Renal afferent arteriolar structure in the genetically hypertensive (GH) rat and the ability of losartan and enalapril to cause structural remodelling.
This study aimed to compare the structure of renal afferent arterioles in the genetically hypertensive (GH) rat strain with the normotensive (N) control strain in relation to pathogenesis, and to quantify structural remodelling in GH rats after treatment with losartan and enalapril and to relate this to blood pressure (BP) and left ventricular (LV) mass. GH rats were given losartan 15 mg/kg/day, enalapril 10 mg/kg/day (enalapril 10) or 3 mg/kg/day (enalapril 3) from the age of 4 to 10 weeks. Untreated GH and N groups served as controls. Tail-cuff systolic BP was measured weekly from 4 weeks. At the age of 10 weeks, kidneys were perfused with microspheres to identify afferent arterioles, kidney pieces were fixed, embedded in Technovit and stained sections analysed. Lumen and media plus lumen diameters were measured; media width, media cross-sectional area (CSA) and media/lumen (M/L) ratio were derived. BP and LV mass were elevated in GH compared with N rats, and reduced by losartan and enalapril 10 and to a lesser degree by enalapril 3. In afferent arterioles, lumen diameter, media width and CSA were smaller in GH than N and M/L ratio was larger. Losartan and enalapril 10 reduced media width and increased lumen diameter, while enalapril 3 increased CSA (in distal arterioles) and lumen diameter. M/L ratio was reduced by losartan and enalapril. Abnormal structure of the afferent arteriole, resulting in an increased M/L ratio, could explain abnormalities of renal blood flow and vascular resistance in GH and contribute to the hypertension. In GH, losartan and enalapril reduce BP and LV mass, cause remodelling of afferent arterioles, and lower the M/L ratio to below N levels.


Isolation of a Novel Recombinant Canine Coronavirus From a Visitor to Haiti: Further Evidence of Transmission of Coronaviruses of Zoonotic Origin to Humans.
We isolated a novel coronavirus from a medical team member presenting with fever and malaise after travel to Haiti. The virus showed 99.4% similarity with a recombinant canine coronavirus recently identified in a pneumonia patient in Malaysia, suggesting that infection with this virus and/or recombinant variants occurs in multiple locations.


Absenteeism in the First Decade of Education Forecasts Civic Engagement and Educational and Socioeconomic Prospects in Young Adulthood.
Much has been established about the short-term consequences of missing school, yet little is known about the longer-term outcomes of absenteeism. To address this gap in knowledge, the current study considered the consequences of school absenteeism between kindergarten and eighth grade for the behavioral, economic, and educational outcomes of young adults. Participants were drawn from the National Institute of Child Health and Human Development Study of Early Child Care and Youth Development (age 22-23; 54% female and 86% White, n = 648). The findings indicated that individuals who were more regularly absent from school were not more frequently engaged in risky, deviant, or criminal behaviors in young adulthood. However, those who were more regularly absent described being less likely to be politically engaged, reported themselves as experiencing greater economic difficulties, with less optimal educational outcomes, and as marginally more likely to have a child. The outcomes of absenteeism were largely cumulative and there was little evidence to suggest that the outcomes of absenteeism varied across urban and rural communities or as a function of socioeconomic status. Taken together, this study provides new insight into the long-term consequences of missing school and points to the importance of addressing absenteeism in the first ten years of students' educational careers.


Myocarditis Following mRNA COVID-19 Vaccine.
A growing number of adolescents are being diagnosed with acute myocarditis following mRNA COVID-19 vaccinations. This case describes an adolescent who presented to the emergency department with chest pain and tachycardia following the Pfizer-BioNTech COVID-19 vaccination. Point-of-care ultrasound was performed prior to the return of laboratory studies and revealed depressed left ventricular systolic function. Point-of-care ultrasound may be a tool used to rapidly diagnose or risk stratify patients with potential post-COVID-19 vaccine myocarditis.


Isolated traumatic posterior dislocation of the radial head in an adult, a rare injury: New case report.
Isolated radial head dislocations are rare in adults with only 23 cases published in 45 years. The diagnosis may be easily missed on radiographs and a CT-scan is often required. If managed promptly patient can restore normal range of motion and elbow function. Authors report a new case of a 67-year-old female presenting a posttraumatic isolated posterior dislocation of the radial head. Treatment consisted of closed reduction followed by immobilization for four weeks in a plaster cast with the elbow flexed at 90°, followed by active mobilization and physiotherapy. At 18 months of follow-up, functional outcome is excellent with no differences between both sides.


