based on combination of three polymers namely; hydroxypropylmethylcellulose K4M, carbopol 934P and sodium alginate exhibited desired floating and prolonged drug release for 24 h. Carbopol loading showed negative effect on floating properties but were found helpful to control the release rate of drug.


Discovery of N-((4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-methylpyridin-2-yl)-1H-imidazol-2-yl)methyl)-2-fluoroaniline (EW-7197): a highly potent, selective, and orally bioavailable inhibitor of TGF-β type I receptor kinase as cancer immunotherapeutic/antifibrotic agent.
A series of 2-substituted-4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-methylpyridin-2-yl)imidazoles was synthesized and evaluated to optimize a prototype inhibitor of TGF-β type I receptor kinase (ALK5), 6. Combination of replacement of a quinoxalin-6-yl moiety of 6 with a [1,2,4]triazolo[1,5-a]pyridin-6-yl moiety, insertion of a methyleneamino linker, and a o-F substituent in the phenyl ring markedly increased ALK5 inhibitory activity, kinase selectivity, and oral bioavailability. The 12b (EW-7197) inhibited ALK5 with IC50 value of 0.013 μM in a kinase assay and with IC50 values of 0.0165 and 0.0121 μM in HaCaT (3TP-luc) stable cells and 4T1 (3TP-luc) stable cells, respectively, in a luciferase assay. Selectivity profiling of 12b using a panel of 320 protein kinases revealed that it is a highly selective ALK5/ALK4 inhibitor. Pharmacokinetic study with 12b·HCl in rats showed an oral bioavailability of 51% with high systemic exposure (AUC) of 1426 ng × h/mL and maximum plasma concentration (Cmax) of 1620 ng/mL. Rational optimization of 6 has led to the identification of a highly potent, selective, and orally bioavailable ALK5 inhibitor 12b.


Not enough by half: NFAT5 haploinsufficiency in two patients with Epstein-Barr virus susceptibility.
The transcription factor Nuclear factor of activated T cells 5 (NFAT5), pivotal in immune regulation and function, can be induced by osmotic stress and tonicity-independent signals. We aimed to investigate and characterize two unrelated patients with Epstein-Barr virus susceptibility and no known genetic etiology. After informed consent, we reviewed the electronic charts, extracted genomic DNA, performed whole-exome sequencing, filtered, and prioritized their variants, and confirmed through Sanger sequencing, family segregation analysis, and some functional assays, including lymphoproliferation, cytotoxicity, and characterization of natural killer cells. We describe two cases of pediatric Mexican patients with rare heterozygous missense variants in NFAT5 and EBV susceptibility, a school-age girl with chronic-active infection of the liver and bowel, and a teenage boy who died of hemophagocytic lymphohistiocytosis. NFAT5 is an important regulator of the immune response. NFAT5 haploinsufficiency has been described as an immunodeficiency syndrome affecting both innate and adaptive immunity. EBV susceptibility might be another manifestation in the spectrum of this disease.


Infection of Brain Pericytes Underlying Neuropathology of COVID-19 Patients.
A wide range of neurological manifestations have been associated with the development of COVID-19 following SARS-CoV-2 infection. However, the etiology of the neurological symptomatology is still largely unexplored. Here, we used state-of-the-art multiplexed immunostaining of human brains (n = 6 COVID-19, median age = 69.5 years; n = 7 control, median age = 68 years) and demonstrated that expression of the SARS-CoV-2 receptor ACE2 is restricted to a subset of neurovascular pericytes. Strikingly, neurological symptoms were exclusive to, and ubiquitous in, patients that exhibited moderate to high ACE2 expression in perivascular cells. Viral dsRNA was identified in the vascular wall and paralleled by perivascular inflammation, as signified by T cell and macrophage infiltration. Furthermore, fibrinogen leakage indicated compromised integrity of the blood-brain barrier. Notably, cerebrospinal fluid from additional 16 individuals (n = 8 COVID-19, median age = 67 years; n = 8 control, median age = 69.5 years) exhibited significantly lower levels of the pericyte marker PDGFRβ in SARS-CoV-2-infected cases, indicative of disrupted pericyte homeostasis. We conclude that pericyte infection by SARS-CoV-2 underlies virus entry into the privileged central nervous system space, as well as neurological symptomatology due to perivascular inflammation and a locally compromised blood-brain barrier.


Fibreoptic assessment of paediatric sized laryngeal mask airways.
Laryngeal mask airways (LMA) are commonly used in paediatric anaesthesia. A well-placed LMA should provide a direct view of the vocal cords facilitating bronchoscopy or fibreoptic intubation. The aim of this audit was to assess the bronchoscopic view of the glottis obtained through an LMA with regard to its size. We prospectively assessed the position of LMAs in relation to the glottic aperture in 350 children (zero to seven years) undergoing elective fibreoptic examination of the upper and/or lower airways. Following induction of anaesthesia and positioning of the LMA, a fibreoptic evaluation of the view of the glottis was performed (complete, partial or no visualisation). Chest movement on manual ventilation was judged as good in the majority of patients and adequate for the remainder. No overt signs of airway obstruction were noted in any patient. However, a complete view of the glottic aperture was present in only 50% of size 1 LMAs, 57.5% of size 1.5, 72.7% of size 2 and 77.8% of size 2.5. The epiglottis impinged on the LMA opening, partially obstructing the view of the glottis in 36.3% of size 1 LMAs, 31.5% of size 1.5, 21% of size 2 and 17.8% of size 2.5. In 13.7% of size 1 LMAs, 11% of size 1.5, 6.3% of size 2 and 4.4% of size 2.5, the epiglottis was completely downfolded, obstructing the view of the glottic aperture. The findings indicate that even if ventilation is judged as adequate, smaller paediatric LMAs are more commonly associated with suboptimal anatomical positioning with partial obstruction of the glottic aperture than larger LMAs, and therefore may require repositioning more often.


Seclusion, restraint, and involuntary medication in Finnish psychiatric care: a register study with root-level data.
Purpose: Despite potentially harmful effects, seclusion, restraint, and involuntary medication continue to be frequently applied in psychiatric care. These restrictive measures are often examined by means of registers, but homogeneous practices in the measurement and description seem to be missing. This nationwide register study aimed to examine the use of seclusion, mechanical and physical restraint, and involuntary medication in Finland.Material and methods: Root-level register data concerning the year 2017 were collected directly from 140 inpatient psychiatric wards within 21 organizations. The data were analyzed statistically.Results: In 2017, the most used restrictive measure in Finnish psychiatric wards was seclusion (4006 episodes), followed by involuntary medication (2187 episodes), mechanical restraint (2113 episodes) and physical restraint (1064 events). Similarly, the duration of seclusion episodes was longer than the duration of restraint episodes. Remarkable variation between wards in the use of seclusion, restraint and involuntary medication was observable. A negative binomial regression model (NB2) was used to analyze the associations between the use of restrictive measures and regional variables concerning demography, health, substance abuse, and socio-economic status, but reliable interpretations were impossible to generate.Conclusion: This study provides detailed and unique data on the use of seclusion, restraint and involuntary medication in Finland. Compared to previous national-level data, this study highlights the importance of collecting root-level data. Future research should use registries and describe the associations between the use of restrictive measures and ward-level factors, patient-level characteristics, and societal factors.


Lung volume, pulmonary vasculature, and factors affecting survival in congenital diaphragmatic hernia.
There is a wide variation in published mortality from congenital diaphragmatic hernia (CDH). The prevailing opinion is that this variation is related directly to the degree of pulmonary hypoplasia. Our aim was to test the hypothesis that other factors are important for outcome. The specific objectives of this study were: 1) to quantitate the degree of lung hypoplasia and pulmonary arterial wall thickness in infants eligible for, and treated with, extracorporeal membrane oxygenation (ECMO), using postmortem analysis of lung DNA, wet lung weight, lung volume, and vessel morphometrics; 2) to correlate the degree of lung hypoplasia and vascular changes with functional tests of oxygenation and estimated right ventricular systolic pressures (RVSP); 3) to determine the minimum lung volume necessary for survival; and 4) to determine contributory clinical factors as potential causes of death in ECMO-treated infants with CDH. We retrospectively analyzed all 90 infants with CDH admitted consecutively over a 9-year period to a children's hospital with an ECMO program. Infants were categorized as lived or died, with or without ECMO. Indication for ECMO was an evolving process; however, in general, it was the therapy of last resort for pulmonary insufficiency. Clinically, the single best oxygenation index before ECMO or CDH repair while on conventional ventilation, and serial echocardiograms before, during, and after ECMO, were obtained. Twelve of 14 infants dying with ECMO and 6 of 12 without ECMO had postmortem examinations. Lung volume, DNA content, wet weights, and arterial wall thickness at the level of alveolar ducts were measured in both lungs. Postmortem morphometric findings were correlated with in vivo tests of cardiopulmonary function and contributory clinical factors in mortality. Sixty-three percent of all infants with CDH and 61% of ECMO-treated infants lived. All infants with CDH requiring ECMO had elevated RVSP/systolic systemic blood pressure ratios before ECMO (0.98 +/- 0.24). Eighty-eight percent of ECMO-treated infants with CDH decreased this ratio to < 0.5 within 14 days, regardless of lung size. However, infants dying with normal ratios still had increased arterial wall thickness and muscle in both lungs. In infants whose lung volume, DNA, and weight were > 45% of values predicted for age-matched controls, the oxygenation index ranged from 4 to 29, significantly less than that in infants with values < 45% of predicted values (range, 25 to 133). We speculate that eight infants with lung volumes > 45% of that for controls died from potentially preventable surgical and medical complications. A minimum lung volume of 45% of the value predicted from age-matched controls is required for survival in ECMO-treated infants. The RVSP/systolic systemic blood pressure ratio can be reduced with ECMO to < 0.5 in the majority of infants, even with lung volumes inadequate for survival. We speculate that 9% of infants with adequate lung volume were potentially survivable, but died of medical and surgical complications.


