Effect of double ipsilateral stimulation on vibrotactile sensation magnitude.
The phenomena of enhancement and suppression of vibrotactile subjective magnitude were investigated using a matching procedure. Results support earlier reports for audition and vibrotaction suggesting that enhancement is a fundamental sensory process. The time course is described for suppression of stimuli delivered to several different to several different pats of the body. The results are consistent with earlier studies of vibrotactile masking at threshold levels.


Phase 1 gene therapy for Duchenne muscular dystrophy using a translational optimized AAV vector.
Efficient and widespread gene transfer is required for successful treatment of Duchenne muscular dystrophy (DMD). Here, we performed the first clinical trial using a chimeric adeno-associated virus (AAV) capsid variant (designated AAV2.5) derived from a rational design strategy. AAV2.5 was generated from the AAV2 capsid with five mutations from AAV1. The novel chimeric vector combines the improved muscle transduction capacity of AAV1 with reduced antigenic crossreactivity against both parental serotypes, while keeping the AAV2 receptor binding. In a randomized double-blind placebo-controlled phase I clinical study in DMD boys, AAV2.5 vector was injected into the bicep muscle in one arm, with saline control in the contralateral arm. A subset of patients received AAV empty capsid instead of saline in an effort to distinguish an immune response to vector versus minidystrophin transgene. Recombinant AAV genomes were detected in all patients with up to 2.56 vector copies per diploid genome. There was no cellular immune response to AAV2.5 capsid. This trial established that rationally designed AAV2.5 vector was safe and well tolerated, lays the foundation of customizing AAV vectors that best suit the clinical objective (e.g., limb infusion gene delivery) and should usher in the next generation of viral delivery systems for human gene transfer.


Incidence and management of acute otitis media in adults: a primary care-based cohort study.
Although primarily considered a childhood disease, acute otitis media (AOM) also occurs in adults. Data on the burden of this condition in adults are, however, scarce. To explore the primary care incidence and current management of AOM in adults. All patients aged 15 and older included in the routine health care database of the Julius General Practitioners' Network were followed from 2015 to 2018 (contributing to a total of 1 261 575 person-years). We extracted data on AOM episodes, AOM-related consultations, comorbidities, and antibiotic and analgesic prescriptions. Five thousand three hundred and fifty-eight patients experienced one or more AOM episodes (total number of AOM episodes: 6667; mean 1.2 per patient). The overall AOM incidence was 5.3/1000 person-years and was fairly stable over the study period. Incidence was particularly high in atopic patients (7.3/1000 person-years) and declined with age (from 7.1 in patients 15-39 years of age to 2.7/1000 person-years in those aged 64 years and older). Oral antibiotics, predominantly amoxicillin, were prescribed in 46%, and topical antibiotics in 21% of all episodes. Over the past years, the incidence of AOM in adults in primary care has been stable. Oral antibiotic prescription rates resemble those in children with AOM, whereas a remarkably high topical antibiotic prescription rate was observed. Future prognostic research should inform on the need and feasibility of prospective studies into the best management strategy in this condition.


[Experimental study of the phenomenon of antibody dependent tick-borne encephalitis virus infectivity enhancement in vitro].
Phenomenon of antibody dependent tick-borne encephalitis virus (TBEV) infectivity enhancement in the human monocytic cell culture J-96 has been studied. Three specific commercial sera that are generally used for therapy and prevention of TBE in humans were used. Results showed that enhancement of TBEV infectivity was markedly apparent following use of 2 out of 3 studied sera. Data obtained in the study prove that phenomenon of antibody dependent TBEV infectivity enhancement in monocytes cell culture may exist, but conditions for its realization in the organism are very unlikely due to the narrow range of antibodies' concentration and quantity of viral particles. A the same time, the fact of possible aggravation of TBE course after use of specific antisera for treatment and prevention of TBE in humans should not be ignored.


Effect of renin-angiotensin system on limb circulation in normal subjects.
It is not known whether the renin-angiotensin-aldosterone (RAA) system contributes to the regulation of the limb circulation in normal human beings. Accordingly, the effect of the angiotensin converting-enzyme inhibitor, captopril, on forearm vascular resistance (FVR) and forearm venous volume (FVV) was studied in nine normal subjects during states of both sodium loading and sodium depletion. All subjects were studied in the supine position and during 60 degrees head-up tilt. By analysis of variance, the combined intervention of sodium depletion and converting-enzyme inhibition was responsible for a decrease in both FVR and mean blood pressure (BP). In sodium-depleted subjects, converting-enzyme inhibition decreased supine mean BP 7.0% and supine FVR 22.8% but did not change FVV. Neither the fall in BP nor the fall in FVR, however, was significantly augmented by tilting from a supine to upright posture. In sodium-loaded subjects, captopril did not alter BP, FVR, or FVV in recumbent or upright positions. Therefore, the RAA system contributes to the maintenance of blood pressure and limb vascular resistance only in sodium-depleted subjects. Limb venous capacitance in normal subjects is not regulated by the RAA system.


Determination of the temperature rise within UHMWPE tibial components during tribological loading.
The wear of ultrahigh molecular weight polyethylene (UHMWPE) is considered as one of the major reasons for revision of artificial joints. While in vivo measurements have shown a significant temperature increase in knee implants, the amount of heat dissipated within the UHMWPE tibial component and its influence on the friction behavior when paired with a cobalt-chromium (CoCrMo) femoral component is unknown. Our goal was to address these questions by measuring the temperature rise over a wide range of tribological loading conditions that mimic certain spots on artificial knee joints. The temperature rise as a function of lubricant, sliding velocity, coefficient of friction and maximum load was determined and analyzed. Additionally, the heat gradient during constant loading was investigated that allows the calculation of heat flow. The test setup consists of a wheel-on-flat laboratory testing device. Tests were performed in ambient air and different lubricants. During the tests, the temperature rise in the polyethylene was recorded with embedded thermocouples. The temperature rise was high and shown to be directly linked to load, coefficient of friction and relative velocity. Because it is generally assumed that the applied energy is an indicator for the development of wear in particles, some considerations for the design of knee joints are proposed based on our observations. The amount of heat dissipated in the polyethylene under cyclic loading was measured and is discussed in comparison with the theoretical model of temperature in friction pairs.


Past and current thyroid function in subjects with panic disorder.
Disturbances in thyroid function can result in symptoms similar to those occurring in patients with anxiety disorders, especially panic disorder. An association between thyroid illness and panic and phobic disorders has been suggested, but few studies have directly investigated this issue. To assess this possible relationship, the authors measured indices of thyroid function in 165 subjects who had a current DSM-III diagnosis of panic disorder, either with or without phobic avoidance. These subjects reported a higher prevalence of thyroid illness by history compared with the prevalence of thyroid illness in the general population; however, less than 1% of all subjects had current thyroid dysfunction. The presence of a major depressive episode (MDE) was unrelated to current thyroid function, although subjects with MDE reported a higher prevalence of thyroid disease by history. Indices of thyroid function were not correlated with the severity of panic attacks or phobias.


A socially situated approach to inform ways to improve health and wellbeing.
Mainstream health psychology supports neoliberal notions of health promotion in which self-management is central. The emphasis is on models that explain behaviour as individually driven and cognitively motivated, with health beliefs framed as the favoured mechanisms to target in order to bring about change to improve health. Utilising understandings exemplified in critical health psychology, we take a more socially situated approach, focusing on practicing health, the rhetoric of modernisation in UK health care and moves toward democratisation. While recognising that within these new ways of working there are opportunities for empowerment and user-led health care, there are other implications. How these changes link to simplistic cognitive behavioural ideologies of health promotion and rational decision-making is explored. Utilising two different empirical studies, this article highlights how self-management and expected compliance with governmental authority in relation to health practices position not only communities that experience multiple disadvantage but also more seemingly privileged social actors. The article presents a challenge to self-management and informed choice, in which the importance of navigational networks is evident. Because health care can become remote and inaccessible to certain sections of the community, yet pervasive and deterministic for others, we need multiple levels of analysis and different forms of action.


Associating 197 Chinese herbal medicine with drug targets and diseases using the similarity ensemble approach.
Chinese herbal medicine (CHM) addresses complex diseases through polypharmacological interactions. However, systematic studies of herbal medicine pharmacology remain challenging due to the complexity of CHM ingredients and their interactions with various targets. In this study, we aim to address this challenge with computational approaches. We investigated the herb-target-disease associations of 197 commonly prescribed CHMs using the similarity ensemble approach and DisGeNET database. We demonstrated that this method can be applied to associate herbs with their putative targets. In the case study of three well-known herbs, Radix Glycyrrhizae, Flos Lonicerae, and Rhizoma Coptidis, approximately 70% of the predicted targets were supported by scientific literature. By linking 406 targets to 2439 annotated diseases, we further analyzed the pharmacological functions of 197 herbs. Finally, we proposed a strategy of target-oriented herbal formula design and illustrated the target profiles for four common chronic diseases, namely, Alzheimer's disease, depressive disorder, hypertensive disease, and non-insulin-dependent diabetes mellitus. This computational approach holds great potential in the target identification of herbs, understanding the molecular mechanisms of CHM, and designing novel herbal formulas.


Review: Improving our knowledge of male mosquito biology in relation to genetic control programmes.
The enormous burden placed on populations worldwide by mosquito-borne diseases, most notably malaria and dengue, is currently being tackled by the use of insecticides sprayed in residences or applied to bednets, and in the case of dengue vectors through reduction of larval breeding sites or larviciding with insecticides thereof. However, these methods are under threat from, amongst other issues, the development of insecticide resistance and the practical difficulty of maintaining long-term community-wide efforts. The sterile insect technique (SIT), whose success hinges on having a good understanding of the biology and behaviour of the male mosquito, is an additional weapon in the limited arsenal against mosquito vectors. The successful production and release of sterile males, which is the mechanism of population suppression by SIT, relies on the release of mass-reared sterile males able to confer sterility in the target population by mating with wild females. A five year Joint FAO/IAEA Coordinated Research Project brought together researchers from around the world to investigate the pre-mating conditions of male mosquitoes (physiology and behaviour, resource acquisition and allocation, and dispersal), the mosquito mating systems and the contribution of molecular or chemical approaches to the understanding of male mosquito mating behaviour. A summary of the existing knowledge and the main novel findings of this group is reviewed here, and further presented in the reviews and research articles that form this Acta Tropica special issue.