Retrospective immunogenicity analysis of seasonal flu H3N2 vaccines recommended in the past ten years using immunized animal sera.
Influenza A (H3N2) virus (A/H3N2) has complex antigenic evolution, resulting in frequent vaccine strain updates. We aimed to evaluate the protective effect of the vaccine strains on the circulating strains from past ten years and provide a basis for finding a broader and more efficient A/H3N2 vaccine strain. Eighty-four representative circulating A/H3N2 strains were selected from 65,791 deposited sequences in 2011-2020 and pseudotyped viruses were constructed with the VSV vector. We immunized guinea pigs with DNA vaccine containing the A/H3N2 components of the vaccine strains from 2011 to 2021 and tested neutralizing antibody against the pseudotyped viruses. We used a hierarchical clustering method to classify the eighty-four representative strains into different antigenic clusters. We also immunized animals with monovalent vaccine stock of the vaccine strains for the 2020-2021 and 2021-2022 seasons and tested neutralizing antibody against the pseudotyped viruses. The vaccine strains PE/09, VI/11 and TE/12 induced higher levels of neutralizing antibody against representative strains circulating in recommended year and the year immediately prior whereas vaccine strains HK/14, HK/19 and CA/20 induced poor neutralization against all representative strains. The representative strains were divided into five antigenic clusters (AgV), which were not identical to gene clades. The AgV5 strains were most difficult to be protected among the five clusters. Compared with single-dose immunization, three doses of monovalent vaccine stock (HK/19 or CA/20) could induce stronger and broader neutralizing antibodies against strains in each of the antigenic clusters. The protective effect of vaccine strains indicated that the accurate selection of A/H3N2 vaccine strains must remain a top priority. By increasing the frequency of immunization, stronger and broader neutralizing antibodies against strains in all antigenic clusters were induced, which provides direction for a new immunization strategy. This work was supported by a grant from National Key R&D Program of China (No. 2021YFC2301700).


A possible association between paternal longevity and major depression among elderly men.
Ancestral longevity is sometimes thought to contribute to psychosocial well-being in late life. The present paper aims to examine if parental longevity is associated with mental health among the elderly. The age at death of the parents was compared between 68 patients with major depression who were aged 65 or over and 40 subjects of the same age range without any history of psychiatric disorder. Cox regression revealed that the fathers of the elderly men with unipolar depression died at a significantly younger age than those of the control group. Several hypotheses are advanced to explain this unexpected and intriguing association.


Tumor targeting potential of liposomes encapsulating Ga-67 and antibody to Dalton's lymphoma associated antigen (anti-DLAA).
Dalton's lymphoma (solid tumor) was induced in Swiss mice by an 'Air-pouch' technique using ascites cells. A liposomal technique for radioimmunodetection and localization using Ga-67 and antibody has been developed. Dalton's lymphoma associated antigen (DLAA) was isolated and purified by ammonium sulfate fractionation and chromatography. The antibody to this antigen, anti-DLAA, was prepared by immunization of rabbits and purified by CNBr activated chromatography. The specificity of this antibody to the solid tumor antigen was ascertained by agar gel diffusion. Scintiscan studies were carried out using controls and Dalton's lymphoma bearing mice at various time intervals after i.p. administration of 10-20 mu ci of Ga-67, Ga-67 Ga-67 as liposomes and Ga-67 incorporated with antibody to DLAA as liposomes. Extensive studies carried out using liposomes of different sizes and charges revealed that anti-DLAA significantly improved the tumor uptake of Ga-67, thereby facilitating better visualization of the tumor. Negative and neutral liposomes delivered maximum radioactivity at the target tissue, whereas positive liposomes did not cause significant tumor accumulation of 67Ga. Biodistribution studies showed maximum tumor-associated activity that is 15.43% of the injected dose per gram tumor tissue was achieved with Ga-67 anti-DLAA liposomes compared to 6.6% with Ga-67 administered as such. Injection of Ga-67 liposome resulted in minimum tumor-associated activity that is 5.33%, with maximum uptake by liver and spleen. This might be caused by accumulation of liposomes in these organs. Incorporation of anti-DLAA might significantly improve uptake of Ga-67 by target tissue, due to the specificity of the antigen antibody reaction.