Perceptions of Incivility Among Dental Hygiene Students and Faculty/Administrators.
Purpose While incivility has been part of higher education for many years, there has been a documented increase as both students and educators have begun to recognize this behavior and its effects on student learning, faculty satisfaction and stress. The purpose of this descriptive study was to investigate the perceptions of incivility among dental hygiene students and faculty/administrators.Methods This study utilized a convenience sample of five dental hygiene programs in California. The Incivility in Higher Education-Revised survey (IHE-R) was adapted to obtain data regarding perceptions of incivility among dental hygiene students and faculty/administrators. The survey required participants to describe incivil encounters and the perceived reasons for and consequences of the incivil behavior. An online survey was used for faculty and a paper survey was administered for dental hygiene students. Data from the open-ended questions were reviewed, summarized, edited for redundancy, and analyzed using categories.Results Of the 196 participants, 81.63% were dental hygiene students (n = 160) and 18.37% were dental hygiene faculty and administrators (n = 36). Data analysis of participant responses related to the primary reason for incivil behavior in dental hygiene education revealed five categories including lack of consequences, personality traits, miscommunication, stress, and lack of professionalism. Upon data analysis of participant responses related to the most significant consequence of incivil behavior in dental hygiene education, five categories emerged including hostile environment, decreased student success, emotional distress, relationship damage, and professional damage.Conclusion Both faculty and students felt there was a lack of consequences for incivil behavior and did not feel adequately equipped to manage these situations when they arose. Dental hygiene institutions and professional organizations need to consider offering advanced training in creating a culture of civility to prevent and address incivil behaviors.


Histological findings after hemicerebellectomy in man: anterograde, retrograde and transneuronal degeneration.
Histological changes are described in the brain of a patient in whom a hemicerebellectomy had been performed 14 years before death. There is cell and fibre loss, partial or total, in nuclei known to have direct connections with the cerebellum. In some nuclei the sequel to cell loss is marked fibrillary gliosis. In other nuclei the cells have disappeared without trace. The degeneration of these tracts with a direct connection with the cerebellum has also led to degeneration of other tracts in synaptic relationship with them. This transneuronal degeneration has occurred in the corticopontine tracts and in the central tegmental tract, in the former definitely, and in the latter probably, retrogradely. It is probable that transneuronal degeneration has also occurred in other tracts. The extent of the degeneration and, in particular, the occurrence of overt transneuronal degeneration, suggest that the examination of material after a very long term of survival might be of value in experimental work concerned with mapping neuroanatomical networks.


Change detection in naturalistic pictures among children with autism.
Persons with autism often show strong reactions to changes in the environment, suggesting that they may detect changes more efficiently than typically developing (TD) persons. However, Fletcher-Watson et al. (Br J Psychol 97:537-554, 2006) reported no differences between adults with autism and TD adults with a change-detection task. In this study, we also found no initial differences in change-detection between children with autism and NVMA-matched TD children, although differences emerged when detection failures were related to the developmental level of the participants. Whereas detection failures decreased with increasing developmental level for TD children, detection failures remained constant over the same developmental range for children with autism, pointing to an atypical developmental trajectory for change-detection among children with autism.


Ligand-binding mass spectrometry to study biotransformation of fusion protein drugs and guide immunoassay development: strategic approach and application to peptibodies targeting the thrombopoietin receptor.
The knowledge of in vivo biotransformation (e.g., proteolysis) of protein therapeutic candidates reveals structural liabilities that impact stability. This information aids the development and confirmation of ligand-binding assays with the required specificity for bioactive moieties (including intact molecule and metabolites) for appropriate PK profiling. Furthermore, the information can be used for re-engineering of constructs to remove in vivo liabilities in order to design the most stable candidates. We have developed a strategic approach of ligand-binding mass spectrometry (LBMS) to study biotransformation of fusion proteins of peptides fused to human Fc ("peptibodies") using anti-human Fc immunoaffinity capture followed by tiered mass spectrometric interrogation. LBMS offers the combined power of selectivity of ligand capture with the specificity and detailed molecular-level information of mass spectrometry. In this paper, we demonstrate the preclinical application of LBMS to three peptibodies, AMG531 (romiplostim), AMG195(linear), and AMG195(loop), that target the thrombopoietin receptor. The data show that ligand capture offers excellent sample cleanup and concentration of intact peptibodies and metabolites for subsequent query by matrix-assisted laser desorption ionization time-of-flight mass spectrometry for identification of in vivo proteolytic points. Additional higher-resolution analysis by nanoscale liquid chromatography interfaced with electrospray ionization mass spectrometry is required for identification of heterogeneous metabolites. Five proteolytic points are accurately identified for AMG531 and two for AMG195(linear), while AMG195(loop) is the most stable construct in rats. We recommend the use of LBMS to assess biotransformation and in vivo stability during early preclinical phase development for all novel fusion proteins.


Great expectations: what do patients expect and how can expectations be managed?
Patients' expectations of their treatment are a key determinant in their satisfaction with treatment. Expectations may encompass not only notions of the outcome of treatment, but also the process of treatment. This article explores the processes by which expectations are formed, differences in expectations across patient groups, and the psychopathology of individuals with unrealistic expectations of treatment manifest in body dysmorphic disorder.


The Gcn4p activation domain interacts specifically in vitro with RNA polymerase II holoenzyme, TFIID, and the Adap-Gcn5p coactivator complex.
The Gcn4p activation domain contains seven clusters of hydrophobic residues that make additive contributions to transcriptional activation in vivo. We observed efficient binding of a glutathione S-transferase (GST)-Gcn4p fusion protein to components of three different coactivator complexes in Saccharomyces cerevisiae cell extracts, including subunits of transcription factor IID (TFIID) (yeast TAFII20 [yTAFII20], yTAFII60, and yTAFII90), the holoenzyme mediator (Srb2p, Srb4p, and Srb7p), and the Adap-Gcn5p complex (Ada2p and Ada3p). The binding to these coactivator subunits was completely dependent on the hydrophobic clusters in the Gcn4p activation domain. Alanine substitutions in single clusters led to moderate reductions in binding, double-cluster substitutions generally led to greater reductions in binding than the corresponding single-cluster mutations, and mutations in four or more clusters reduced binding to all of the coactivator proteins to background levels. The additive effects of these mutations on binding of coactivator proteins correlated with their cumulative effects on transcriptional activation by Gcn4p in vivo, particularly with Ada3p, suggesting that recruitment of these coactivator complexes to the promoter is a cardinal function of the Gcn4p activation domain. As judged by immunoprecipitation analysis, components of the mediator were not associated with constituents of TFIID and Adap-Gcn5p in the extracts, implying that GST-Gcn4p interacted with the mediator independently of these other coactivators. Unexpectedly, a proportion of Ada2p coimmunoprecipitated with yTAFII90, and the yTAFII20, -60, and -90 proteins were coimmunoprecipitated with Ada3p, revealing a stable interaction between components of TFIID and the Adap-Gcn5p complex. Because GST-Gcn4p did not bind specifically to highly purified TFIID, Gcn4p may interact with TFIID via the Adap-Gcn5p complex or some other adapter proteins. The ability of Gcn4p to interact with several distinct coactivator complexes that are physically and genetically linked to TATA box-binding protein can provide an explanation for the observation that yTAFII proteins are dispensable for activation by Gcn4p in vivo.


Overexpression of the Aldehyde Dehydrogenase Gene ZmALDH Confers Aluminum Tolerance in Arabidopsis thaliana.
Aluminum (Al) toxicity is the main factor limiting plant growth and the yield of cereal crops in acidic soils. Al-induced oxidative stress could lead to the excessive accumulation of reactive oxygen species (ROS) and aldehydes in plants. Aldehyde dehydrogenase (ALDH) genes, which play an important role in detoxification of aldehydes when exposed to abiotic stress, have been identified in most species. However, little is known about the function of this gene family in the response to Al stress. Here, we identified an ALDH gene in maize, ZmALDH, involved in protection against Al-induced oxidative stress. Al stress up-regulated ZmALDH expression in both the roots and leaves. The expression of ZmALDH only responded to Al toxicity but not to other stresses including low pH and other metals. The heterologous overexpression of ZmALDH in Arabidopsis increased Al tolerance by promoting the ascorbate-glutathione cycle, increasing the transcript levels of antioxidant enzyme genes as well as the activities of their products, reducing MDA, and increasing free proline synthesis. The overexpression of ZmALDH also reduced Al accumulation in roots. Taken together, these findings suggest that ZmALDH participates in Al-induced oxidative stress and Al accumulation in roots, conferring Al tolerance in transgenic Arabidopsis.