The 'heritability' of domestication and its functional partitioning in the pig.
We propose to estimate the proportion of variance explained by regression on genome-wide markers (or genomic heritability) when wild/domestic status is considered the phenotype of interest. This approach differs from the standard Fst in that it can accommodate genetic similarity between individuals in a general form. We apply this strategy to complete genome data from 47 wild and domestic pigs from Asia and Europe. When we partitioned the total genomic variance into components associated to subsets of single nucleotide polymorphisms (SNPs) defined in terms of their annotation, we found that potentially deleterious non-synonymous mutations (9566 SNPs) explained as much genetic variance as the whole set of 25 million SNPs. This suggests that domestication may have affected protein sequence to a larger extent than regulatory or other kinds of mutations. A pathway-guided analysis revealed ovarian steroidogenesis and leptin signaling as highly relevant in domestication. The genomic regression approach proposed in this study revealed molecular processes not apparent through typical differentiation statistics. We propose that at least some of these processes are likely new discoveries because domestication is a dynamic process of genetic selection, which may not be completely characterized by a static metric like Fst. Nevertheless, and despite some particularly influential mutation types or pathways, our analyses tend to rule out a simplistic genetic basis for the domestication process: neither a single pathway nor a unique set of SNPs can explain the process as a whole.


Viscoelasticity of children and adolescent brains through MR elastography.
Magnetic Resonance Elastography (MRE) is an elasticity imaging technique that allows a safe, fast, and non-invasive evaluation of the mechanical properties of biological tissues in vivo. Since mechanical properties reflect a tissue's composition and arrangement, MRE is a powerful tool for the investigation of the microstructural changes that take place in the brain during childhood and adolescence. The goal of this study was to evaluate the viscoelastic properties of the brain in a population of healthy children and adolescents in order to identify potential age and sex dependencies. We hypothesize that because of myelination, age dependent changes in the mechanical properties of the brain will occur during childhood and adolescence. Our sample consisted of 26 healthy individuals (13 M, 13 F) with age that ranged from 7-17 years (mean: 11.9 years). We performed multifrequency MRE at 40, 60, and 80 Hz actuation frequencies to acquire the complex-valued shear modulus G = G' + iG″ with the fundamental MRE parameters being the storage modulus (G'), the loss modulus (G″), and the magnitude of complex-valued shear modulus (|G|). We fitted a springpot model to these frequency-dependent MRE parameters in order to obtain the parameter α, which is related to tissue's microstructure, and the elasticity parameter k, which was converted to a shear modulus parameter (μ) through viscosity (η). We observed no statistically significant variation in the parameter μ, but a significant increase of the microstructural parameter α of the white matter with increasing age (p < 0.05). Therefore, our MRE results suggest that subtle microstructural changes such as neural tissue's enhanced alignment and geometrical reorganization during childhood and adolescence could result in significant biomechanical changes. In line with previously reported MRE data for adults, we also report significantly higher shear modulus (μ) for female brains when compared to males (p < 0.05). The data presented here can serve as a clinical baseline in the analysis of the pediatric and adolescent brain's viscoelasticity over this age span, as well as extending our understanding of the biomechanics of brain development.


Mammary implants: laboratory simulation of recreational diving conditions.
To ascertain whether mammary implants are prone to changes in conformation or structure if they are submitted to recreational dives, eight mammary implants were submitted to 40 simulated dives to imitate an average recreational diving schedule. Matching implants were used as a control group. Photographs were taken before and after completion of the protocol. All implants were observed for changes in volume and checked for integrity. Variations in density were evaluated using a Tc scan. No changes in volume occurred after each dive. None of the implants showed ruptures, and Tc scanning failed to reveal any differences in density between tested and control implants. Cohesive-gel implants submitted to the simulated dives showed some morphological alterations. This study indicates that the mammary implants tested could be implanted in a sports diver, but raises concern about whether the increased exposure to stress could negatively affect their durability.


[Examining the connection between physical exertion in pregnancy and premature birth].
The relationship between physical activity at home and at work during pregnancy and preterm birth was studied. Using a case-control design, 99 women who delivered preterm were compared with 189 women who had term deliveries. The risk of preterm birth was tested in relation to characteristics of work in and outside the home. All women were interviewed post-partum before discharge. There were no statistically significant differences between the groups in relation to sociodemographic and obstetrical factors, but level of education was significantly lower in the study group versus the control group (p = 0.001). Women who delivered preterm had devoted less time 3 months prior to delivery to household chores (mean of 3.7 hours vs. 4.8 hours in the control group, p = 0.002). They also had spent less time walking around the home than the controls (1.2 vs. 1.5 hours, p = 0.02). There were no differences between the groups in relation to physical activity outside the home, not during working hours, nor in duration of work. Significantly fewer women who delivered preterm were active in sports (odds ratio 0.22; 95% confidence interval 0.50-0.65; p = 0.002). A low level of education was significantly related to the risk of preterm birth, which may have resulted from lesser compliance with their physician's recommendations. It appears that in women not used to significant physical activity but who had access to adequate prenatal care, physical effort during pregnancy was not related to a higher risk of preterm birth.


Combining service marketing and strategic alliances in health care.
With or without federal health care reform to impact the delivery of health care services in the U.S., hospitals must commit to service marketing and strategic alliances as a fundamental business strategy. Service marketing not only differentiates the provider, but with the proper programs in place, it may actually facilitate the formation of strategic alliances. The combination of these strategies will be particularly effective in preparing for any health care policy change.


UK population based study of severe retinopathy of prematurity: screening, treatment, and outcome.
Retinopathy of prematurity (ROP) is one of the few causes of childhood blindness in which severe vision impairment is largely preventable. Ophthalmic screening for ROP is required to identify disease that requires treatment whereby the development of potentially blinding disease can be minimised. To make the first UK population based estimate of the incidence of babies with severe ROP (stage 3 or more); to document their clinical characteristics and management and to evaluate the appropriateness of current ROP screening guidelines in the UK. Cases were recruited through a national surveillance programme with 1 year ophthalmic follow up and data from clinician completed questionnaires. Between 1 December 1997 and 31 March 1999, 233 preterm babies with stage 3 ROP were identified. Severity (location, extent, and presence of plus disease) was associated with degree of prematurity, most severe in the most premature babies. Fifty nine percent were treated. The UK screening protocol was followed in two thirds of cases, but in the remainder it was begun too late or was too infrequent. Three quarters of the cases were followed up at 1 year, and 13% had a severe vision deficit as a result of ROP. Visual deficit as a result of ROP in premature babies continues to be a severe disability in some of the survivors of neonatal intensive care. Further efforts are needed to organise treatment regionally to improve outcome and standards of practice.


Influence of Confinement by COVID-19 on the Quality of Sleep and the Interests of University Students.
To check for changes in sleep in three temporary times: before COVID-19 lockdown in university students, and also twenty days and forty days afterwards, as well as to see how it has influenced in their daily activities. A longitudinal study was conducted with a sample of 75 participants from different Spanish universities. The Pittsburgh Sleep Quality Index and the Adapted Interest List were administered to evaluate the main variables of the study. About 70.7% of the sample showed worse sleep quality at 20 days, almost twice as much as before confinement (37.3%), there were more problems falling asleep (F(2, 75) = -3.14, p = 0.002), and more difficulty getting back to sleep when waking up at night (F(2.75) = 2.08, p = 0.037) at 40 days of lockdown. In addition, as confinement time went on, students showed less activities. Factors such as working, in addition to studying, and relaxing activities (reading, listening to music) were associated with better sleep quality. Sleep quality worsened during lockdown in university students, as well as both 20 and 40 days later. Staying busy during the day (not only studying but also working) and spending free time on relaxing activities are related to better sleep quality.


Apoptosis and proliferation in childhood acute proliferative glomerulonephritis.
Acute proliferative glomerulonephritis is characterized by glomerular hypercellularity that can be caused by many different etiologies and pathogenetic mechanisms. A balance between cell birth by mitosis and cell death by apoptosis is crucial. In this study, apoptosis and the regenerative activity (Ki67/apoptosis index) were investigated in acute proliferative glomerulonephritis. Thirty-five children with biopsy-proven acute proliferative glomerulonephritis and five controls with MCD were studied retrospectively. According to the clinical outcome, patients were divided into 2 groups: group 1 (n =21) were patients with normal renal functions at follow-up; group 2 (n =8) were patients with end-stage renal failure or those who died. Immunohistochemical staining of proliferating cells (Ki67) was done. In situ end labeling of DNA was used to evaluate apoptosis. Glomerular cell apoptosis was 45% in the patients with acute proliferative glomerulonephritis and 3% in controls ( p <0.001). Apoptotic cells were identified in the tubulointerstitial compartment with higher and heavier immunostaining in patients than controls (p =0.001). Tubular proliferative index (= tubular proliferation/tubular apoptosis ratio) was significantly higher in group 1 patients than in group 2 patients (2.03+/-2% versus 0.32+/-0.6%, p =0.002). Tubulointerstitial regenerative ratio (=tubular proliferation/interstitial proliferation ratio) was significantly higher in controls than in patients (3.4+/-1.9 versus 1.52+/-0.8, p =0.01). In addition, it was significantly increased in group 1 patients when compared with those in group 2 patients (1.89+/-0.8 versus 0.73+/-0.2, p =0.001). Since 17 patients presented with postinfectious proliferative glomerulonephritis, which is known to exhibit better course, we also evaluated those parameters in patients with postinfectious proliferative glomerulonephritis separately. We found statistically significant differences only in the tubulointerstitial regenerative ratio, which was higher in postinfectious cases when compared with those in other cases [1.60 interquartile range (IQR) 1.54 versus 1.22 IQR 1.26, respectively, p =0.003]. In conclusion, tubular proliferative index and tubulointerstitial regenerative ratio might be useful parameters for predicting final functional outcome in acute proliferative glomerulonephritis. Further studies, however, are still needed to clarify the importance of these histopathological parameters.


Factors influencing the output of rural cataract surgical facilities in China: the SHARP study.
To identify factors associated prospectively with increased cataract surgical rate (CSR) in rural Chinese hospitals. Annual cataract surgical output was obtained at baseline and 24 months later from operating room records at 42 rural, county-level hospitals. Total local CSR (cases/million population/y), and proportion of CSR from hospital and local competitors were calculated from government records. Hospital administrators completed questionnaires providing demographic and professional information, and annual clinic and outreach screening volume. Independent cataract surgeons provided clinical information and videotapes of cases for grading by two masked experts using the Ophthalmology Surgical Competency Assessment Rubric (OSCAR). Uncorrected vision was recorded for 10 consecutive cataract cases at each facility, and 10 randomly-identified patients completed hospital satisfaction questionnaires. Total value of international nongovernmental development organization (INGDO) investment in the previous three years and demographic information on hospital catchment areas were obtained. Main outcome was 2-year percentage change in hospital CSR. Among the 42 hospitals (median catchment population 530,000, median hospital CSR 643), 78.6% (33/42) were receiving INGDO support. Median change in hospital CSR (interquartile range) was 33.3% (-6.25%, 72.3%). Predictors of greater increase in CSR included higher INGDO investment (P = 0.02, simple model), reducing patient dissatisfaction (P = 0.03, simple model), and more outreach patient screening (P = 0.002, simple and multiple model). Outreach cataract screening was the strongest predictor of increased surgical output. Government and INGDO investment in screening may be most likely to enhance output of county hospitals, a major goal of China's Blindness Prevention Plan.