[Nuclear medicine imaging in patients with Parkinson's syndrome: an update].
Nuclear medicine imaging using positron emission tomography (PET) or single photon emission computed tomography (SPECT) has enabled to study not only the metabolism and blood flow in specific brain areas but also the quantification of the function of distinct molecules. With respect to Parkinson's disease PET and later SPECT allowed the number of dopaminergic neurons to be assessed in vivo. These quantifications are relevant to establishing a clinical diagnosis, assessing the progression of the disease or the survival of transplanted dopaminergic neurons. In addition both techniques have markedly contributed to our understanding of the pathophysiology of this disorder. More recently, molecular imaging has been directed towards understanding the pathophysiology of non-motor symptoms in this disorder.


High frequency ventilation in the neonatal period.
There are three forms of high frequency ventilation, high frequency jet ventilation (HFJV, up to 400/min), high frequency oscillation (HFO, up to 40 Hz), and high frequency positive pressure ventilation (HFPPV, rates between 60 and 150/min). The first two forms of ventilation are still experimental and have been used only in critically ill children where respiratory failure has been unresponsive to more conventional therapy. Unfortunately, however, HFJV has already been associated with a high incidence of tracheal lesions. High-frequency positive pressure ventilation, on the other hand, using conventional ventilators, has been used and studied widely. Certain neonatal ventilators function suboptimally at increased rates, resulting in a reduction in tidal exchange with a consequent clinical deterioration. Using appropriate ventilators, arterial oxygen tensions improve and carbon dioxide tensions are reduced at fast rates in non-paralysed infants. Air-trapping, however, may be a problem in infants paralysed and ventilated at fast rates. HFPPV have been associated with a reduced incidence of pneumothoraces, but there is no knowledge of the effect of this form of ventilation on subsequent lung growth.


Long-stay medical-surgical intensive care unit patients in South Africa: Quality of life and mortality 1 year after discharge.
Although mortality is the primary measure of critical care outcome, the health-related quality of life (HRQOL) of survivors is often diminished. There is a paucity of South African research on HRQOL in intensive care unit (ICU) survivors. To evaluate the 1-year post-discharge data of long-stay ICU patients, a group known to consume 20 - 40% of ICU resources. A 1-year prospective observational study was conducted in a multidisciplinary medical-surgical ICU. Adult patients who were mechanically ventilated beyond 6 days were included. Clinical and mortality data were collected. Pre-admission and 6- and 12-month HRQOL were measured with the Short Form-36 questionnaire. Physical and mental component summary scores (PCS and MCS) were calculated. Associations between 12-month mortality and poor HRQOL scores were determined. Of 119 patients enrolled, 40.3% had sustained trauma, 19.3% were post-surgical and 40.3% had medical conditions; 29.2% were HIV-positive (HIV status was known for 74.8% of the cohort). The hospital and 12-month mortality rates were 42.9% and 57.4% (n=66/115), respectively. Age, longer ICU stay, higher disease severity scores and vasopressor use were associated with 12-month mortality. The survivors' median PCS and MCS at 6 and 12 months were significantly lower compared with pre-admission scores (both p<0.001). At 12 months, 53.1% of survivors demonstrated a poor PCS and 42.9% a poor MCS. Associations with poor 12-month PCS included longer ICU stay, male gender and trauma, while trauma and sepsis were associated with a poor 12-month MCS. Among the 19 trauma survivors, 78.9% had a poor MCS and/or PCS. Of previously employed patients, 54.8% were unemployed at 12 months. Patients ventilated beyond 6 days in a multidisciplinary ICU had a high mortality. Poor HRQOL at 12 months post discharge was frequently observed among survivors. Trauma was associated with poor 12-month outcomes. These findings highlight the need to further explore the outcomes of long-stay ICU patients in Africa.