Effect of Subject Rotation on Assessment of Esthetic Dental Ratios: A Simulation Study.
Objective. This study aimed to find out the change in esthetic ratios during rotation of patient's head using a simulation. Materials and Methods. A plaster study model was photographed placing its midline along the long axis of the camera. Then a series of photographs were taken by rotating the model each degree till 10° on both right and left sides. These photographs were digitally measured and the ratio of the maxillary anterior teeth at zero-degree rotation was compared with that at various degrees of rotation. Results. As the model was rotated to the right side till 10°, the ratio of the right lateral to central incisor gradually decreased while the ratio of the left lateral to central incisor gradually increased. However, the ratio of the canine to lateral incisor on both sides gradually increased. Similar results were obtained when the model was rotated to the left side. The ratio of the lateral to central incisor deviated from the acceptable range (±10%) when there was rotation of more than 7°, whereas the ratio of the canine to lateral incisor was within the acceptable range till 10° rotation on either side. Conclusions. Rotation of the model by more than 7° leads to a substantial change in the esthetic ratio.


Patients' experience of sexuality 1-year after allogeneic Haematopoietic Stem Cell Transplantation.
This study explores how patients' experience of sexuality is influenced by physical, psychological and social changes one year after undergoing haematopoietic stem cell transplantation (HSCT). A qualitative study using semi-structured in-depth interviews. The respondents (n = 9) were recruited from the Department of Haematology, Copenhagen University Hospital, one year after HSCT. The interviews were analysed from a phenomenological-hermeneutic perspective. Bodily changes and symptoms related to chronic graft vs. host disease led to physical limitations or altered body image, which directly or indirectly resulted in sexual dysfunction or problems with intimacy. Symptoms related to chronic GVHD, could explain experiences of sexual dysfunction. Sexual needs were deprioritized as survival became paramount. The experience of changed social roles, both in family life and social network, affected self-image and identity. Finally, communication about sexuality and sexual needs was of significant importance to the current state of their relationship. Physical body alterations, challenges in mastering their new life situation and identity changes affected sexuality and sexual function one year after HSCT. As symptoms resided, sexuality and sex life became more and more prominent in their thoughts and lives. Increased focus is needed on sexuality and sexual dysfunction in the HSCT clinical setting.


Measuring Labor Input: Construction Activity Counting Using IMU on Hand Tools.
Efficient measurement of labor input is a critical aspect of on-site control and management in construction projects, as labor input serves as the primary and direct determinant of project outcomes. However, conventional manual inspection methods are off-line, tedious, and fail to capture their effectiveness. To address this issue, this research presents a novel method that leverages Inertial Measurement Unit (IMU) sensors attached to hand tools during construction activities to measure labor input in a timely and precise manner. This approach encompasses three steps: temporal-spatial feature extraction, self-similarity matrix calculation, and local specific structure identification. The underlying principle is based on the hypothesis that repetitive use data from hand tools can be systematically collected, analyzed, and converted into quantitative measures of labor input by the automatic recognition of repetition patterns. To validate this concept and assess its feasibility for general construction activities, we developed a preliminary prototype and conducted a pilot study focusing on rotation counting for a screw-connection task. A comparative analysis between the ground truth and the predicted results obtained from the experiments demonstrates the effectiveness and efficiency of measuring labor input using IMU sensors on hand tools, with a relative error of less than 5%. To minimize the measurement error, further work is currently underway for accurate activity segmentation and fast feature extraction, enabling deeper insights into on-site construction behaviors.


Expression of normal myeloid-associated antigens by acute leukemia cells.
Monoclonal antibodies that react with hematopoietic cells and their precursors in a stage and lineage restricted fashion were used in indirect immunofluorescence assays to examine leukemic cells from 105 pediatric age patients. The differentiative states of blasts from 42 patients with acute nonlymphocytic leukemia (ANLL) were defined by these antibodies. When these were compared to their morphologic and histochemical levels of differentiation as defined by the French-American-British (FAB) classification, no direct relationship was found. The reactivity of these antibodies with leukemic cells from 63 patients with acute lymphocytic leukemiA (ALL) was also investigated, and the usefulness of these antibodies in distinguishing leukemias of myeloid from those of lymphoid origin was demonstrated.


Update on key emerging challenges in cystic fibrosis.
Cystic fibrosis (CF) is a multisystem disease causing severe chronic sinopulmonary disease and loss of pancreatic exocrine function, which affects approximately 70,000 individuals worldwide. New therapeutic developments over the last few decades have resulted in a significant increase in survival, with the median predicted survival now reaching the late thirties and more and more CF patients living well into adulthood. However, with this advent of new therapies and the associated increase in survival, new challenges in CF care have also emerged. Two of these challenges, i.e. chronic methicillin-resistant Staphylococcus aureus lung infection and patient adherence to very complicated and time-consuming therapeutic regimens, are reviewed in detail here. In addition, the ultimate challenge of treating the underlying cause of CF by correcting the dysfunction of the CF transmembrane conductance regulator chloride channel is reviewed, as agents to correct channel function will likely significantly alter CF clinical outcomes and treatment approaches in the next decade.


Microfluidic cardiac cell culture model (μCCCM).
Physiological heart development and cardiac function rely on the response of cardiac cells to mechanical stress during hemodynamic loading and unloading. These stresses, especially if sustained, can induce changes in cell structure, contractile function, and gene expression. Current cell culture techniques commonly fail to adequately replicate physical loading observed in the native heart. Therefore, there is a need for physiologically relevant in vitro models that recreate mechanical loading conditions seen in both normal and pathological conditions. To fulfill this need, we have developed a microfluidic cardiac cell culture model (μCCCM) that for the first time allows in vitro hemodynamic stimulation of cardiomyocytes by directly coupling cell structure and function with fluid induced loading. Cells are cultured in a small (1 cm diameter) cell culture chamber on a thin flexible silicone membrane. Integrating the cell culture chamber with a pump, collapsible pulsatile valve and an adjustable resistance element (hemostatic valve) in series allow replication of various loading conditions experienced in the heart. This paper details the design, modeling, fabrication and characterization of fluid flow, pressure and stretch generated at various frequencies to mimic hemodynamic conditions associated with the normal and failing heart. Proof-of-concept studies demonstrate successful culture of an embryonic cardiomyoblast line (H9c2 cells) and establishment of an in vivo like phenotype within this system.


Pharmacogenomics of CYP2D6: molecular genetics, interethnic differences and clinical importance.
CYP2D6 has received intense attention since the beginning of the pharmacogenetic era in the 1970s. This is because of its involvement in the metabolism of more than 25% of the marketed drugs, the large geographical and inter-ethnic differences in the genetic polymorphism and possible drug-induced toxicity. Many interesting reviews have been published on CYP2D6 and this review aims to reinstate the importance of the genetic polymorphism of CYP2D6 in different populations as well as some clinical implications and important drug interactions.


Detection of astrocytic tau pathology facilitates recognition of chronic traumatic encephalopathy neuropathologic change.
Traumatic brain injury (TBI) is associated with the development of a range of neurodegenerative pathologies, including chronic traumatic encephalopathy (CTE). Current consensus diagnostic criteria define the pathognomonic cortical lesion of CTE neuropathologic change (CTE-NC) as a patchy deposition of hyperphosphorylated tau in neurons, with or without glial tau in thorn-shaped astrocytes, typically towards the depths of sulci and clustered around small blood vessels. Nevertheless, although incorporated into consensus diagnostic criteria, the contribution of the individual cellular components to identification of CTE-NC has not been formally evaluated. To address this, from the Glasgow TBI Archive, cortical tissue blocks were selected from consecutive brain donations from contact sports athletes in which there was known to be either CTE-NC (n = 12) or Alzheimer's disease neuropathologic change (n = 4). From these tissue blocks, adjacent tissue sections were stained for tau antibodies selected to reveal either solely neuronal pathology (3R tau; GT-38) or mixed neuronal and astroglial pathologies (4R tau; PHF-1). These stained sections were then randomised and independently assessed by a panel of expert neuropathologists, blind to patient clinical history and primary antibody applied to each section, who were asked to record whether CTE-NC was present. Results demonstrate that, in sections stained for either 4R tau or PHF-1, consensus recognition of CTE-NC was high. In contrast, recognition of CTE-NC in sections stained for 3R tau or GT-38 was poor; in the former no better than chance. Our observations demonstrate that the presence of both neuronal and astroglial tau pathologies facilitates detection of CTE-NC, with its detection less consistent when neuronal tau pathology alone is visible. The combination of both glial and neuronal pathologies, therefore, may be required for detection of CTE-NC.


Incidental 68Ga-DOTATATE uptake in the pancreatic head: A case report and a unique opportunity to improve clinical care.
Neuroendocrine tumors (NETs) are neoplasms that can arise from the neuroendocrine cells distributed widely throughout the body. Majority of NETs overexpress somatostatin receptors (SSTR) on their cell surface. This biologic characteristic is exploited by SSTR-based imaging such as In octreotide scintigraphy and Ga DOTATATE positron emission tomography (PET)/computed tomography (CT), which are considered standard for initial evaluation of NETs. Although highly sensitive and specific, recent reports demonstrate a concerning incidence of "false-positive" physiologic uptake of these tracers in the pancreatic head - a common site of neuroendocrine tumor (NET) involvement. We present false positive uptake on Ga DOTATATE PET/CT along with false positive CT findings. Role of other imaging modalities is discussed. A 78-year-old woman presented with a year-long history of diarrhea. Serum vasoactive intestinal peptide (VIP) levels were slightly elevated at 134.2 pg/mL (normal <75 pg/mL). CT showed a mildly enhancing 2.5 cm × 1.8 cm × 2.8 cm area in the pancreatic uncinate process which corresponded to focal uptake with Ga DOTATATE PET/CT. A presumptive diagnosis of pancreatic NET (vipoma) was made, and the patient was scheduled to undergo Whipple's surgery. She sought a second opinion and a subsequent magnetic resonance imaging (MRI) showed no lesion and the patient's surgery was deferred. Thereafter, her VIP levels spontaneously normalized. Endoscopic ultrasound (EUS) with fine needle aspiration cytology of the uncinate process showed normal pancreatic acini with no evidence of NET. Patient is currently pursuing workup for alternative etiologies for chronic diarrhea. Conspicuous physiological uptake has been reported in the pancreatic head on 16% to 70% of Ga DOTATATE or Ga DOTANOC PET/CT scans, and 26% of the In octreotide scintigraphy scans. Image-based quantitative attempts to distinguish physiologic from pathologic uptake using SUVmax have rendered mixed results. When evaluating SSTR-based imaging uptake in the pancreatic head, patients can benefit from a higher index of suspicion of false positive uptake. Such cases require additional confirmation by MRI or EUS. Interestingly, the patient described also had mild contrast enhancement on CT, but without an MRI correlate. Because of potential morbidity and mortality related to false positive uptake, a systematic review with evidence-based recommendations for imaging may benefit patient care.