Collagenous colitis and lymphocytic colitis: clinical and endoscopic findings.
collagenous colitis (CC) and lymphocytic colitis (LC) are two entities of unknown cause, characterized by chronic watery diarrhea, grossly normal-appearing colonic mucosa and abnormal histopathological findings in colonic biopsies. The clinical features of the disease are based mainly on case reports or small uncontrolled series. Although normal colonoscopic findings are, as a rule, part of the diagnosis of CC, several cases of macroscopic colitis associated with CC have been reported, and the spectrum of endoscopic mucosal changes has not been described in large series. we present a retrospective study of all patients who underwent total colonoscopy and mucosal biopsy in our Endoscopy Unit between 1991 and 1997. Clinical and endoscopic findings in patients diagnosed as having CC or LC were recorded. of 676 patients studied, 398 suffered from chronic diarrhea. Collagenous colitis was diagnosed in 22 patients and LC in 10. Eleven per cent of the patients with CC and 20% of those with LC did not have diarrhea. Macroscopic colitis was observed in 6 out of 22 patients with CC (27%) and in 4 out of 10 with LC (40%). Macroscopic lesions included edema, erythema, abnormal vascular pattern, superficial erosions or ulcerations and hemorrhagic lacerations. In this series 7.03% of the patients with chronic diarrhea were diagnosed as having CC or LC. collagenous colitis and LC are two entities that should be considered in the differential diagnosis of chronic diarrhea. Total colonoscopy with multiple biopsies that include the right colon are mandatory. The presence of macroscopic lesions on endoscopy does not rule out a diagnosis of either entity. We identified patients who fulfilled the histopathological criteria for CC or LC but who did not have diarrhea.


[Comparative study of the ESR spectra of normal and regenerating liver tissue in mice].
Low temperature ESR spectra of gamma-irradiated samples of mouse liver regenerating after partial hepatectomy were studied. As compared to ESR spectra of gamma-irradiated samples of health animals liver, in regenerating liver samples new ESR signals from paramagnetic centres S(2.0005) and S(2.0025) were revealed; these signals were earlier recorded by the authors in gamma-irradiated samples of hepatoma 22a. It is concluded that the paramagnetic centres S(2.0005) and S(2.0025) are typical of proliferating tissues of different ethiology.


End-stage renal disease versus death in a Portuguese cohort of elderly patients: an approach using competing event analysis.
Chronic kidney disease (CKD) is higher in elderly, but mortality outweighs the risk of end-stage renal disease (ESRD). Our aim was to identify prognostic markers for ESRD or death in elderly CKD, within a competing-risk analysis. This is a longitudinal study of consecutive newly referred patients with CKD ages 65 years, followed until the time of the first event (ESRD or death), using a competing-risk analysis. A modified Charlson Comorbidity Index (mCCI) was subdivided into subgroups (0-2, 3-4, ≥5). Patients were followed for hospitalizations that occurred prior to the outcomes. Among 416 patients, age 76±8 years, 52% male, median estimated glomerular filtration rate of 32 mL/min per 1.73 m2, 50% had diabetes, and 67% cardiovascular disease. Over a median follow-up of 3.6 years, 36 patients progressed to ESRD (8.7%) and 103 died (24.8%). Older age (subdistribution HR (sHR)=1. 06; p<0.001), creatinine≥1.6 mg/dL (sHR=2.03, p=0.004), hemoglobin <11 g/dL (sHR=1.91, p=0.003), mCCI score≥5 (sHR=3.01, p<0.001) and having one or more hospitalizations (sHR=1.73, p<0.001) were associated with death before ESRD. The independent predictors for ESRD with competing risk of death were: lower age (sHR=0.94; p=0.009), creatinine≥1.6 mg/dL (sHR=3.26, p=0.006), hemoglobin <11 g/dL (sHR=2.15, p=0.027), peripheral vascular disease (sHR=3.45, p=0.001) and having one or more hospitalizations (sHR=1.56, p=0.031). Elderly referred patients with CKD are near threefold more likely to die than progress to ESRD. A competing-risk framework based on available clinical and laboratory data may discriminate between those outcomes and could be used as a decision-making tool.


Disclosing intimate partner violence to health care clinicians - what a difference the setting makes: a qualitative study.
Despite endorsement by national organizations, the impact of screening for intimate partner violence (IPV) is understudied, particularly as it occurs in different clinical settings. We analyzed interviews of IPV survivors to understand the risks and benefits of disclosing IPV to clinicians across specialties. Participants were English-speaking female IPV survivors recruited through IPV programs in Massachusetts. In-depth interviews describing medical encounters related to abuse were analyzed for common themes using Grounded Theory qualitative research methods. Encounters with health care clinicians were categorized by outcome (IPV disclosure by patient, discovery evidenced by discussion of IPV by clinician without patient disclosure, or non-disclosure), attribute (beneficial, unhelpful, harmful), and specialty (emergency department (ED), primary care (PC), obstetrics/gynecology (OB/GYN)). Of 27 participants aged 18-56, 5 were white, 10 Latina, and 12 black. Of 59 relevant health care encounters, 23 were in ED, 17 in OB/GYN, and 19 in PC. Seven of 9 ED disclosures were characterized as unhelpful; the majority of disclosures in PC and OB/GYN were characterized as beneficial. There were no harmful disclosures in any setting. Unhelpful disclosures resulted in emotional distress and alienation from health care. Regardless of whether disclosure occurred, beneficial encounters were characterized by familiarity with the clinician, acknowledgement of the abuse, respect and relevant referrals. While no harms resulted from IPV disclosure, survivor satisfaction with disclosure is shaped by the setting of the encounter. Clinicians should aim to build a therapeutic relationship with IPV survivors that empowers and educates patients and does not demand disclosure.


The interaction between D-2 dopamine receptors and GTP-binding proteins.
D-2 dopamine receptors were solubilized from porcine striatal membranes with 0.3% sodium cholate/1 M NaCl and separated from the bulk of the guanine nucleotide-binding regulatory proteins (G-proteins) by Ultrogel AcA34 gel filtration chromatography. The partially purified D-2 receptors were reconstituted in phospholipid vesicles with Gi or Go purified from porcine brain. The dissociation constant (Kd) of the D-2 receptors in the reconstituted vesicles for [3H]spiperone binding was 82-89 pm, which was not affected by the presence or absence of G-proteins. The displacement curve for [3H]spiperone/dopamine was analyzed, assuming that there are two populations of binding sites. The Kd values for the binding sites with high affinity for agonists (HAS) and that for the binding sites with low affinity for agonists (LAS) were approximately 1 microM and 100 microM, respectively. The proportion of HAS was 8% when the receptor preparation was reconstituted into phospholipid vesicles without G-proteins, but it increased to 58-64% with increasing G-protein concentrations. The potency of Go was a little higher than that of Gi. The proportion of HAS in the presence of G-proteins decreased to about 11% on addition of GTP. When G-proteins were treated with islet-activating protein, GTP-sensitive HAS were not observed. These results indicate that at least 50% of the partially purified D-2 receptors interact with both Gi and Go.


Ictal perfusion changes during occipital lobe seizures in infancy: report of two serial ictal observations.
Serial-ictal single-photon-emission computed tomography (SPECT) examinations are presented in two infants (ages 1 and 2 years), with early ictal and ictal in one, and ictal and late ictal images in the other. Both had pharmacoresistant occipital epilepsy, due to focal cortical dysplasia. In the first case, size of ictal hyperperfusion increased in the course of the seizure from early ictal to ictal state. A concomitant ictal hypoperfusion was observed around the hyperperfused area. In the second patient, there was a dramatic difference between ictal and late ictal images. In the late ictal state, the previous occipital ictal hyperperfusion and extraoccipital ictal hypoperfusion disappeared, together with homolateral posterotemporal and contralateral occipital hyperperfusion, corresponding to seizure propagation. Ictal extratemporal blood-flow changes are therefore highly dynamic, particularly in very young children.


Mindfulness Ameliorates the Relationship between Weight Concerns and Smoking Behavior in Female Smokers: A Cross-Sectional Investigation.
Weight concerns are common among female smokers and may interfere with smoking cessation. It is imperative to identify protective factors to lessen the likelihood that smoking-related weight concerns prompt smoking and hinder cessation efforts. Mindfulness is one potential protective factor that might prevent weight concerns from triggering smoking. In the current study, relationships among facets of trait mindfulness, smoking-related weight concerns, and smoking behavior were examined among 112 young adult female smokers (70.5% daily smokers; 83% Caucasian; mean age 20 [SD = 1.69]). After controlling for demographic variables, the Describing facet of trait mindfulness predicted lower smoking-related weight concerns. The mindfulness characteristics of Acting with Awareness, Nonreactivity, and Describing moderated the relationship between smoking-related weight concerns and smoking frequency, such that smoking-related weight concerns predicted greater smoking frequency in female smokers with low and medium levels of these mindfulness characteristics but did not in those with higher levels of mindfulness. These results suggest that mindfulness-based interventions may be effective for weight-concerned smokers.


Identification of post acute myocardial infarction patients with potential benefit from prophylactic treatment with amiodarone. A substudy of EMIAT (the European Myocardial Infarct Amiodarone Trial).
To perform a retrospective analysis of subgroups of patients enrolled into the European Myocardial Infarct Amiodarone Trial (EMIAT) in order to identify patients who might benefit from prophylactic amiodarone treatment and patients in whom amiodarone might be harmful. Baseline characteristics of the 1486 patients enrolled in EMIAT were used to investigate the all-cause mortality effect of amiodarone (intention-to-treat) in patients with a left ventricular ejection fraction 30-40% and < 30%, in patients with and without arrhythmia signs on Holter recordings, in patients with high and low baseline resting heart rate, in patients on and off beta-blocker treatment, and in a combination of these groups. A univariate analysis suggested that all-cause mortality is reduced on amiodarone in patients with an ejection fraction < 30%, with arrhythmia on the initial Holter, on beta-blocker treatment, and with an increased initial heart rate. A trend towards an increase of all-cause mortality was noted in patients with an ejection fraction 30-40%, without arrhythmia on Holter, off beta-blockers, and with a low baseline heart rate. A multivariate analysis suggested that the univariate observations are mutually additive. The study might serve as a basis for future prospective trials where amiodarone could be tested in patients with a recent myocardial infarction, having a reduced left ventricular ejection fraction, a high initial heart rate, and taking beta-blockers.