Modernizing innovation governance to meet policy ambitions through trusted environments.
A vision for modernization of nanotechnology innovation governance is a Safe Innovation Approach (SIA). SIA combines two concepts: Safe-by-Design (SbD) and Regulatory Preparedness (RP). SbD aims to motivate industry to integrate safety considerations early in the innovation process and onwards. RP aspires to improve the anticipation capabilities of regulators and develop legislation that can keep pace with innovations. The pace, scope and complexity of nanotechnology present novel challenges for governance, especially law and regulation. A possible option forward for nanotechnology is to move towards a more goal-based governance system including anticipatory regulation. Anticipatory regulation and experimentation can be considered as an agile approach with emphasis on flexibility, collaboration and innovation. SIA can be seen as part of experimentation in support of agile regulatory practices. A trusted environment is needed in which innovators, regulators and other stakeholders are motivated to understand each other's concerns and together develop solutions to anticipate and address safety whilst also facilitating the development of safe, sustainable and socially beneficial innovations. Trust drivers to facilitate trusted environments include focusing on the public interest, competence, respect, integrity, inclusion, fairness and openness. Here, we explore the concept of building trusted environments in the context of the SIA for nanotechnologies.


Physical activity and daily steps cut offs points for overweight/obesity prevention among eight Latin American countries.
This study aims to establish cut-off points for the number of minutes of physical activity intensity and the number of daily steps that identify overweight/obesity in adolescents, adults, and older adults. This study examined data from 2737 participants. Physical activity intensity and the number of daily steps were assessed using GT3X+ ActiGraph model accelerometers. Body mass index, waist-to-height ratio, and waist-to-hip ratio were used as indicators of overweight/obesity. The cut-off points for moderate-to-vigorous physical activity for the prevention of overweight/obesity according to body mass index in women ranged from 15.1 to 30.2 min/day; in men, the values were from 15.4 to 33.8 min/day. The lowest cut-off point for daily steps was established in the adolescent group for women and men (7304 and 5162). The highest value in women was 11,412 (51-65 years) and 13,234 in men (18-30 years). Results from measurements different from BMI, show average cut-off points for moderate-to-vigorous physical activity and daily steps of 29.1/8348 and 43.5/10,456 according to waist-to-height ratio; and results of 29.3/11,900 and 44.3/11,056 according to the waist-to-hip ratio; in women and men respectively. A more specific recommendation of physical activity and daily steps adjusted by sex and age range is suggested to prevent overweight/obesity.


Distribution of serotonin immunoreactivity in the spiral ganglion neurons of mouse cochlea.
Serotonin (5-hydroxytryptamine, 5-HT) is a neuromodulator/neurotransmitter with multiple biological functions. Spiral ganglion cells in the cochlea are the primary neurons of the afferent system in the auditory transmission. In this study, we used the immunohistochemical technique to investigate the distribution of serotonin in the spiral ganglion of mouse cochlea. The cochlea tissue of four adult mice was dissected and fixed. The immunohistochemical staining was applied by using goat anti-serotonin polyclonal antibody as primary antibody. Tissue sections were treated with biotin-labeled rabbit anti-goat immunoglobulin G, followed by adding streptavidin-biotin-peroxidase complex. Finally, the sections were stained with 3,3-diaminobenzidine (DAB) solution. The spiral ganglion exhibited pronounced immunoreactivity for serotonin. Specifically, serotonin immunoreactivity was detected in the cytoplasma of spiral ganglion neurons located in Rosenthal's canal of the bony modiolus of mouse cochlea. Since spiral ganglion neurons are the afferent neurons to the auditory sense organ, our result strongly suggests that serotonin molecule may function as a neuromodulator/neurotransmitter in the peripheral auditory processing.


Monte Carlo based calibration of an air monitoring system for gamma and beta+ radiation.
Marinelli beaker systems are used to monitor the activity of radioactive samples. These systems are usually calibrated with water solutions and the determination of the activity in gases requires correction coefficients accounting for the different mass-thickness of the sample. For beta+ radionuclides the different distribution of the positrons annihilation points should be also considered. In this work a Monte Carlo simulation based on Geant4 is used to compute correction coefficients for the measurement of the activity of air samples.


An N-shaped current-voltage relationship in rat sympathetic neurones.
Neurones in the rat isolated superior cervical ganglion were voltage clamped using 2 independent microelectrodes. From a holding potential of -40mV, depolarizing voltage commands to potentials more positive than -20mV elicited outward currents. The current-voltage relationship displayed an N-characteristic with a minimum at +80 to +100mV. Replacement of the external Ca++ ions with Mn++ reversibly abolished a part of the total outward current. The results indicate that rat sympathetic neurones exhibit two potassium currents, a delayed rectifier current and a Ca++-dependent potassium current.