Combined therapies in osteoporosis: bisphosphonates and vitamin D-hormone analogs.
During the last two decades, the development of new, highly effective therapeutics (e.g. bisphosphonates, SERMs, strontium ranelate and PTH) has significantly extended the spectrum of osteoporosis therapy. However, the interest of combining bone-active agents and/or Vitamin D and calcium is still being debated, and is restricted to a very marginal set of compounds (Alendronate and native Vitamin D). On the other hand, Vitamin D-hormone analogs, calcitriol, and alfacalcidol, have repeatedly demonstrated their effectiveness in being valuable alternatives compared to native Vitamin D in this setting. A growing amount of data documents the pre-clinical and clinical efficacies of combinations of bisphosphonates with calcitriol, or with alfacalcidol in primary and secondary osteoporosis. This exhaustive review of the available animal and clinical data aimed at comparing the theoretical with demonstrated absolute and relative benefits of those therapeutic approaches. Most of the pre-clinical and clinical data in PMOP suggest significant, clinical improvements in response to combination therapies versus monotherapies in postmenopausal osteoporosis. As a investigated by most of the currently available trials, a daily dose of alendronate 10 mg or a weekly dose of Alendronate 70 m plus alfacalcidol 0.5-1.0 microg daily plus alfacalcidol 0.5 microg seems to surpass other combinations when BMD and bone metabolism markers are considered. A synergy with bisphosphonates in reducing the fracture episodes may lie in the pleiotropic effects of D-hormone analogs on musculoskeletal, immunological and neurological systems. Negative interactions between both drugs have not yet been reported, while a reduction of hypercalcuria episodes has been noted in combination therapies, as compared to monotherapies involving high doses of Vitamin D, calcitriol, or alfacalcidol. Based on the possible reduction of periodic safety checks of calcemia, an improved compliance could then be expected, which would, in turn, generate a better end result. However, to document this, long-term, high quality comparative studies with factorial designs are needed to determine which role this alternative should play in the management of postmenopausal, male, and glucocorticoid-induced osteoporosis.


Electrochemical characteristics of bioresorbable binary MgCa alloys in Ringer's solution: Revealing the impact of local pH distributions during in-vitro dissolution.
Biodegradable magnesium-calcium (MgCa) alloy is a very attractive biomaterial. Two MgCa alloys below the solid solubility of Ca were considered, as to solely investigate the effect of Ca content on the behavior of magnesium and the pH changes associated to metal dissolution. X-ray diffraction analysis and optical microscopy showed that both Mg-0.63Ca and Mg-0.89Ca alloys were solely composed of α(Mg) phase. Degradation characteristics and electrochemical characterization of MgCa alloys were investigated during exposure to Ringer's solution at 37 °C by electrochemical impedance spectroscopy and scanning electrochemical microscopy. The impedance behavior showed both capacitive and inductive features that are related to the alloy charge transfer reaction and the relaxation of the absorbed corrosion compounds, and can be described in terms of an equivalent circuit. Scanning electron microscopy (SEM) was employed to view the surface morphology of the MgCa samples after 1 week immersion in Ringer's solution showing extensive precipitation of corrosion products, whereas the substrate shows evidence of a non-uniform corrosion process. Energy dispersive analysis showed that the precipitates contained oxygen, calcium, magnesium and chlorine, and the Mg:Ca ratios were smaller than in the alloys. Scanning electrochemical microscopy (SECM) was used to visualize local pH changes associated to these physicochemical processes with high spatial resolution. The occurrence of pH variations in excess of 3 units between anodic and cathodic half-cell reactions was monitored in situ.


Targeting KRAS in pancreatic adenocarcinoma: Progress in demystifying the holy grail.
Pancreatic cancer (PC) remains one of the most challenging diseases, with a very poor 5-year overall survival of around 11.5%. Kirsten rat sarcoma virus (KRAS) mutation is seen in 90%-95% of PC patients and plays an important role in cancer cell proliferation, differentiation, metabolism, and survival, making it an essential mutation for targeted therapy. Despite extensive efforts in studying this oncogene, there has been little success in finding a drug to target this pathway, labelling it for decades as "undruggable". In this article we summarize some of the efforts made to target the KRAS pathway in PC, discuss the challenges, and shed light on promising clinical trials.


Carbohydrate recognition domain of surfactant protein D mediates interactions with Pneumocystis carinii glycoprotein A.
Pneumocystis carinii continues to cause severe pneumonia in immunocompromised patients. Surfactant protein D (SP-D), a lung collectin, markedly accumulates during P. carinii pneumonia and binds to glycoprotein A (gpA) on the surface of P. carinii, thereby enhancing interactions with alveolar macrophages. Herein, we report the structural basis of the interaction of SP-D with gpA. We demonstrate that natural SP-D binds to purified gpA in the presence of 2 mM calcium in a saturable, concentration-dependent manner, which is abolished by 10 mM ethylenediaminetetraacetic acid. Increasing concentrations of calcium under otherwise cation-free conditions significantly enhance SP-D binding to gpA, whereas manganese and magnesium cations have minimal effect. Maximal SP-D binding occurs at pH 7.4, with significant inhibition at pH 4. SP-D binding to gpA is also competitively inhibited by maltose>glucose>mannose>N-acetyl-glucosamine. Comparison of the binding of various natural and recombinant forms of SP-D to gpA reveals that the number of carbohydrate recognition domains (CRDs) in a given SP-D form determines the relative extent of binding to gpA. Maximal binding is observed with natural SP-D (dodecamers and higher order SP-D complexes) followed by recombinant dodecamers. In contrast, recombinant full-length trimers exhibit substantially less binding, which is similar to that observed with a recombinant truncated molecule consisting of the CRD and neck regions, and containing trimers of this portion of the molecule. Taken together, these findings strongly indicate that the CRD of SP-D mediates interaction with P. carinii gpA through its attached oligosaccharides and that the extent of SP-D binding to P. carinii is greatest with dodecamers and higher order forms of SP-D.


Dysmyelination revisited.
Dysmyelination describes an inborn error of metabolism affecting myelinogenesis that causes it to be abnormal, arrested, or delayed. Abiotrophy or myelin as defined by Gowers, due to metabolic failure of the myelin maintenance system, is yet another feature of dysmyelination. In addition to the leukodystrophies, genetically determined conditions such as infantile amaurotic idiocy, hematosidosis, Niemann-Pick's disease and several of the aminoacidopathies are examples of dysmyelinating diseases. In order to reconcile morphological and neurochemical data in these conditions, it is necessary to reexamine a number of pathogenetic hypotheses based on known enzymatic deficiencies, and the interpretation of fragmentary biochemical analyses. The obligatory role of the neuron and axon in myelin formation and maintenance is reviewed. The hypothesis is advanced that gangliosides and their degradative products constitue precursors for the synthesis of the characteristic myelin sphingolipids cerebrosides, sulfatides, and sphingomyelin. Alterations in axoplasmic flow and of ganglioside metabolism must be condidered as important factors in the pathogenesis of dysmyelination.


Humidity-induced charge leakage and field attenuation in electric field microsensors.
The steady-state zero output of static electric field measuring systems often fluctuates, which is caused mainly by the finite leakage resistance of the water film on the surface of the electric field microsensor package. The water adsorption has been calculated using the Boltzmann distribution equation at various relative humidities for borosilicate glass and polytetrafluoroethylene surfaces. At various humidities, water film thickness has been calculated, and the induced charge leakage and field attenuation have been theoretically investigated. Experiments have been performed with microsensors to verify the theoretical predictions and the results are in good agreement.


DeepMainmast: integrated protocol of protein structure modeling for cryo-EM with deep learning and structure prediction.
Three-dimensional structure modeling from maps is an indispensable step for studying proteins and their complexes with cryogenic electron microscopy. Although the resolution of determined cryogenic electron microscopy maps has generally improved, there are still many cases where tracing protein main chains is difficult, even in maps determined at a near-atomic resolution. Here we developed a protein structure modeling method, DeepMainmast, which employs deep learning to capture the local map features of amino acids and atoms to assist main-chain tracing. Moreover, we integrated AlphaFold2 with the de novo density tracing protocol to combine their complementary strengths and achieved even higher accuracy than each method alone. Additionally, the protocol is able to accurately assign the chain identity to the structure models of homo-multimers, which is not a trivial task for existing methods.