Modeling cardiac fibroblast heterogeneity from human pluripotent stem cell-derived epicardial cells.
Cardiac fibroblasts play an essential role in the development of the heart and are implicated in disease progression in the context of fibrosis and regeneration. Here, we establish a simple organoid culture platform using human pluripotent stem cell-derived epicardial cells and ventricular cardiomyocytes to study the development, maturation, and heterogeneity of cardiac fibroblasts under normal conditions and following treatment with pathological stimuli. We demonstrate that this system models the early interactions between epicardial cells and cardiomyocytes to generate a population of fibroblasts that recapitulates many aspects of fibroblast behavior in vivo, including changes associated with maturation and in response to pathological stimuli associated with cardiac injury. Using single cell transcriptomics, we show that the hPSC-derived organoid fibroblast population displays a high degree of heterogeneity that approximates the heterogeneity of populations in both the normal and diseased human heart. Additionally, we identify a unique subpopulation of fibroblasts possessing reparative features previously characterized in the hearts of model organisms. Taken together, our system recapitulates many aspects of human cardiac fibroblast specification, development, and maturation, providing a platform to investigate the role of these cells in human cardiovascular development and disease.


Facilely Direct Construction, White-Light Emission, and Color-Adjustable Luminescence of LaF3 :Pr3+ @SiO2 Yolk-Shell Nanospheres with Moisture Resistance.
Poor water stability and single luminous color are the major drawbacks of the most phosphors reported. Therefore, it is important to realize multicolor luminescence in a phosphor with single host and single activator as well as moisture resistance. LaF3 :Pr3+ @SiO2 yolk-shell nanospheres are facilely obtained by a designing new technology of a simple and cost-effective electrospray ionization combined with a dicrucible fluorating technique without using protective gas. In addition, tunable photoluminescence, especially white-light emission, is successfully obtained in LaF3 :Pr3+ @SiO2 yolk-shell nanospheres by adjusting Pr3+ ion concentrations, and the luminescence mechanism of Pr3+ ion is advanced. Compared with the counterpart LaF3 :Pr3+ nanospheres, the water stability of LaF3 :Pr3+ @SiO2 yolk-shell nanospheres is improved by 15% after immersion in water for 72 h, and the fluorescence intensity can be maintained at 86% of the initial intensity. Furthermore, by treating the yolk-shell nanospheres with hydrofluoric acid, it is not only demonstrated that the shell-layer is SiO2 but also core-LaF3 :Pr3+ nanospheres are obtained. Particularly, only fluorination procedure among the halogenation can produce such special yolk-shell nanospheres, the formation mechanism of yolk-shell nanospheres is proposed detailedly based on the sound experiments and a corresponding new technology is built. These findings broaden practical applications of LaF3 :Pr3+ @SiO2 yolk-shell nanospheres.


Primary lymphomas of the major salivary glands.
The finding of a lymphoma of the major salivary glands (almost always parotid gland) has two diagnostic implications; it is only part of a known disseminated process, or it may be the first clinical-pathologic evidence of lymphoma. In the latter instance, the disease may be localized or, most often, be a precursory lesion to regional or systemic disease. Patients with Sjögren's or sicca syndrome are at increased risk for the development of lymphoma, and their lymphomas are biologically more aggressive.


Beacon Success Rate versus Gateway Density in Sub-GHz Sensor Networks.
Multiple Gateways (GWs) provide network connectivity to Internet of Things (IoT) sensors in a Wide Area Network (WAN). The End Nodes (ENs) can connect to any GW by discovering and acquiring its periodic beacons. This provides GW diversity, improving coverage area. However, simultaneous periodic beacon transmissions among nearby GWs lead to interference and collisions. In this study, the impact of such intra-network interference is analyzed to determine the maximum number of GWs that can coexist. The paper presents a new collision model that considers the combined effects of the Medium Access Control (MAC) and Physical (PHY) layers. The model takes into account the partial overlap durations and relative power of all colliding events. It also illustrates the relationship between the collisions and the resulting packet loss rates. A performance evaluation is presented using a combination of analytical and simulation methods, with the former validating the simulation results. The system models are developed from experimental data obtained from field measurements. Numerical results are provided with Gaussian Frequency Shift Keying (GFSK) modulation. This paper provides guidance on selecting GFSK modulation parameters for low bit-rate and narrow-bandwidth IoT applications. The analysis and simulation results show that larger beacon intervals and frequency hopping help in reducing beacon loss rates, at the cost of larger beacon acquisition latency. On the flip side, the gateway discovery latency reduces with increasing GW density, thanks to an abundance of beacons.


Comprehensive analysis of circRNA expression profiles in humans by RAISE.
Circular RNAs (circRNAs) are pervasively expressed circles of non‑coding RNAs. Even though many circRNAs have been reported in humans, their expression patterns and functions remain poorly understood. In this study, we employed a pipeline named RAISE to detect circRNAs in RNA‑seq data. RAISE can fully characterize circRNA structure and abundance. We evaluated inter-individual variations in circRNA expression in humans by applying this pipeline to numerous non‑poly(A)-selected RNA‑seq data. We identified 59,128 circRNA candidates in 61 human liver samples, with almost no overlap in the circRNA of the recruited samples. Approximately 89% of the circRNAs were detected in one or two samples. In comparison, 10% of the linear mRNAs and non‑coding RNAs were detected in each sample. We estimated the variation in other tissues, especially the circRNA high-abundance tissues, in advance. Only 0.5% of the 50,631 brain circRNA candidates were shared among the 30 recruited brain samples, which is similar to the proportion in liver. Moreover, we found inter- and intra-individual diversity in circRNAs expression in the granulocyte RNA‑seq data from seven individuals sampled 3 times at one-month intervals. Our findings suggest that careful consideration of inter-individual diversity is required when extensively identifying human circRNAs or proposing their use as potential biomarkers and therapeutic targets in disease.


Solid-in-oil nanodispersions as a novel delivery system to improve the oral bioavailability of bisphosphate, risedronate sodium.
The aim of the current study was to modify the oral absorption of risedronate sodium (RS) using solid-in-oil nanodispersions (SONDs) technology. The oral therapeutic effect of RS is limited in vivo because of its low membrane permeability and the formation of insoluble precipitates with bivalent cations (such as Ca2+) in the gastrointestinal (GI) tract.We used SONDs to prepare medium-chain triglyceride (MCT)-based nanodispersions of the hydrophilic drug, which used the oral absorption mechanism of MCT digestion to improve bioavailability of RS in vivo. SONDs exhibited high encapsulation efficiency of RS and excellent enzymatic degradation-dependent release behavior. The result of an everted gut sac test showed that the Papp value of the SONDs was 6.29-fold (p<0.05) higher than that of RS aqueous solutions in simulated intestinal fluid containing 5 mM Ca2+, this was because MCT can be digested to form the fatty acids C8 and C10, which have an adsorption-promoting effect on RS. Further, solid-in-oil-in-water (S/O/W) emulsion droplets formedafter emulsification by bile salts and MCT digestionwere effective in disrupting epithelial tight junctions (TJs), facilitating the paracellular permeation of RS throughout the intestine. Moreover, in vivo absorption study in rats revealed that the AUC0-12h of RS in SONDs was approximately 4.56-fold (p<0.05) higher than with RS aqueous solutions at the same dose (15 mg/kg). This approach demonstrates a potential drug delivery system to improve the bioavailability of risedronate sodium.


The therapeutic effects of rehmannia oral liquid for the syndrome of heat accumulation with Yin consumption in esophagus cancer patients undergoing radiotherapy--a report of 60 cases.
To observe the clinical therapeutic effects of Rehmannia Oral Liquid on the syndrome of heat accumulation with Yin consumption in intermediate or late esophagus cancer patients undergoing radiotherapy. The IFN-alpha, TNF-alpha, IL-1beta and TGF-beta1 levels in sera were determined by the method of ABC-WLISA before and after the treatment with Rehmannia Oral Liquid. At the same time, the observation was carried out on the patient's general condition, symptoms and signs, barium meal or CT examinations, and biopsy. Another 30 cases of esophagus cancer were treated singly with radiotherapy as the control group. Rehmannia Oral Liquid could obviously improve the patient's general condition, and the symptoms and signs after radiotherapy. Based on the X-ray examination and biopsy, the short-term local control rate of the treatment group and the control group was 70.0% and 40.0% respectively, showing a significant difference (P<0.05). Before the treatment, the level of serum IFN-alpha of both cancer groups was lower and the levels of TNF-alpha, IL-1beta and TGF-beta1 were higher than that of normal group. After treatment, the level of IFN-alpha in both treatment group and control group increased significantly (P<0.01), and the treatment group improved more obviously than the control group (P<0.05). The level of TNF-alpha of both groups decreased significantly (P<0.01) after treatment, and the level of IL-1beta decreased in treatment group and increased in control group without the significant difference as compared with that before treatment The level of TGF-beta1 was significantly increased in control group (P<0.05) and decreased in treatment group (P>0.05) after treatment. The difference between groups was significant (P<0.05). Rehmannia Oral Liquid can obviously reduce the radiotherapy reaction, improve the quality of life, and raise the therapeutic effects. The action mechanism of the Liquid may lie in balancing the cytokine network and regulating the disordered signal transmission.