Minimum detectable change for knee joint contact force estimates using an EMG-driven model.
Adequate test-retest reliability of model estimates is a necessary precursor to examining treatment effects or longitudinal changes in individuals. The purpose of this study was to establish thresholds for minimal detectable change (MDC) for joint contact forces obtained using a patient specific EMG-driven musculoskeletal model of the knee. A sample of young, active individuals was selected for this study, and subjects were tested on 2 separate days. Three-dimensional motion analysis with electromyography (EMG) was used to obtain data from each subject during gait for model input. An EMG-driven modeling approach was used to estimate joint contact forces at each session. MDC's for contact force variables ranged from 0.30 to 0.66 BW. The lowest MDC was for peak medial compartment force (0.30 BW) and the highest was for peak tibiofemoral contact force (0.66 BW). Test-retest reliability coefficients were also reported for comparison with previous work. Using the present model, changes in joint contact forces between baseline and subsequent measurements that are greater than these MDCs are greater than typical day-to-day variation and can be identified as real change.


Genome-Wide Analysis of A-to-I RNA Editing.
Adenosine (A)-to-inosine (I) RNA editing is a fundamental posttranscriptional modification that ensures the deamination of A-to-I in double-stranded (ds) RNA molecules. Intriguingly, the A-to-I RNA editing system is particularly active in the nervous system of higher eukaryotes, altering a plethora of noncoding and coding sequences. Abnormal RNA editing is highly associated with many neurological phenotypes and neurodevelopmental disorders. However, the molecular mechanisms underlying RNA editing-mediated pathogenesis still remain enigmatic and have attracted increasing attention from researchers. Over the last decade, methods available to perform genome-wide transcriptome analysis, have evolved rapidly. Within the RNA editing field researchers have adopted next-generation sequencing technologies to identify RNA-editing sites within genomes and to elucidate the underlying process. However, technical challenges associated with editing site discovery have hindered efforts to uncover comprehensive editing site datasets, resulting in the general perception that the collections of annotated editing sites represent only a small minority of the total number of sites in a given organism, tissue, or cell type of interest. Additionally to doubts about sensitivity, existing RNA-editing site lists often contain high percentages of false positives, leading to uncertainty about their validity and usefulness in downstream studies. An accurate investigation of A-to-I editing requires properly validated datasets of editing sites with demonstrated and transparent levels of sensitivity and specificity. Here, we describe a high signal-to-noise method for RNA-editing site detection using single-molecule sequencing (SMS). With this method, authentic RNA-editing sites may be differentiated from artifacts. Machine learning approaches provide a procedure to improve upon and experimentally validate sequencing outcomes through use of computationally predicted, iterative feedback loops. Subsequent use of extensive Sanger sequencing validations can generate accurate editing site lists. This approach has broad application and accurate genome-wide editing analysis of various tissues from clinical specimens or various experimental organisms is now a possibility.


Post-traumatic Growth in Cancer Patients: A Correlational Study in Turkey.
This study aims to evaluate the factors that influence post-traumatic growth (PTG), including religious coping and resilience. This descriptive and correlational study involved 111 cancer patients, followed up at a hematology inpatient clinic of a university hospital in Turkey. Religious coping scale, resilience scale, and PTG inventory were used for data collection. PTG was positively associated with negative religious coping and was negatively associated with age. PTG scores were higher for patients without children, who were recently diagnosed, had higher knowledge about the disease, and used negative religious coping.


Land plants of amphibious Littorella uniflora (L.) Aschers. maintain utilization of CO2 from the sediment.
Submerged macrophytes of the isoetid life form derive the majority of their CO2 for photosynthesis from the sediment. The experiments described here were designed to test the hypothesis that root uptake of CO2 is important also in the terrestrial form of Littorella uniflora. The results of 14CO2 experiments showed that sediment CO2 contributed 56% of the total fixation at 0.1MM CO2 in the rhizosphere, 83% at 0.5MM and 96% at 2.5MM. Sediment CO2 in emergent Littorella stands ranged from 0.1 to 1.0MM and averaged 0.5MM. Measurements of the net CO2 exchange over the leaves showed an even higher dependence of the sediment as CO2 source. Littorella leaves had no stomata at the base and densities (ca. 100 mm-2) typical of terrestrial plants at the tip, allowing sediment-derived CO2 to be supplied along the length of the leaf. The stomata permit supply of CO2 from the air during periods of reduced sediment CO2 concentrations (e.g. if the sediment dries up) and regulate transpiration.