Auditing the reliability of recall of patients for minor surgical procedures.
The aim of this study was to document the reliability of patients in an ENT clinic for the history of previous operations and to investigate the effect of asking more detailed questions. 162 Patients were questioned using one of two questionnaires, followed by examination. The results of the survey call in question the reliability of the history of previous surgery, particularly of procedures performed in childhood or regarded as minor. Thirty-eight patients did not admit to having undergone dental extraction under general anaesthetic until directly questioned. No male patients admitted to genitourinary surgery unless directly questioned. Four out of 84 patients did not admit to tonsillectomy until directly questioned and a further 5 patients were discovered to have undergone tonsillectomy only by examination, despite direct questions. In conclusion, this study illustrates the importance of direct questioning and highlights the poor reliability of some patients in revealing surgical procedures under general anesthetic which may be regarded as trivial.


The RBCC gene RFP2 (Leu5) encodes a novel transmembrane E3 ubiquitin ligase involved in ERAD.
RFP2, a gene frequently lost in various malignancies, encodes a protein with RING finger, B-box, and coiled-coil domains that belongs to the RBCC/TRIM family of proteins. Here we demonstrate that Rfp2 is an unstable protein with auto-polyubiquitination activity in vivo and in vitro, implying that Rfp2 acts as a RING E3 ubiquitin ligase. Consequently, Rfp2 ubiquitin ligase activity is dependent on an intact RING domain, as RING deficient mutants fail to drive polyubiquitination in vitro and are stabilized in vivo. Immunopurification and tandem mass spectrometry enabled the identification of several putative Rfp2 interacting proteins localized to the endoplasmic reticulum (ER), including valosin-containing protein (VCP), a protein indispensable for ER-associated degradation (ERAD). Importantly, we also show that Rfp2 regulates the degradation of the known ER proteolytic substrate CD3-delta, but not the N-end rule substrate Ub-R-YFP (yellow fluorescent protein), establishing Rfp2 as a novel E3 ligase involved in ERAD. Finally, we show that Rfp2 contains a C-terminal transmembrane domain indispensable for its localization to the ER and that Rfp2 colocalizes with several ER-resident proteins as analyzed by high-resolution immunostaining. In summary, these data are all consistent with a function for Rfp2 as an ERAD E3 ubiquitin ligase.


Positive and negative network correlations in temporal lobe epilepsy.
Temporal lobe seizures are accompanied by complex behavioral phenomena including loss of consciousness, dystonic movements and neuroendocrine changes. These phenomena may arise from extended neural networks beyond the temporal lobe. To investigate this, we imaged cerebral blood flow (CBF) changes during human temporal lobe seizures with single photon emission computed tomography (SPECT) while performing continuous video/EEG monitoring. We found that temporal lobe seizures associated with loss of consciousness produced CBF increases in the temporal lobe, followed by increases in bilateral midline subcortical structures. These changes were accompanied by marked bilateral CBF decreases in the frontal and parietal association cortex. In contrast, temporal lobe seizures in which consciousness was spared were not accompanied by these widespread CBF changes. The CBF decreases in frontal and parietal association cortex were strongly correlated with increases in midline structures such as the mediodorsal thalamus. These results suggest that impaired consciousness in temporal lobe seizures may result from focal abnormal activity in temporal and subcortical networks linked to widespread impaired function of the association cortex.


Evidence for radiosensitizing by gliotoxin in HL-60 cells: implications for a role of NF-kappaB independent mechanisms.
Radioresistance markedly impairs the efficacy of tumor radiotherapy and may involve antiapoptotic signal transduction pathways that prevent radiation-induced cell death. A common cellular response to genotoxic stress induced by radiation is the activation of the nuclear factor kappa B (NF-kappaB). NF-kappaB activation in turn can lead to an inhibition of radiation-induced apoptotic cell death. Thus, inhibition of NF-kappaB activation is commonly regarded as an important strategy to abolish radioresistance. Among other compounds, the fungal metabolite gliotoxin (GT) has been reported to be a highly selective inhibitor of NF-kappaB activation. Indeed, low doses of GT were sufficient to significantly enhance radiation-induced apoptosis in HL-60 cells. However, this effect turned out to be largely independent of NF-kappaB activation since radiation of HL-60 cells with clinically relevant doses of radiation induced only a marginal increase in NF-kappaB activity, and selective inhibition of NF-kappaB by SN50 did not result in a marked enhancement of GT-induced apoptosis. GT induced activation of JNKs, cytochrome c release from the mitochondria and potently stimulated the caspase cascade inducing cleavage of caspases -9, -8, -7 and -3. Furthermore, cleavage of the antiapoptotic protein X-linked IAP and downregulation of the G2/M-specific IAP-family member survivin were observed during GT-induced apoptosis. Finally, the radiation-induced G2/M arrest was markedly reduced in GT-treated cells most likely due to the rapid induction of apoptosis. Our data demonstrate that various other pathways apart from the NF-kappaB signaling complex can sensitize tumor cells to radiation and propose a novel mechanism for radiosensitization by GT, the interference with the G2/M checkpoint that is important for repair of radiation-induced DNA damage in p53-deficient tumor cells.


Traumatic subarachnoid hemorrhage due to motor vehicle crash versus fall from height: a 4-year epidemiologic study.
Traumatic brain injury (TBI) is a common cause of morbidity and mortality worldwide. It is difficult to estimate the real incidence of traumatic subarachnoid hemorrhage (TSAH). Although TSAH after trauma is associated with poor prognoses, the impact of mechanism of injury (MOI) and the pathophysiology remains unknown. We hypothesized that outcome of TSAH caused by motor vehicle crash (MVC) or fall from height (FFH) varies based on the MOI. Data were collected retrospectively from a prospectively created database registry in the section of Trauma Surgery at Hamad General Hospital between January 2008 and July 2012. All patients presented with head trauma and TSAH were included. Patient data included age, gender, nationality, mechanism of injury, injury severity score (ISS), types of head injuries, and associated injuries. Ventilator days, intensive care unit length of stay, pneumonia, and mortality were also studied. A total of 1665 patients with TBI were identified, of them 403 had TSAH with a mean age of 35 ± 15 years. Of them 93% were male patients and 86% were expatriates. MVC (53%) and FFH (35%) were the major mechanisms of injury. The overall mean ISS and head abbreviated injury score were 19 ± 10.6 and 3.4 ± 0.96, respectively. Patients in MVC group sustained severe TSAH, had significantly greater head abbreviated injury score (3.5 ± 0.9 vs. 3.2 ± 0.9; P = 0.009) and ISS (21.6 ± 10.6 vs. 15.9 ± 9.5; P = 0.001), and lower scene Glasgow coma scale (10.8 ± 4.8 vs. 13.2 ± 3.4; P = 0.001) compared with the FFH group. In addition, the MVC group sustained more intraventricular hemorrhage (4.7 vs. 0.7; P = 0.001) and diffuse axonal injury (4.2 vs. 2.9; P = 0.001). In contrast, extradural hemorrhage (14.3% vs. 11.6%; P = 0.008) was higher in the FFH group. Lower extremities (14% vs. 4.3%; P = 0.004) injury was mainly associated with the MVC group. The overall mortality was 19 % among patients with TSAH. The mortality rate was higher in the MVC group when compared with the FFH group (24% vs. 10%; P = 0.001). In both groups, ISS and Glasgow coma scale at the scene were independent predictors of mortality. Patients with TSAH have a higher mortality rate. In this population, MVCs are associated with a 3-fold increased risk of mortality. Therefore, prevention of MVC and fall can reduce the incidence and severity of TBI in Qatar.


[Dispneic patient: their's problematic (part II)].
The author presents the results of a study of the reactions of cardiac and pulmonary patients to an attach of dispnea. She discusses the prevalent problems and the desirable attitude of nursing personnel.


Fever in the Returned Pediatric Traveler.
Global mobility has been steadily increasing in recent years. The assessment of the febrile child returning from international travel is a diagnostic challenge. The COVID-19 pandemic has profoundly affected international travel and made evaluation and management of the sick returned traveler more challenging. Children visiting friends and relatives abroad remain at higher risk of infection compared to tourists. This review presents a guidance on the initial assessment of a traveling febrile child including interpretation of medical history, physical examination, and laboratory findings. Important clues to etiology include exposure to different infectious agents, incubation periods of pathogens, and prophylaxis regimens and vaccines received. Early identification of potentially life-threatening and highly contagious infections is essential. In this article, we discuss the epidemiology, evaluation, and management of specific travel related infections such as malaria, typhoid fever, dengue fever, viral hemorrhagic fever, rickettsiosis, leptospirosis, schistosomiasis, gastrointestinal, and respiratory infections.


Female chimpanzees use copulation calls flexibly to prevent social competition.
The adaptive function of copulation calls in female primates has been debated for years. One influential idea is that copulation calls are a sexually selected trait, which enables females to advertise their receptive state to males. Male-male competition ensues and females benefit by getting better mating partners and higher quality offspring. We analysed the copulation calling behaviour of wild female chimpanzees (Pan troglodytes schweinfurthii) at Budongo Forest, Uganda, but found no support for the male-male competition hypothesis. Hormone analysis showed that the calling behaviour of copulating females was unrelated to their fertile period and likelihood of conception. Instead, females called significantly more while with high-ranking males, but suppressed their calls if high-ranking females were nearby. Copulation calling may therefore be one potential strategy employed by female chimpanzees to advertise receptivity to high-ranked males, confuse paternity and secure future support from these socially important individuals. Competition between females can be dangerously high in wild chimpanzees, and our results indicate that females use their copulation calls strategically to minimise the risks associated with such competition.