[Ventricular arrhythmias. A potential risk associated with the use of non-cardiovascular drugs prolonging the QT interval].
The electrocardiogram shows a sequence of cardiac electrical events generated by individual electrical currents generated mainly by sodium (Na+), potassium (K+) and calcium (Ca++) ions transiting via specialized transport pathways, such as ion channels, inserted in the membranes of excitable cardiac cells. Na+ and Ca++, entering the cells, are messengers of activating, inward, depolarizing currents (INa, ICa), generating the QRS wave of the electrocardiogram, whereas K+, leaving the cells, carries outward repolarizing currents (e.g. Ito, IKr, IKs and IK1), generating the T wave of the electrocardiogram, which drives the cell to a rest condition. Therefore, a significantly prolonged repolarization process results in a prolonged QT interval which can initiate ectopic cardiac beats that may evolve into a potentially lethal ventricular tachyarrhythmia, called torsades de pointes. This implies that the measurement of QT interval, appropriately corrected (QTc) for heart rate values by applying available algorithms, is a current tool of diagnostic investigation to reveal abnormalities of the cardiac repolarisation process. Numerous non cardiovascular drugs in general clinical use (psychotropics, prokinetics, antimalarials, antibiotics, antihistamines, etc.) can prolong QT interval, often by a mechanism not necessary for their therapeutic effects, which is a reduction of the potassium current IKr conveyed by the HERG channel. The torsadogenic potential of these drugs can be facilitated by factors (female gender, bradycardia, electrolyte imbalances, cardiac diseases, simultaneous use of multiple drugs prolonging QT interval, etc.) known to have the propensity to reduce the redundant cardiac repolarization reserve, characterizing the healthy myocardium. Presently, drug candidates are routinely subjected to preclinical and clinical examination for cardiac safety, a property required by health authorities for any new medicine before allowing marketing authorization. Finally, before prescribing a medicinal product prolonging QT interval, a physician should carefully evaluate not only the disease he wants to treat but also the availability of equally effective, alternative drugs. The golden rule, to which such a prescription has always to abide, requires that the beneficial effects expected from a therapy should for each treated patient outweigh any possible adverse consequence, particularly when the latter one could be of lethal nature.


Evaluating Nebraska EMS Providers' Ability and Willingness to Respond to Emergencies Resulting from Bioterrorist Attacks.
Previous studies have found that public health systems within the United States are inadequately prepared for an act of biological terrorism. As the coronavirus disease (COVID-19) pandemic continues, few studies have evaluated bioterrorism preparedness of Emergency Medical Services (EMS), even in the accelerating environment of biothreats. This study utilized an Internet-based survey to assess the level of preparedness and willingness to respond to a bioterrorism attack and identify factors that predict preparedness and willingness among Nebraska EMS providers. The survey was available for 1 month in 2021 during which 190 EMS providers responded to the survey. Only 56.8% of providers were able to recognize an illness or injury as potentially resulting from exposure to a biological agent. The provider Clinical Competency levels ranged from a low of 13.6% (ability to initiate patient care within his/her professional scope of practice and arrange for prompt referral appropriate to the identified condition(s)) to a high of 74% (the ability to respond to an emergency within the emergency management system of his/her practice, institution, and community). Only 10% of the respondents were both willing and able to effectively function in a bioterror environment. To effectively prepare for and respond to a bioterrorist attack, all levels of the health care system need to have the clinical skills, knowledge, and abilities necessary to treat patients exposed to biological agents. Policy changes and increased focus on training and drills are needed to ensure a prepared EMS system, which is crucial to a resilient state. EMS entities need to be aware of the extent of their available workforce so that the country can be prepared for the increasing threat of bioterrorism or other novel emerging infectious disease outbreaks. A resilient nation relies on a prepared set of EMS providers who are willing to respond to biological terrorism events.


[An analysis of advertisements for psychotropic drugs in the Dutch Journal of Psychiatry ('Tijdschrift voor Psychiatrie')].
Through the marketing of psychotropics the pharmaceutical industry is able to influence the way in which psychiatrists practise their profession. To look at the image of psychiatry as reflected in advertisements for psychotropics. method Quantitative and qualitative analysis of the advertisements for psychotropics in the Tijdschrift voor Psychiatrie between 1999 and 2006. On average 6 per cent of the total number of pages was given over annually to advertisements of psychotropics. The number of pages used for these advertisements changed over the years, with a sharp decline between 2002 and 2004. Before 2002 the majority of advertisements was for antidepressants, but later most of them were for antipsychotics. Three-quarters of the illustrations for antidepressants featured women whereas three-quarters of the illustrations for antipsychotics featured men. In general, the advertisements were of an 'emotional' nature and surprisingly few of them contained any scientific information. The advertisements for psychotropics portrayed a stereotyped image implying that it is mainly women who are depressed and mainly men who are psychotic. In its advertisements the pharmaceutical industry seeks primarily emotional reactions and uses hardly any scientific arguments. We wonder if the editorial boards of scientific journals should perhaps adopt a more critical attitude to these kinds of advertisements.


[Recovery after serious mushroom poisoning (grade IV encephalopathy) with intensive care support and without liver transplantation. Clinical case].
Despite consistent improvement in its treatment, amatoxin poisoning still extolls an elevated overall mortality, ranging between 10 and 15%, which approaches 100% when severe (grade 3-4 encephalopathy) hepatic failure supervened. Therefore, the proper treatment of intoxication by amatoxin containing mushrooms, and particularly of its complications, remains a challenge in emergency medicine. Klein and coworkers reviewed the role of liver transplantation in amatoxin poisoning as a useful therapeutic tool for patients with severe impairment of liver function. Their indication for intervention is the presence of any of the following signs: grade 2 encephalopathy or higher; prothrombin time twice than normal, despite fresh frozen plasma infusion; hypoglycemia requiring hypertonic glucose infusion; hyperbilirubinemia (greater than 25 mg/dl). During the past autumn two patients with fulminant hepatic failure due to amatoxin poisoning were referred to our institutions as candidates for liver transplantation, since both satisfied Klein's criteria. However, due to shortage of organ donors it was impossible to transplant them over the following days. Despite they did not receive liver transplantation, both patients wakened from coma, their liver function improved, and they recovered from terminal amatoxin poisoning. After one year, both patients are long-term survivors, in good health and without any sequelae either in brain or liver function.


Associations between NBS1 polymorphisms, haplotypes and smoking-related cancers.
Constituents of tobacco smoke can cause DNA double-strand breaks (DSBs), leading to tumorigenesis. The NBS1 gene product is a vital component in DSB detection and repair, thus genetic variations may influence cancer development. We examined the associations between NBS1 polymorphisms and haplotypes and newly incident smoking-related cancers in three case-control studies (Los Angeles: 611 lung and 601 upper aero-digestive tract (UADT) cancer cases and 1040 controls; Memorial Sloan-Kettering Cancer Center: 227 bladder cancer cases and 211 controls and Taixing, China: 218 esophagus, 206 stomach, 204 liver cancer cases and 415 controls). rs1061302 was associated with cancers of the lung [adjusted odds ratio (OR(adj)) = 1.6, 95% confidence interval (CI): 1.2, 2.4], larynx (OR(adj) = 0.56, 95% CI: 0.32, 0.97) and liver (OR(adj) = 1.7, 95% CI: 1.0, 2.9). Additionally, positive associations were found for rs709816 with bladder cancer (OR(adj) = 4.2, 95% CI: 1.4, 12) and rs1063054 with lung cancer (OR(adj) = 1.6, 95% CI: 1.0, 2.3). Some associations in lung and stomach cancers varied with smoking status. CAC haplotype was positively associated with smoking-related cancers: lung (OR(adj) = 1.7, 95% CI: 1.1, 2.9) and UADT (OR(adj) = 2.0, 95% CI: 1.1, 3.7), specifically, oropharynx (OR(adj) = 2.1, 95% CI: 1.0, 4.2) and larynx (OR(adj) = 4.8, 95% CI: 1.7, 14). Bayesian false-discovery probabilities were calculated to assess Type I error. It appears that NBS1 polymorphisms and haplotypes may be associated with smoking-related cancers and that these associations may differ by smoking status. Our findings also suggest that single-nucleotide polymorphisms located in the binding region of the MRE-RAD50-NBS1 complex or microRNA targeted pathways may influence tumor development. These hypotheses should be further examined in functional studies.


Pain reduction on insertion of a feeding tube in preterm infants: a randomized controlled trial.
Gavage feeding is required in preterm infants who cannot feed by themselves. Insertion of the feeding tube is painful, and reducing the discomfort in these patients is desirable. The aim of this study was to assess pain and discomfort during nasal insertion of a feeding tube, and to evaluate different measures for pain relief. We included 24 preterm infants with postmenstrual age 28 to 32 weeks' who were in stable condition. Each infant acted as his or her own control over a 3-week period during which the tube was changed 6 times. On these occasions, 6 different treatment combinations were given in randomized order: pacifier or no pacifier, combined with no fluid, sterile water, or 30% sucrose. Pain and discomfort were assessed by at least 2 independent and experienced observers using a pain assessment tool, the Premature Infant Pain Profile; score range: 0 to 21. In general, scores of 4 to 6 are interpreted as normal or no discomfort; ≥ 12 usually signals significant pain and distress. The median Premature Infant Pain Profile score during the procedure was 9 and decreased gradually toward 4 after 5 minutes. The lowest pain score was achieved by combining a pacifier with oral sucrose. Sterile water without a pacifier gave the highest score. Insertion of a feeding tube in preterm infants leads to a measurable degree of pain and discomfort, according to the Premature Infant Pain Profile assessment tool. Pain relief was best achieved by combining a pacifier with 30% sucrose.


Effects of inhibitors of RNA and protein synthesis on the subcellular distribution of the eukaryotic translation initiation factor, eIF-5A, and the HIV-1 Rev protein.
The subcellular distributions of the endogenous eukaryotic translation initiation factor, eIF-5A, and Rev, a protein of the human immunodeficiency virus proposed to interact with eIF-5A, were studied in COS-7 cells treated with inhibitors of RNA or protein synthesis. We have previously shown that transiently expressed Rev is localized in the nucleolus, whereas eIF-5A is primarily in the cytoplasm. The subcellular localization of Rev was not affected by treatment with protein synthesis inhibitors (cycloheximide, CHX, 10 micrograms/ml; puromycin, 10 micrograms/ml), although its location changed from predominantly the nucleolus to the cytoplasm after treatment with RNA synthesis inhibitors (actinomycin D, 4 micrograms/ml, and 5,6-dichloro-1 beta-D-ribofuranosylbenzimidazole, DRB; 0.1 mM), as previously reported. In contrast, none of the RNA synthesis inhibitors (alpha-amanitin, 10 micrograms/ml; actinomycin D, 4 micrograms/ml, and DRB, 0.1 mM) caused any significant changes in the subcellular distribution pattern of eIF-5A. However, treatment with puromycin, a protein synthesis inhibitor known to dissociate ribosomes, dramatically altered the subcellular distribution pattern of eIF-5A in 30% of the cell population. In these cells, the staining of eIF-5A was changed from an endoplasmic reticulum (ER) net work-like perinuclear structure to a patched dotted pattern dispersed throughout the cytoplasm. This change was not observed in the same cells stained for calnexin, an ER resident protein, nor in cells treated with CHX, which freezes the ribosomes to block protein synthesis. Our data suggest that eIF-5A does not shuttle between the nucleus and cytoplasm in the same way as Rev. Our findings are consistent with our previous conclusion that eIF-5A is associated with the ER through ribosomes and support a role for eIF-5A in protein synthesis.