Hepatocyte function in long-term organ culture of Amphimuma means liver.
Fragments of liver from the adult urodele Amphiuma means, the Congo eel, were maintained in organ culture for up to 70 days. The normal electrophoretic patterns of several enzymes were retained. The activities of ornithine transcarbamylase, arginase, glutamate oxalacetate transaminase and glutamate pyruvate transaminase, and urea production, glucose uptake and tissue glycogen content remained relatively constant throughout the culture period. Histological organization and hepatocyte ultrastructure were also retained. Liver fragments survived better in media based on MEM or BME than in medium based on Leibovitz L15. Since many aspects of tissue-specific structure and function are retained, long-term amphibian organ culture is well suited to studies on the control of hepatocyte function and on the effects of metabolites, hormones, drugs and toxins.


D-Ala-D-Ala ligases from glycopeptide antibiotic-producing organisms are highly homologous to the enterococcal vancomycin-resistance ligases VanA and VanB.
The crisis in antibiotic resistance has resulted in an increasing fear of the emergence of untreatable organisms. Resistance to the glycopeptide antibiotic vancomycin in the enterococci, and the spread of these pathogens throughout the environment, has shown that this scenario is a matter of fact rather than fiction. The basis for vancomycin resistance is the manufacture of the depsipeptide D-Ala-D-lactate, which is incorporated into the peptidoglycan cell wall in place of the vancomycin target D-Ala-D-Ala. Pivotal to the resistance mechanism is the production of a D-Ala-D-Ala ligase capable of ester formation. Two highly efficient depsipeptide ligases have been cloned from vancomycin-resistant enterococci: VanA and VanB. These ligases show high amino acid sequence similarity to each other ( approximately 75%), but less so to other D-Ala-D-X ligases (<30%). We have cloned ddls from two glycopeptide-producing organisms, the vancomycin producer Amycolatopsis orientalis and the A47934 producer Streptomyces toyocaensis. These ligases show strong predicted amino acid homology to VanA and VanB (>60%) but not to other D-Ala-D-X ligases (<35%). The D-Ala-D-Ala ligase from S. toyocaensis shows D-Ala-D-lactate synthase activity in cell-free extracts of S. lividans transformed with the ddl gene and confirms the predicted enzymatic activity. These results imply a close evolutionary relationship between resistance mechanisms in the clinics and in drug-producing bacteria.


Survey of current management of prolapse in Australia and New Zealand.
To compare current practice in the treatment of pelvic organ prolapse between Australian/New Zealand and United Kingdom (UK) gynaecologists. A postal questionnaire containing questions on four case scenarios, which examined contentious areas of contemporary prolapse management, was sent to 1471 Australian and New Zealand gynaecologists in mid-2007. The results were compared with those of an identical survey conducted in the UK in 2006. The response rate was 13% as only 196 complete responses were received. For primary anterior vaginal prolapse, anterior colporrhaphy was the procedure of choice in 54% followed by vaginal repair with graft in 20%. For recurrence, 75% used a graft. Procedure of choice for uterovaginal prolapse was a vaginal hysterectomy with anterior colporrhaphy (79%) and for vault support, 54% performed uterosacral colpopexy. In women wishing to retain their fertility, 23% would operate and a laparoscopic uterosacral hysteropexy (39%) was preferred. For posterior vaginal prolapse, the procedure of choice was midline plication in 56% and site-specific repair in 24%. A graft was used in 13% for primary repair and 61% for recurrence, most preferring permanent mesh. Procedure of choice for apical prolapse was sacrospinous fixation with anterior and posterior colporrhaphy (37%), followed by vaginal mesh repair (33%) and abdominal sacrocolpopexy (11%). Few respondents objectively measured prolapse (20%) or followed up patients over one year (12%). Australian/New Zealand gynaecologists used fewer traditional transvaginal procedures and more vaginal grafts than their UK colleagues in all compartments. Most respondents favoured permanent mesh (eg mesh kits) and many are missing an opportunity to gather valuable prospective data on these new procedures.


Understanding complex systems: lessons from Auzoux's and von Hagens's anatomical models.
Animal and human anatomy is among the most complex systems known, and suitable teaching methods have been of great importance in the progress of knowledge. Examining the human body is part of the process by which medical students come to understand living forms. However, the need to preserve cadavers has led to the development of various techniques to manufacture models for teaching purposes. A variety of materials, such as wax, wood, papier-mache, or glass, have long been used to construct animal and plant models. In the case of the human body, the most innovative, yet controversial, method of preservation has been plastination, invented by the German physician Gunther von Hagens, by which actual human bodies are preserved as odourless and aesthetic models for teaching and exhibitions. We point out in our study that the 'hands-on' approach that some anatomical models allow, namely, the (clastic) disassembly and reassembly of the parts of complex systems and their models, is not only a crucial tool for learning, but is far superior to the simple passive observation that rigid, single-piece models allow. And what is valid for the learning of anatomy can be generalized to the acquisition of knowledge of other complex physical systems.


[The effect of the mechanical conditions of myocardial perfusion on the oxygen consumption of the arrested heart].
The oxygen consumption in the rat isolated arrested perfused heart correlated with the perfusion velocity and with the perfusion pressure. No correlation was found between the oxygen consumption and the degree of distension of the heart's walls. The mechanism of the effect of perfusion velocity upon the oxygen consumption in arrested heart remains unrevealed.


[The regulation of Bacillus intermedius glutamyl endopeptidase biosynthesis in the recombinant Bacillus subtilis strain during sporulation].
The growth of the recombinant Bacillus subtilis strain AJ73 carrying the Bacillus intermedius 3-19 glutamyl endopeptidase gene on a multicopy plasmid and the effect of some nutrients on the efficiency of extracellular glutamyl endopeptidase production in the stationary growth phase were studied. In this phase, the concentration of glutamyl endopeptidase in the culture liquid peaked at the 48th and 78th h of cultivation and depended on the composition of the cultivation medium. Unlike the synthesis of glutamyl endopeptidase in the trophophase (i.e., during vegetative growth), which was suppressed by glucose, the synthesis of this enzyme during sporulation was resistant to glucose present in the cultivation medium. A multifactorial experimental design allowed optimal proportions between the concentrations of major nutrients (peptone and inorganic phosphate) to be determined. Inorganic phosphate and ammonium ions augmented the production of glutamyl endopeptidase by 30-150%, and complex organic substrates, such as casein and gelatin, enhanced the production of glutamyl endopeptidase by 50-100%. During sporulation, the production of glutamyl endopeptidase was stimulated by some bivalent cations (Ca2+, Mg2+, and Co2+) and inhibited by others (Zn2+, Fe2+, and Cu2+). The inference is drawn that the regulatory mechanisms of glutamyl endopeptidase synthesis during vegetative growth and sporulation are different.


[Fracture of the femoral diaphysis in children. Ascending or descending centro-medullary nailing? A choice of principle or of necessity?].
Over a period of 4 years, 40 children between the ages of 6 and 14 years (mean: 10 years) were treated for a fracture of the femoral shaft (39 closed fractures and 1 Cauchoix type I open fracture) by flexible medullary nailing, either ascending (5 cases) or descending (35 cases). Although it is classical to use the ascending route described by the Nancy team, the sub-trochanteric descending route was preferred for its simplicity; non-involvement of the knee by the insertion of the nail allows earlier autonomy in children. The results have been found to be satisfactory; no complications related to the method were observed. The biomechanical principles are also conserved.


Does dental indifference influence the oral health-related quality of life of prisoners?
Prisoners have worse oral health and greater unmet dental treatment needs than the general population. However, little is known about the impact of the mouth, or attitudes such as dental indifference and consequent patterns of dental service use in this disadvantaged group. The aim was to determine whether dental indifference was associated with the oral health-related quality of life (OHQoL) of prisoners using Andersen's behavioural model of service utilization as the theoretical framework. The sample was male prisoners aged 20-35 years attending three prisons in the north of England. Participants took part in interviews and oral examinations. The variables were selected to populate Andersen's model including: predisposing characteristics (socioeconomic status), enabling resources (dental indifference and dental attendance patterns before prison), perceived need (perceived treatment need, satisfaction with appearance of teeth, global rating of oral health), evaluated need (number of decayed teeth), health behaviours (use of dental services while in prison) and health outcomes (OHQoL). Structural equation modelling was used to estimate direct and indirect pathways between variables. Of the 700 men approached, 659 completed the interview and clinical examination. Worse OHQoL was associated with less dental indifference (i.e. greater interest in oral health), previous regular use of dental services, perceived need for treatment and use of prison dental services. The number of decayed teeth and predisposing factors such as qualifications and employment did not predict OHQoL. Dental indifference was related to the OHQoL of prisoners in addition to previous regular use of dental services, a perceived need for treatment and use of dental services while in prison. Dental services in prisons might incorporate methods to address dental indifference in their attempts to improve oral health. The findings also have general implications for the assessment of population oral health needs.


2,4-Dinitrophenol overdose - Everything old is new again.
A complete case example of a fatal 2,4-dinitrophenol (DNP) overdose involving a 23-year-old male is described. Included are details of not only the patient's presentation symptoms and treatment, but also the subsequent findings of the coronial investigation process including the autopsy, post-mortem computed tomography (PMCT) scanning and toxicological analysis and results. The patient presented with elevated temperature, heart rate and blood pressure. Multiple treatments were conducted to counteract these symptoms, however the patient died approximately 1.5 hours after hospital admission and some 4.5 hours after the DNP was initially consumed. Autopsy revealed the presence of cardiovascular disease that was contributory to death and post-mortem computed tomography showed evidence of decompositional intravascular gas in the neck, head, face, lower abdomen, heart and hepatic systems. Toxicological analysis was completed by protein precipitation with methanol and subsequent instrumental analysis by LC/MS/MS in negative ion mode. The antemortem blood specimen showed the presence of tadalafil, two anabolic steroids and a DNP concentration of 110 mg/kg which is consistent with other reported DNP fatalities. Despite the small amount of time between the antemortem specimen collection and death, the DNP concentration identified in the femoral blood post-mortem specimen was comparably low (5.5 mg/kg). DNP concentrations also reduced during an extended period of specimen storage prior to analysis indicating some instability in biological specimens even when refrigerated or frozen. DNP was found to be distributed primarily in the aqueous tissues (blood, vitreous, bile) rather than solid matrices (liver, kidney, muscle).


Activation of pro-MMP-2 mediated by MT1-MMP in human salivary gland carcinomas: possible regulation of pro-MMP-2 activation by TIMP-2.
Matrix metalloproteinases (MMPs), a family of extracellular matrix-degrading enzymes, are considered to play important roles in cancer invasion and metastasis. The present study examined the production levels of eight different MMPs (MMP-1, 2, 3, 7, 8, 9 and 13, and MT1-MMP) and two tissue inhibitors of metalloproteinases (TIMP-1 and 2) in homogenates of human salivary gland carcinomas [mucoepidermoid carcinomas (MECs), adenoid cystic carcinomas (ACCs), and adenocarcinomas (ADEs)] and non-neoplastic control salivary glands using sandwich enzyme immunoassay systems. The levels of MMP-1, MMP-2, MMP-13, MT1-MMP, and TIMP-1 were significantly higher in the carcinoma samples than in the controls (p < 0.05). Gelatin zymography demonstrated that the activation ratio of the MMP-2 zymogen (pro-MMP-2) was significantly higher in the carcinomas than in the controls (p < 0.05). In addition, the activation ratio in MECs was significantly higher than that in ACCs or ADEs (p < 0.01) and also correlated with histological grade and lymph node metastasis in MECs (p < 0.05), whereas the ratio showed no such correlation in ACCs or ADEs. Although the production levels of pro-MMP-2 and MT1-MMP were similar among these carcinoma groups, TIMP-2 levels were significantly higher in ACCs and ADEs than in MECs (p < 0.01). In carcinoma samples, the pro-MMP-2 activation ratio correlated directly with the MT1-MMP/TIMP-2 ratio (r = 0.736, n = 23; p < 0.01). Immunohistochemistry and in situ zymography demonstrated localization of MMP-2, MT1-MMP, and TIMP-2 to carcinoma cells, but only in MECs did carcinoma cell nests exhibit gelatinolytic activity, which was inhibited by 1,10-phenanthroline. These results suggest that enhanced activation of pro-MMP-2 mediated by MT1-MMP is implicated in the invasion and metastasis of MECs and that TIMP-2 may regulate pro-MMP-2 activation in salivary gland carcinomas.


Alpha-1-antitrypsin deficiency in New Zealand.
A severe deficiency of the serum protein alpha-1-antitrypsin can be expected to occur in 1 in 750 European New Zealanders. It can usually be identified by a faint or absent alpha-1 band on serum protein electrophoresis. Forty-seven cases are presented. 31 phenotype ZZ and 16 phenotype SZ. Eighteen have developed emphysema usually by age 40 years, two show childhood liver disease. One adult died of liver disease and three of the emphysema patients had liver abnormalities at post mortem. The remainder, mainly aged less than 30 years, are as yet asymptomatic. Individuals at risk should be protected from respiratory irritants (cigarettes, dusty environments and chest infections) and liver toxins (e.g., alcohol). The partial deficiency state (MZ) which occurs in 4 percent of the population also predisposes to respiratory and perhaps liver disease.


The pathway of Edwardsiella piscicida infecting Lateolabrax maculatus via the immersion bath.
Edwardsiella piscicida, an infectious bacterium, causes great economic losses to the aquaculture industry. Immersion bath which is the closest way to how the fish infect bacterial pathogens in the natural environment is an effective route of artificial infection. In this study, the dynamic process of E. piscicida infection, in the spotted sea bass (Lateolabrax maculatus) was evaluated via the immersion bath. The results showed that soaking the spotted sea bass with 3 × 106 CFU mL-1 E. piscicida for 30 min could artificially induce edwardsiellosis. The higher culture temperature (28.5 ± 0.5°C) or the longer bath time (30 min) would lead to higher mortality of fish. E.piscicida first invaded the gill, then entered the blood circulation to infect the spleen and kidney, where it is colonized, and gradually multiplied in the liver and brain. Meanwhile, the fluorescence in situ hybridization showed that the localization of E. piscicida in the gill and foregut after the immersion challenge proceeded from the exterior to the interior. The invasion of pathogens triggers the immune response of fish and causes tissue damage to the host. The quantitative real-time PCR results displayed an increase in the relative expression level of immune genes (NK-lysin, LZM, IgM and IgD). Otherwise, the most notable histopathological changes of the infected spotted sea bass were multifocal necrosis. Findings in this study broaden our understanding of the infection conditions of E. piscicida and its pathogenicity to the spotted sea bass.


Hospital Stays for Harm Caused by Substance Use among Youth in Canada.
The rise in harms associated with misuse of substances such as cannabis, alcohol and opioids is a public health issue gaining increasing importance in Canada. Taking a closer look at who is being hospitalized, and for which substances, helps inform efforts to improve access to services for youth. Between 2017 and 2018, hospitalizations for harm caused by substance use accounted for about one in 20 of all hospital stays among youths aged 10-24 years in Canada. Cannabis use was documented in nearly 40% of these hospitalizations, while alcohol was associated with 26%. Approximately one in every six youths (17%), who were hospitalized for harm caused by substance use, was hospitalized more than once for substance use within the same year.


Methamphetamine abstinence induces changes in μ-opioid receptor, oxytocin and CRF systems: Association with an anxiogenic phenotype.
The major challenge in treating methamphetamine addicts is the maintenance of a drug free-state since they experience negative emotional symptoms during abstinence, which may trigger relapse. The neuronal mechanisms underlying long-term withdrawal and relapse are currently not well-understood. There is evidence suggesting a role of the oxytocin (OTR), μ-opioid receptor (MOPr), dopamine D2 receptor (D2R), corticotropin-releasing factor (CRF) systems and the hypothalamic-pituitary-adrenal (HPA)-axis in the different stages of methamphetamine addiction. In this study, we aimed to characterize the behavioral effects of methamphetamine withdrawal in mice and to assess the modulation of the OTR, MOPr, D2R, CRF and HPA-axis following chronic methamphetamine administration and withdrawal. Ten-day methamphetamine administration (2 mg/kg) increased OTR binding in the amygdala, whilst 7 days of withdrawal induced an upregulation of this receptor in the lateral septum. Chronic methamphetamine treatment increased plasma OT levels that returned to control levels following withdrawal. In addition, methamphetamine administration and withdrawal increased striatal MOPr binding, as well as c-Fos(+)/CRF(+) neuronal expression in the amygdala, whereas an increase in plasma corticosterone levels was observed following METH administration, but not withdrawal. No differences were observed in the D2R binding following METH administration and withdrawal. The alterations in the OTR, MOPr and CRF systems occurred concomitantly with the emergence of anxiety-related symptoms and the development of psychomotor sensitization during withdrawal. Collectively, our findings indicate that chronic methamphetamine use and abstinence can induce brain-region specific neuroadaptations of the OTR, MOPr and CRF systems, which may, at least, partly explain the withdrawal-related anxiogenic effects.


Urban residential greenspace and mental health in youth: Different approaches to testing multiple pathways yield different conclusions.
Urban greenspace can benefit mental health through multiple mechanisms. They may work together, but previous studies have treated them as independent. We aimed to compare single and parallel mediation models, which estimate the independent contributions of different paths, to several models that posit serial mediation components in the pathway from greenspace to mental health. We collected cross-sectional survey data from 399 participants (15-25 years of age) in the city of Plovdiv, Bulgaria. Objective "exposure" to urban residential greenspace was defined by the Normalized Difference Vegetation Index (NDVI), Soil Adjusted Vegetation Index, tree cover density within the 500-m buffer, and Euclidean distance to the nearest urban greenspace. Self-reported measures of availability, access, quality, and usage of greenspace were also used. Mental health was measured with the General Health Questionnaire. The following potential mediators were considered in single and parallel mediation models: restorative quality of the neighborhood, neighborhood social cohesion, commuting and leisure time physical activity, road traffic noise annoyance, and perceived air pollution. Four models were tested with the following serial mediation components: (1) restorative quality → social cohesion; (2) restorative quality → physical activity; (3) perceived traffic pollution → restorative quality; (4) and noise annoyance → physical activity. There was no direct association between objectively-measured greenspace and mental health. For the 500-m buffer, the tests of the single mediator models suggested that restorative quality mediated the relationship between NDVI and mental health. Tests of parallel mediation models did not find any significant indirect effects. In line with theory, tests of the serial mediation models showed that higher restorative quality was associated with more physical activity and more social cohesion, and in turn with better mental health. As for self-reported greenspace measures, single mediation through restorative quality was significant only for time in greenspace, and there was no mediation though restorative quality in the parallel mediation models; however, serial mediation through restorative quality and social cohesion/physical activity was indicated for all self-reported measures except for greenspace quality. Statistical models should adequately address the theoretically indicated interdependencies between mechanisms underlying association between greenspace and mental health. If such causal relationships hold, testing mediators alone or in parallel may lead to incorrect inferences about the relative contribution of specific paths, and thus to inappropriate intervention strategies.