Cardiovascular risk profiling of long-lived people shows peculiar associations with mortality compared with younger individuals.
Centenarians represent a biological model of successful aging because they escaped/postponed most invalidating age-related diseases, such as cardiovascular diseases. The aim of the present study was to clarify whether a favorable cardiovascular risk profile increases the survival chances in long-lived people. A total of 355 community-dwelling nonagenarians and centenarians living in Southern Italy were recruited in the study. Patients were classified as at low and high cardiovascular risk on the basis of serum cholesterol, diabetes, hypertension and smoking status. The relationship between cardiovascular risk factors and 10-year mortality was investigated by Cox regression analysis. Splines-based hazard ratio curves were also estimated for total cholesterol, low-density lipoprotein cholesterol, and systolic and diastolic blood pressure. Low levels of selected cardiovascular risk factors usually associated with lower mortality in adults do not increase survival chances among oldest-old individuals. In particular, after adjusting for age, sex, and cognitive, functional and nutritional status, serum cholesterol >200 mg/dL increased the survival chances during the follow-up period (hazard ratio 0.742, 95% CI 0.572-0.963). The present results showed that in nonagenarians and centenarians, the clinical and prognostic meaning associated with traditional cardiovascular risk factors is very different from younger populations. Consequently, considering the increase of this population segment, further studies are required to confirm these results and to translate them into clinical practice/primary care. Geriatr Gerontol Int 2019; 19: 165-170.


Comparison of Constant-Posture Force-Varying EMG-Force Dynamic Models About the Elbow.
Numerous techniques have been used to minimize error in relating the surface electromyogram (EMG) to elbow joint torque. We compare the use of three techniques to further reduce error. First, most EMG-torque models only use estimates of EMG standard deviation as inputs. We studied the additional features of average waveform length, slope sign change rate and zero crossing rate. Second, multiple channels of EMG from the biceps, and separately from the triceps, have been combined to produce two low-variance model inputs. We contrasted this channel combination with using each EMG separately. Third, we previously modeled nonlinearity in the EMG-torque relationship via a polynomial. We contrasted our model versus that of the classic exponential power law of Vredenbregt and Rau (1973). Results from 65 subjects performing constant-posture, force-varying contraction gave a "baseline" comparison error (i.e., error with none of the new techniques) of 5.5 ± 2.3% maximum flexion voluntary contraction (%MVCF). Combining the techniques of multiple features with individual channels reduced error to 4.8 ± 2.2 %MVCF, while combining individual channels with the power-law model reduced error to 4.7 ± 2.0 %MVCF. The new techniques further reduced error from that of the baseline by ≈ 15 %.


Combined effect of cardiorespiratory fitness and adiposity on mortality in patients with coronary artery disease.
High cardiorespiratory fitness and body mass index (BMI) are associated with decreased mortality in patients with coronary artery disease. Our objective was to determine the joint impact of fitness and adiposity measures on all-cause mortality in this subgroup. Coronary artery disease patients (n = 855) enrolled in the Mayo Clinic cardiac rehabilitation program from 1993 to 2007 were included. Fitness levels were determined by cardiopulmonary exercise testing. Patients were divided into low and high fitness by sex-specific median values of peak oxygen consumption and total treadmill time. Adiposity was measured through BMI and waist-to-hip ratio (WHR). There were 159 deaths during 9.7 ± 3.6 years of mean follow-up. After adjusting for potential confounding factors, low fitness, shorter treadmill time, low BMI, and high WHR were significantly associated with increased mortality. Using low WHR-high fitness group as reference, significantly increased mortality was noted in low WHR-low fitness (hazard ratio 4.2, 95% CI, 1.8-9.8), centrally obese-high fitness (2.3, 1.0-5.4), and centrally obese-low fitness (6.1, 2.7-13.6) groups. Overweight-high fitness (2.2, 0.63-7.4), obese-high fitness (3.2, 0.88-11.4), and obese-low fitness (3.3, 0.96-11.4) subjects did not have a significantly different mortality as compared with the reference group of normal weight-high fitness subjects, whereas normal weight-low fitness (9.6, 2.9-31.8) and overweight-low fitness (6.8, 2.1-22.2) groups had significantly increased mortality. Low fitness and central obesity were independently and cumulatively associated with increased mortality in coronary artery disease patients attending cardiac rehabilitation. The association of BMI with mortality is complex and altered by fitness levels.


Viscoelastic properties of liver measured by oscillatory rheometry and multifrequency magnetic resonance elastography.
The mechanical properties of liver can sensitively indicate the progression of hepatic fibrosis. Mechanical tissue characterization involves the analysis of the complex shear modulus measured either by oscillatory rheometry or by in vivo elastography. In this study, bovine liver specimens were investigated by oscillatory rheometry and multifrequency magnetic resonance elastography (MRE) in a common frequency range between 25.0 and 62.5 Hz. The results were compared with in vivo MRE of human liver. Storage and loss moduli were quantified, and the data were also analyzed employing a springpot model, yielding a stiffness-related parameter of 2.96+/-0.53 kPa in bovine liver by rheometry and of 2.20+/-0.45 kPa in human liver by in vivo MRE. Furthermore, MRE of excised bovine liver showed that stiffness tended to increase with decreasing sample temperature. In conclusion, mechanical tissue characterization by multifrequency MRE agrees well with oscillatory rheometry, which validates MRE as a method for investigating the rheology of liver tissue.


VEGF induces Mcl-1 up-regulation and protects multiple myeloma cells against apoptosis.
Interleukin-6 (IL-6) triggers multiple myeloma (MM) cell proliferation and protects against apoptosis by up-regulating myeloid cell leukemia 1 (Mcl-1). Vascular endothelial growth factor (VEGF) induces modest proliferation of MM cells and induces IL-6 secretion in a paracrine loop involving MM cells and bone marrow stromal cells. Using murine embryonic fibroblast cell lines as a model (Mcl-1(wt/wt) and Mcl-1(Delta/null) MEFs), we here demonstrate that deletion of Mcl-1 reduces fetal bovine serum (FBS)-, VEGF-, and IL-6-induced proliferation. We also show that VEGF up-regulates Mcl-1 expression in a time- and dose-dependent manner in 3 human MM cell lines and MM patient cells. Importantly, we demonstrate that the pan-VEGF inhibitor, GW654652, inhibits VEGF-induced up-regulation of Mcl-1 and, as with Mcl-1 siRNA, is associated with decreased proliferation and induction of apoptosis. Finally, we show that VEGF protects MM patient cells against FBS starvation-induced apoptosis. Our studies therefore demonstrate that VEGF-induced MM cell proliferation and survival are mediated via Mcl-1, providing the preclinical framework for novel therapeutics targeting Mcl-1 and/or VEGF to improve patient outcome in MM.


"Lone aspiration thrombectomy" without stenting in young patients with ST elevation myocardial infarction.
Plaque rupture with thrombotic occlusion without severe underlying coronary atherosclerosis is frequently observed during primary percutaneous coronary intervention (pPCI) for ST-segment elevation myocardial infarction (STEMI). These lesions are stented even if post thrombectomy mild underlying coronary artery disease (CAD) is noted. The value of mechanical thrombus aspiration alone "lone aspiration thrombectomy" (LAT) without stenting is not well studied. We present a retrospective analysis of patients receiving LAT as the only pPCI therapy for STEMI. Between January 2008 and March 2012, 202 young patients underwent pPCI for acute STEMI at our institution. From this group 10 patients had LAT as definitive therapy. LAT was favored if post thrombectomy minimal underlying CAD was noted, and concerns regarding long term treatment cost and compliance with dual antiplatelet therapy (DAPT) was an issue. All patients received ASA, clopidogrel, heparin and eptifibatide. DAPT was maintained for at least 1 month. One patient was lost to follow-up. At one month, all remaining 9 patients were free of MACE. At six weeks one patient had recurrent STEMI after abruptly discontinuing all his medications. Re-occlusion at the site of prior plaque rupture was stented, and treatment compliance was urged. Short term follow up at 2 months available for 5 patients and 2 years for 3 patients revealed no adverse consequences, the remaining patients had returned to their home countries. In selected young patients presenting with acute STEMI, LAT without balloon angioplasty or stenting is feasible and is associated with favorable short and long-term outcome.


Polyarginine Decorated Polydopamine Nanoparticles With Antimicrobial Properties for Functionalization of Hydrogels.
Polydopamine (PDA) nanoparticles are versatile structures that can be stabilized with proteins. In this study, we have demonstrated the feasibility of developing PDA/polypeptides complexes in the shape of nanoparticles. The polypeptide can also render the nanoparticle functional. Herein, we have developed antimicrobial nanoparticles with a narrow size distribution by decorating the polydopamine particles with a chain-length controlled antimicrobial agent Polyarginine (PAR). The obtained particles were 3.9 ± 1.7 nm in diameter and were not cytotoxic at 1:20 dilution and above. PAR-decorated nanoparticles have exhibited a strong antimicrobial activity against S. aureus, one of the most common pathogen involved in implant infections. The minimum inhibitory concentration is 5 times less than the cytotoxicity levels. Then, PAR-decorated nanoparticles have been incorporated into gelatin hydrogels used as a model of tissue engineering scaffolds. These nanoparticles have given hydrogels strong antimicrobial properties without affecting their stability and biocompatibility while improving their mechanical properties (modulus of increased storage). Decorated polydopamine nanoparticles can be a versatile tool for the functionalization of hydrogels in regenerative medicine applications by providing bioactive properties.


Differentiation of Metastatic and Non-Metastatic Mesenteric Lymph Nodes by Strain Elastography in Surgical Specimens.
To investigate if strain elastography could differentiate between metastatic and non-metastatic mesenteric lymph nodes ex-vivo. 90 mesenteric lymph nodes were examined shortly after resection from 25 patients including 17 patients with colorectal cancer and 8 patients with Crohn's disease. Ultrasound-based strain elastography was performed with a linear probe. Tissue hardness in lymph nodes was assessed using visual scales and measuring the strain ratio. B-mode characteristics were also recorded. Pathological diagnosis with grading of fibrosis served as the reference standard. 20 lymph nodes were metastatic and 70 lymph nodes were non-metastatic. The strain ratios of metastatic and non-metastatic lymph nodes were significantly different (1.83 vs. 1.42, p = 0.021). The VAS scale (0 - 100) for tissue hardness gave higher mean values for metastatic than non-metastatic nodes, but the difference was not significant (65.5 vs. 55.0, p = 0.055). There was no difference between lymph nodes in Crohn's and non-metastatic cancer specimens. The metastatic lymph nodes were significantly more fibrotic than the non-metastatic lymph nodes by the ordinal fibrosis score (0 - 3). In an ROC analysis, quantitative strain imaging was not superior to the measurement of the short-axis diameter of lymph nodes in differentiating metastatic from non-metastatic mesenteric lymph nodes ex-vivo. Strain elastography is correlated to fibrosis in lymph nodes and a significant difference was observed on a group level using the strain ratio. Due to measurement overlap, individual mesenteric lymph nodes could not be identified accurately as metastatic or not in this ex-vivo model by strain imaging alone.


Vitamin D receptor gene polymorphisms and bone mineral density in elderly Chinese men and women in Hong Kong.
Although genetic factors have been strongly implicated in determining bone mineral density (BMD), the role of the vitamin D receptor (VDR) polymorphism remains controversial. An overall consensus is difficult, as the populations studied have been heterogeneous with respect to menopausal status and ethnicity. Moreover, some studies have examined only small populations, and relatively few studies have been conducted in Asian populations. There is mounting evidence that calcium homeostasis in Asian populations differs from that in Caucasians. This difference may be mediated, in part, through VDR effects. In a cross-sectional study we have examined the relationship between the VDR polymorphism and BMD in 272 women (mean age 75 years) and 237 men (mean age 73 years) of Chinese origin from Hong Kong. Consistent with other studies in Asian populations we found higher frequencies of the T, b and a alleles compared with those reported in Caucasian populations. Moreover, no significant difference in BMD was observed when subjects were grouped by a combination of the genotypes (bbAATT, bbAaTT, bbaaTT, BbAaTt, BbAATt). These results suggest that VDR polymorphism is not associated with BMD in elderly Hong Kong Chinese men and women.


Interstitial immunofluorescence in nephritis of Sjögren's syndrome.
A patient with Sjögren's syndrome (SS) developed mild renal insufficiency without significant proteinuria; the diagnosis of interstitial nephritis secondary to SS was made on the basis of history, serological data and renal biopsy. The renal biopsy revealed immunofluorescence of the interstital infiltrates and the importance of this finding in the differential diagnosis of interstitial nephritis is considered. In addition, further studies to detect anti-renal antibodies and circulating immune complexes are reported and the possible interpretation of the results is discussed in regard to pathogenesis.


A comparison of ultrasonic and mechanical stadiometry.
To compare an ultrasonic height measuring device (Gulliver) with mechanical stadiometry and the classical "book and tape measure" method. Blinded duplicate measurements of height were made on each of 14 children by a pair of observers using a stadiometer (H) and Gulliver (G). Height was measured on a further 18 children by parents and an auxologist using Gulliver and the book and tape method (TM), and the results were compared with those obtained with a single stadiometry measurement. Finally, measurement of a rigid metal box was made on 10 occasions by the three methods. In the group of 14 children, the mean difference (range) in height (H minus G) was +2.8 cm (+0.5 to +4.55 cm), with H giving a systematically higher value in 276 of 280 individual measurements. In the group of 18 children, height by H was greater than by G or TM in 47 of 52 individual measurements. The mean (SD) height of the box by H (61.60 (0.07) cm) was greater than by G (60.96 (0.15) cm; p < 0.001) but not TM (61.4 (0.16) cm; p > 0.05). G and TM produced three times less reliable estimations of height than H, but with a large difference in cost, and there was evidence of systematic underrecording of height by 0.5 cm with G. Stadiometry is precise and reproducible, and can detect true changes in height over one month periods in mid-childhood, and should remain the standard way of observing growth. The book and tape method can produce clinically acceptable quarterly estimations of height that can be performed in the home.


IFN-alpha beta promote priming of antigen-specific CD8+ and CD4+ T lymphocytes by immunostimulatory DNA-based vaccines.
Immunostimulatory sequence (ISS) DNA containing unmethylated CpG dinucleotides stimulate NK and APC to secrete proinflammatory cytokines, including IFN-alphabeta and -gamma, TNF-alpha, and IL-6 and -12, and to express costimulatory surface molecules such as CD40, B7-1, and B7-2. Although ISS DNA has little direct effect on T cells by these criteria, immunization of wild-type mice with ISS DNA and OVA results in Ag-specific CTL and Th1-type T helper activity. This investigation examines the mechanisms by which ISS DNA primes CD8(+) and CD4(+) lymphocyte activities. In this report we demonstrate that ISS DNA regulates the expression of costimulatory molecules and TAP via a novel autocrine or paracrine IFN-alphabeta pathway. Coordinated regulation of B7 costimulation and TAP-dependent cross-presentation results in priming of Ag-specific CD8(+) CTL, whereas CD40, B7, and IL-12 costimulation is required for priming of CD4(+) Th cells by ISS-based vaccines.


Epigenetic quantification of circulating immune cells in peripheral blood of triple-negative breast cancer patients.
A shift in the proportions of blood immune cells is a hallmark of cancer development. Here, we investigated whether methylation-derived immune cell type ratios and methylation-derived neutrophil-to-lymphocyte ratios (mdNLRs) are associated with triple-negative breast cancer (TNBC). Leukocyte subtype-specific unmethylated/methylated CpG sites were selected, and methylation levels at these sites were used as proxies for immune cell type proportions and mdNLR estimation in 231 TNBC cases and 231 age-matched controls. Data were validated using the Houseman deconvolution method. Additionally, the natural killer (NK) cell ratio was measured in a prospective sample set of 146 TNBC cases and 146 age-matched controls. The mdNLRs were higher in TNBC cases compared with controls and associated with TNBC (odds ratio (OR) range (2.66-4.29), all Padj. < 1e-04). A higher neutrophil ratio and lower ratios of NK cells, CD4 + T cells, CD8 + T cells, monocytes, and B cells were associated with TNBC. The strongest association was observed with decreased NK cell ratio (OR range (1.28-1.42), all Padj. < 1e-04). The NK cell ratio was also significantly lower in pre-diagnostic samples of TNBC cases compared with controls (P = 0.019). This immunomethylomic study shows that a shift in the ratios/proportions of leukocyte subtypes is associated with TNBC, with decreased NK cell showing the strongest association. These findings improve our knowledge of the role of the immune system in TNBC and point to the possibility of using NK cell level as a non-invasive molecular marker for TNBC risk assessment, early detection, and prevention.


Trajectories of boys' physical aggression, opposition, and hyperactivity on the path to physically violent and nonviolent juvenile delinquency.
A semi-parametric mixture model was used with a sample of 1,037 boys assessed repeatedly from 6 to 15 years of age to approximate a continuous distribution of developmental trajectories for three externalizing behaviors. Regression models were then used to determine which trajectories best predicted physically violent and nonviolent juvenile delinquency up to 17 years of age. Four developmental trajectories were identified for the physical aggression, opposition, and hyperactivity externalizing behavior dimensions: a chronic problem trajectory, a high level near-desister trajectory, a moderate level desister trajectory, and a no problem trajectory. Boys who followed a given trajectory for one type of externalizing problem behavior did not necessarily follow the same trajectory for the two other types of behavior problem. The different developmental trajectories of problem behavior also led to different types of juvenile delinquency. A chronic oppositional trajectory, with the physical aggression and hyperactivity trajectories being held constant, led to covert delinquency (theft) only, while a chronic physical aggression trajectory, with the oppositional and hyperactivity trajectories being held constant, led to overt delinquency (physical violence) and to the most serious delinquent acts.


Can musculoskeletal screening test findings guide interventions for injury prevention and return from injury in field hockey?
The aim of this study is to identify if intrinsic factors tested in the preseason screening (PSS) can identify an elevated risk of injury. This aim has two aspects; to assess whether previous injury is associated with ongoing deficits in performance, and to assess if the PSS can identify differences in intrinsic factors that profile risk of future injury. A cohort of state level field hockey players were tested on a screening test battery including proprioception, postural stability, muscular strength and range of motion, to establish if these intrinsic factors were useful in identifying elevated risk of injury. Retrospective injury data was collated to determine association with previous injury and prospective injury data was collated to determine association with future injury. A total of 130 field hockey players were included in this study, from state level squads (age ± SD = 20.96 (3.75); height = 176.09 cm). Groups for prescreening and post screening injury status (injured/not injured) were established for comparison to screening test results. Right Active Movement Extent Discrimination Assessment (AMEDA), left AMEDA and right Y-balance test (YBT) anterior direction (Ant) were significantly associated (p < 0.05) with injury prior to screening. Right YBTAnt and right and left hip internal rotation (IR) were significantly associated (p < 0.05) with injury post screening. The YBTAnt and YBT posteromedial (PMed) reach directions and Hip IR are associated with previous hamstring injury and show a difference between post screening injured and non-injured groups. AMEDA, R YBTAnt, Hip IR tests should be a focus for recovery after previous injury and during season preparation. Full recovery may improve readiness to return to play and reduce risk of primary injury or re-injury. YBTAnt and YBTPmed and Hip IR show a performance deficit link between previous injury and subsequent re-injury of hamstrings. Since these are the most common re-injury types in this cohort, these tests are clinically useful in informing return to play decisions for hockey players.


Critical appraisal of medical devices in the management of cerebrovascular disease.
Medical devices may revolutionize the management of acute ischemic stroke and prevention of recurrent events. By comparison with pharmaceuticals, the device approval process and subsequent application of these devices in stroke treatment is founded on a paucity of Class I evidence-based clinical trial data. Thromboembolectomy for acute stroke, stenting of cervical or cerebral arteries for stroke prevention, and percutaneous closure of patent foramen ovale for prevention or recurrent cerebral ischemia are being done with an ever-increasing frequency despite few, if any, randomized clinical trials to confirm the appropriateness of the interventions. The current basis, or lack thereof, for these interventions for cerebrovascular disease is therefore discussed. As such, a critical appraisal of the available clinical data does not support widespread use of medical devices at this time outside of well-designed clinical trials.