The CD14(+/low)CD16(+) monocyte subset is more susceptible to spontaneous and oxidant-induced apoptosis than the CD14(+)CD16(-) subset.
Human monocytes can be classified into two subsets with distinctive characteristics. In this study, we report a difference in apoptotic potential between these two subsets with CD14(+/low)CD16(+) monocytes being more susceptible than CD14(+)CD16(-) monocytes to undergo spontaneous apoptosis and apoptosis induced by reactive oxygen species (ROS). By global transcriptomic and proteomic approaches, we observed that CD14(+/low)CD16(+) monocytes expressed higher levels of pro-apoptotic genes and proteins such as TNFα, caspase 3, Bax and cytochrome c and showed more caspases 3 and 7 activities. They also exhibited greater aerobic respiration resulting in a higher production of ROS from the mitochondria. CD14(+)CD16(-) monocytes, in contrast, showed higher expression of glutathione (GSH)-metabolizing genes such as GSH peroxidase and microsomal GSH S-transferase and were more resistant to oxidative stress than CD14(+/low)CD16(+) monocytes. The apoptosis of CD14(+/low)CD16(+) monocytes was ROS dependent as reducing ROS levels significantly reduced cell death. This is the first report of a differential apoptotic propensity of human monocyte subsets, and gaining a better understanding of this process may help to provide a better understanding of the roles of these subsets during homeostasis and under pathological conditions, particularly in situations in which high levels of oxidants are present.


[Therapy of cancer patients with concurrent critical atherosclerosis of the aorta and peripheral arteries].
The results are presented of 5-year experience with therapy of concurrent neoplasia and atherosclerotic lesions of the aorta and peripheral arteries gained at the Center for Oncosurgery, Regional Oncological Dispensary, Chelyabinsk. The analysis was concerned with the treatment received by 118 patients, irrespective of tumor stage or localization: surgical correction of blood flow was carried out in 60. Clinically significant atherosclerotic lesions of the aorta and peripheral arteries in a cancer patient should not be regarded as absolute or relative contraindication for combined treatment. Atherosclerotic occlusion of the femoral or shin arteries was managed conservatively in most cases (p<0.05). In cases of similar lesions of the carotid arteries and aortal aneurysm, surgical correction of blood flow was mostly used.


Effects of short-term simultaneous infusion of dobutamine and terlipressin in patients with septic shock: the DOBUPRESS study.
Terlipressin bolus infusion may reduce cardiac output and global oxygen supply. The present study was designed to determine whether dobutamine may counterbalance the terlipressin-induced depression in mixed-venous oxygen saturation (Svo) in patients with catecholamine-dependent septic shock. Prospective, randomized, controlled study performed in a university hospital intensive care unit. Septic shock patients requiring a continuous infusion of norepinephrine (0.9 microg kg(-1) min(-1)) to maintain mean arterial pressure (MAP) at 70 (sd 5) mm Hg were randomly allocated to be treated either with (i) sole norepinephrine infusion (control, n=20), (ii) a single dose of terlipressin 1 mg (n=19), or (iii) a single dose of terlipressin 1 mg followed by dobutamine infusion titrated to reverse the anticipated reduction in Svo2 (n=20). Systemic, pulmonary, and regional haemodynamic variables were obtained at baseline and after 2 and 4 h. Laboratory surrogate markers of organ (dys)function were tested at baseline and after 12 and 24 h. Terlipressin (with and without dobutamine) infusion preserved MAP at 70 (5) mm Hg, while allowing to reduce norepinephrine requirements to 0.17 (0.2) and 0.2 (0.2) microg kg(-1) min(-1), respectively [vs1.4 (0.3) microg kg(-1) min(-1) in controls at 4 h; each P<0.001]. The terlipressin-linked decrease in Svo2 was reversed by dobutamine at a mean dose of 20 (8) microg kg(-1) min(-1) [Svo2 at 4 h: 59 (11)% vs 69 (12)%, P=0.028]. In human catecholamine-dependent septic shock, terlipressin (with and without concomitant dobutamine infusion) increases MAP and markedly reduces norepinephrine requirements. Although no adverse events were noticed in the present study, potential benefits of increasing Svo2 after terlipressin bolus infusion need to be weighted against the risk of cardiovascular complications resulting from high-dose dobutamine.


Incidental renal artery stenosis among a prospective cohort of hypertensive patients undergoing coronary angiography.
To determine the feasibility, safety, and clinical yield of angiographic screening among hypertensive patients undergoing coronary angiography. This study was a prospective cohort analysis of hypertensive patients who underwent cardiac catheterization at a tertiary care referral center from July 1998 to March 1999. Abdominal aortography was performed to screen for renal artery stenosis, the percentage of which was measured. The mean +/- SD age of the 297 study patients was 64.9+/-10.2 years; 58.6% were male, and 98.0% were white. Mean +/- SD systolic/diastolic blood pressure was 142.8+/-22.5/79.6+/-11.4 mm Hg. Aortography required a mean incremental dose of 62+/-9 mL of nonionic contrast agent. No complications were attributable to aortography. Of 680 renal arteries, 611 (90%) were visualized adequately. Also, 53% of patients had normal renal arteries, 28% had stenoses less than 50%, and 19.2% had stenoses of 50% or more. Renal artery stenosis was bilateral in 3.7% of patients and high grade (>70% stenosis) in 7%. Patients with renal artery stenosis were more likely to have had a previous coronary intervention. In multivariate analysis, systolic blood pressure (odds ratio [OR], 1.2; 95% confidence interval [CI], 1.03-138; P=.02), history of stroke or transient ischemic attack (OR, 2.7; 95% CI, 1.27-5.78; P=.01), and cancer (OR, 2.0; 95% CI, 1.02-3.82; P=.04) independently correlated with renal artery stenosis of 50% or more. The prevalence of incidental renal artery stenosis among hypertensive patients undergoing coronary catheterization is significant. Therefore, screening abdominal aortography should be considered in these patients to better define their risk of cardiovascular complications.


Establishment of the Mouse Model of Social Avoidance Induced by Female-Directed Female Aggression.
Most preclinical research on the effects of stress has been done on male subjects, even though women are more prone than men to experience stress-related problems. Chronic social defeat stress (CSDS) is a rodent model of psychosocial stress. However, this model has been challenged in female mouse studies since neither male nor female resident mice attack intruder females. A female-to-female CSDS model is needed to investigate the physiological and behavioral aspects. The intruders were either male or female C57BL/6J mice, whereas the residents were male or ovariectomized (OVX) female CD-1 mice. The CD-1 aggressor mice had direct physical contact with the C57BL/6J mice for 10 min before initiating sensory contact with them for 24 h. Jump escape and freezing were evaluated during the social defeat of days 1 and 12. Experimental C57BL/6J mice underwent a social interaction test after suffering social defeat for 12 days. We found that the number of attack bites and attack latency had a significant negative correlation during the selection of aggressors. In the single-housed OVX mice, 34% of mice met the criterion of the selection of aggressors. However, single-housed OVX mice did not show sustained aggressive behavior (eg, attack bites) through the 12-day CSDS. As a result, we did not find susceptible mice during the social interaction test. In contrast, during the selection of aggressors, 42% of OVX mice housed with partners satisfied the criterion and displayed consistently aggressive behavior. CSDS produced susceptible (50%) and resilient (50%) phenotypes during the social interaction test. Notably, male and OVX female CD-1 mice housed with partners had similar amounts of attack bites and attack rates over the 12-day CSDS. Finally, we found that chronically socially defeated male and female mice displayed different coping behaviors (eg, active vs passive) with social defeat. Our study demonstrates that OVX CD-1 mice housed with mates exhibited territorial aggression toward female intruders, producing susceptibility and resilience to social avoidance. Additionally, socially defeated male and female mice displayed different behavioral susceptibility to social defeat.


Integrated Analysis of Whole-Genome ChIP-Seq and RNA-Seq Data of Primary Head and Neck Tumor Samples Associates HPV Integration Sites with Open Chromatin Marks.
Chromatin alterations mediate mutations and gene expression changes in cancer. Chromatin immunoprecipitation followed by sequencing (ChIP-Seq) has been utilized to study genome-wide chromatin structure in human cancer cell lines, yet numerous technical challenges limit comparable analyses in primary tumors. Here we have developed a new whole-genome analytic pipeline to optimize ChIP-Seq protocols on patient-derived xenografts from human papillomavirus-related (HPV+) head and neck squamous cell carcinoma (HNSCC) samples. We further associated chromatin aberrations with gene expression changes from a larger cohort of the tumor and normal samples with RNA-Seq data. We detect differential histone enrichment associated with tumor-specific gene expression variation, sites of HPV integration in the human genome, and HPV-associated histone enrichment sites upstream of cancer driver genes, which play central roles in cancer-associated pathways. These comprehensive analyses enable unprecedented characterization of the complex network of molecular changes resulting from chromatin alterations that drive HPV-related tumorigenesis. Cancer Res; 77(23); 6538-50. ©2017 AACR.