Genomic Sequencing of Japanese Plum (Prunus salicina Lindl.) Mutants Provides a New Model for Rosaceae Fruit Ripening Studies.
It has recently been described that the Japanese plum "Santa Rosa" bud sport series contains variations in ripening pattern: climacteric, suppressed-climacteric and non-climacteric types. This provides an interesting model to study the role of ethylene and other key mechanisms governing fruit ripening, softening and senescence. The aim of the current study was to investigate such differences at the genomic level, using this series of plum bud sports, with special reference to genes involved in ethylene biosynthesis, signal transduction, and sugar metabolism. Genomic DNA, isolated from leaf samples of six Japanese plum cultivars ("Santa Rosa", "July Santa Rosa", "Late Santa Rosa", "Sweet Miriam", "Roysum", and "Casselman"), was used to construct paired-end standard Illumina libraries. Sequences were aligned to the Prunus persica genome, and genomic variations (SNPs, INDELS, and CNV's) were investigated. Results determined 12 potential candidate genes with significant copy number variation (CNV), being associated with ethylene perception and signal transduction components. Additionally, the Maximum Likelihood (ML) phylogenetic tree showed two sorbitol dehydrogenase genes grouping into a distinct clade, indicating that this natural group is well-defined and presents high sequence identity among its members. In contrast, the ethylene group, which includes ACO1, ACS1, ACS4, ACS5, CTR1, ERF1, ERF3, and ethylene-receptor genes, was widely distributed and clustered into 10 different groups. Thus, ACS, ERF, and sorbitol dehydrogenase proteins potentially share a common ancestor for different plant genomes, while the expansion rate may be related to ancestral expansion rather than species-specific events. Based on the distribution of the clades, we suggest that gene function diversification for the ripening pathway occurred prior to family extension. We herein report all the frameshift mutations in genes involved in sugar transport and ethylene biosynthesis detected as well as the gene CNV implicated in ripening differences.


Regulation of the SigH stress response regulon by an essential protein kinase in Mycobacterium tuberculosis.
SigH is a key regulator of an extensive transcriptional network that responds to oxidative, nitrosative, and heat stresses in Mycobacterium tuberculosis, and this sigma factor is required for virulence in animal models of infection. SigH is negatively regulated by RshA, its cognate anti-sigma factor, which functions as a stress sensor and redox switch. While RshA provides a direct mechanism for sensing stress and activating transcription, bacteria use several types of signal transduction systems to sense the external environment. M. tuberculosis encodes several serine-threonine protein kinase signaling molecules, 2 of which, PknA and PknB, are essential and have been shown to regulate cell morphology and cell wall synthesis. In this work, we demonstrate that SigH and RshA are phosphorylated in vitro and in vivo by PknB. We show that phosphorylation of RshA, but not SigH, interferes with the interaction of these 2 proteins in vitro. Consistent with this finding, negative regulation of SigH activity by RshA in vivo is partially relieved in strains in which pknB is over-expressed, resulting in increased resistance to oxidative stress. These findings demonstrate an interaction between the signaling pathways mediated by PknB and the stress response regulon controlled by SigH. The intersection of these apparently discrete regulatory systems provides a mechanism by which limited activation of the SigH-dependent stress response in M. tuberculosis can be achieved. Coordination of the PknB and SigH regulatory pathways through phosphorylation of RshA may lead to adaptive responses that are important in the pathogenesis of M. tuberculosis infection.


Prognostic impact of ß-blocker use in patients with stable coronary artery disease.
To assess the association of ß-blocker use with cardiovascular mortality in patients with stable coronary artery disease (CAD). We analysed the data of 4184 outpatients included in a prospective cohort study on stable CAD. Two groups were formed based on ß-blocker use at enrolment. Two propensity score analyses were performed to control for differences in covariates: one with adjustment among the entire cohort, and the other with propensity score matching. The outcome variable was cardiovascular mortality after a 2-year follow-up. There were 3320 patients with ß-blocker use. Younger age, hypertension, diabetes, prior myocardial infarction, multivessel CAD, prior coronary revascularisation, prior stroke, prior hospitalisation for heart failure and a low LVEF were associated with ß-blocker use. Clinical follow-up data were obtained for 4149 patients (99.2%). When adjusted on propensity score, ß-blocker use was associated with a HR for cardiovascular mortality of 0.64 (0.42-0.98) in the whole cohort (p=0.04). After one-to-one propensity score matching, both groups (n=839 in each group) were well matched on covariates. The cardiovascular mortality rate in the propensity-matched cohort was significantly lower in patients with ß-blocker use with a HR of 0.43 (0.22-0.82) (p=0.011). Non-cardiovascular mortality was similar in both groups. These results were consistent across different subgroups. In this observational study of patients with stable CAD, the use of ß-blockers was associated with a lower risk of cardiovascular mortality.


Exploration of experiences in therapeutic groups for patients with severe mental illness: development of the Ferrara group experiences scale (FE- GES).
Group therapies are routinely provided for patients with severe mental illness. The factors important to the group experience of patients are still poorly understood and are rarely measured. To support further research and practice, we aimed to develop a questionnaire that captures how patients experience groups within a community mental health context. An initial pool of 39 items was conceptually generated to assess different aspects of group experiences. Items were completed by 166 patients with severe mental illness attending group therapies in community mental health services in Italy. Patients with different psychiatric diagnoses who attended at least 5 group sessions were included. An exploratory factor analysis was used to identify different dimensions of group experiences and to reduce the number of items for each dimension. The resulting questionnaire has five subscales: 1) sharing of emotions and experiences, 2) cognitive improvement, 3) group learning, 4) difficulties in open expression and 5) relationships. Each subscale has 4 items. The scale and sub-scales have good internal consistency. The Ferrara Group Experiences Scale is conceptually derived and assesses dimensions of group experience that are theoretically and practically relevant. It is brief, easy to use and has good psychometric properties. After further validation, the scale may be used for research into patient experiences across different group therapy modalities and for evaluation in routine care.


Cancer mortality and competing causes of death in older adults with cancer: A prospective, multicentre cohort study (ELCAPA-19).
In older patients with cancer, comorbidities compete with cancer for cause of death. The objectives were to evaluate cancer mortality and factors associated, according to metastatic status. Between 2007 and 2014, patients with cancer aged ≥70 referred for pre-therapeutic geriatric assessment (GA) were included through the ELCAPA prospective cohort study. The underlying cause of death was defined according to the International Classification of Diseases, 10th Revision. The World Health Organisation definition was used to categorise the cause of death as cancer versus another disease (e.g. cardiovascular disease, infectious disease, etc.) Competing risk models were used. Mean (SD) age of the 1445 included patients was 80.2 (5.8) and 48% were women. Most common tumour sites were colorectal (19%), breast (17%) and urinary (15%); 773 patients (49%) had metastases. After a 34-month median follow-up, 706 cancer deaths were observed among 843 deaths. The 6-month and 3-year cancer mortality rates (95% CI) were 12% (9-15) and 34% (29-38) for non-metastatic patients and 43% (39-47) and 79% (75-82) for metastatic patients, respectively. Dependency in activities of daily living and comorbidities were associated with 6-month and 3-year cancer mortality in non-metastatic (adjusted subhazard ratio [aSHR] = 1.68 [0.99-2.85] and 1.69 [1.16-2.45]; and 1.98 [1.08-3.63] and 3.38 [1.47-7.76], respectively) and metastatic patients (aSHR = 2.81 [2.01-3.93] and 2.95 [2.14-4.07]; and 1.63 [1.18-2.25] and 2.06 [1.39-3.05], respectively). Impaired Timed-Get-Up-and-Go test was associated with 6-month and 3-year cancer mortality in metastatic patients (aSHR = 1.5 [1.06-2.12] and 1.38 [1.06-1.81], respectively). Obesity was negatively associated with 3-year cancer death in non-metastatic (aSHR = 0.53 [0.29-0.97]) and metastatic patients (aSHR = 0.71 [0.51-1.00]). The majority of older adults with cancer referred for pre-therapeutic GA die from cancer. Geriatric parameters are independently associated with cancer mortality and should be considered for prognosis assessment, decision-making and care.


Outer membrane vesicles induce the mussel plantigrade settlement via regulation of c-di-GMP.
Despite the importance of outer membrane vesicles (OMVs) in benthic animal settlement, the underlying molecular mechanism remains elusive. Here, the impact of OMVs and OMVs synthesis-related tolB gene in Mytilus coruscus plantigrade settlement was tested. The OMVs were extracted from Pseudoalteromonas marina through density gradient centrifugation, and a tolB knockout strain, achieved by homologous recombination, was utilized for the investigation. Our results demonstrated that OMVs could significantly enhance M. coruscus plantigrades settlement. Deleting the tolB resulted in downregulation of c-di-GMP, accompanied by a reduction of OMV production, a decline in bacterial motility and increasing biofilm-forming ability. Enzyme treatment resulted in a 61.11% reduction in OMV-inducing activity and a 94.87% reduction in LPS content. Thus, OMVs regulate mussel settlement via LPS, and c-di-GMP is responsible for the OMV-inducing capacity. These findings provide new insights into the interactions between bacteria and mussels.


K+-free induced early afterdepolarization in cardiac ventricular fibers of guinea pig after cold treatment.
The genesis and elimination of early afterdepolarizations (EADs) have been investigated in guinea pig cardiac ventricular fibers after a short period of cooling (5 h, 2-4 degrees C). After rewarming them to 37 degrees C, EADs could be induced by K+-free superfusion at an appropriate driving stimulation (0.2 Hz) in all preparations. A high level plateau, which linearly increases its duration with time, appears ahead of EADs. The critical point of the plateau occurred steadily, at the level of -47 +/- 4 mV. Two types of triggered activity, all of which are the rhythmic activities in low level of membrane potential (-50 to -60 mV), appear on the plateau. There is no significant change after overdriving. Agonists of the Na-K pump (K+ and T1+) could stop the rhythmic activity immediately and turn the low level of membrane potential to high one. The results showed that high level plateau is the basis of genesis of EADs, and the activation of Na-K pump plays an important part in stopping triggered rhythms arising from EADs.


New intermediate hosts in the life cycle of Zygocotyle lunata in South America.
Biomphalaria peregrina was found to be naturally infected with cercariae of Zygocotyle lunata in a pond of the Zoological Garden of Buenos Aires. Mice and chicks were fed metacercariae and gravid adults recovered. Eggs recovered from mice feces were used for experimental infections. Laboratory-reared B. peregrina and 4 other Biomphaluria spp. were successfully infected with Z. lunata miracidia. Biomphaleria glabrata was refractory. Species of Helisoma, the only intermediate hosts of Z. lunata so far reported, have never been found in Argentina. Species of Biomphalaria may be intermediate hosts of Z lunata in the southern region of the Parana River Basin.