Uterine effects of clomiphene citrate in women with polycystic ovary syndrome: a prospective controlled study.
Previous data on the efficacy of clomiphene citrate, the most commonly used drug for treating anovulatory infertility in patients with polycystic ovary syndrome (PCOS), have shown a discrepancy between ovulation and pregnancy rates. In the present subanalysis (of a larger previously published randomized controlled trial), the effect of clomiphene citrate on several ultrasonographic markers of uterine receptivity in PCOS patients who ovulated under treatment was studied. Thirty-three PCOS women who ovulated under 150 mg daily clomiphene citrate and 33 healthy controls were studied. Uterine, subendometrial and endometrial blood flows, endometrial thickness and pattern were assessed using serial ultrasonographic assessments. The data were analysed before and after grouping the clomiphene citrate-stimulated ovulatory cycles for reproductive outcome [unfavourable (ovulation alone or early pregnancy loss) or favourable outcome (clinical pregnancy and/or live birth)]. Both before and during treatment, uterine vascularity assessed at all sites was significantly lower in the PCOS group than in controls. Endometrial thickness and pattern were impaired in the PCOS group under clomiphene citrate treatment. A significant difference in all ultrasonographic parameters was observed between cycles ending in unfavourable versus those ended in favourable outcome. Clomiphene citrate administration alters several surrogate ultrasonographic parameters of uterine receptivity, and this effect could be crucial for its efficacy.


Queensland Digital Health Clinical Charter: a clinical consensus statement on priorities for digital health in hospitals.
Digital transformation of Australian hospitals is occurring rapidly. Although the clinical community has had limited ability to influence high-level decision making and investments into digital health technologies, as these technologies increasingly transform the way patients are cared for, the clinical community must influence the digital health agenda and be an integral part of the decision-making process. This case study details the process and lessons learnt during the development of the state-wide consensus statement detailing the clinical requirements for digital health initiatives to form the Queensland Digital Health Clinical Charter. To the best of our knowledge, Queensland is the first Australian jurisdiction to create a Digital Clinical Charter to be specifically referenced in the investment in and governance of digital health in hospitals. By developing this clinical charter for digital health, and in articulating the needs of clinicians, a clinical framework will be added to both the decision-making process around the investments in digital health and the definition and realisation of the expected benefits from these sizable investments.


Device therapy for atrial fibrillation.
Currently, there are more therapeutic options available for AF patients with recurrent symptomatic AF episodes. The studies on the role of device therapy for AF have been promising thus far, but they have not achieved any of the goals of AF management. Based on large randomized clinical trials, patients with SSS should receive atrial-based pacing devices. Moderate sized randomized studies have shown minimal benefit of multi-site pacing in AF prevention, even when combined with antiarrhythmic agents. Alternative site pacing such as septal pacing (high or low), however, may be more advantageous, as it achieves similar results in terms of AF reduction with less hardware. The role of ATP in AF prevention is still in its infancy and will need further studies to determine its role in conjunction with antiarrhythmic agents. Furthermore, the role of radiofrequency ablation of pulmonary veins and other sites of AF initiation has been evolving and may be offered to more patients in the future. This approach may be more acceptable to patients and may gain wider acceptance for some groups of AF patients rather than device therapy. In any event, there is still a large role for pacemaker therapy in the management of AF, especially in patients who cannot benefit from curative ablation or surgery procedures, or patients who have failed these procedures, and particularly elderly patients who typically do not undergo these procedures. Based on current understanding, careful selection of pacing sites and pacing algorithms may help in reducing AF episodes in patients receiving devices.


A systematic review and meta-analysis of the evidence for unaware fear conditioning.
Whether fear conditioning can take place without contingency awareness is a topic of continuing debate and conflicting findings have been reported in the literature. This systematic review provides a critical assessment of the available evidence. Specifically, a search was conducted to identify articles reporting fear conditioning studies in which the contingency between conditioned stimuli (CS) and the unconditioned stimulus (US) was masked, and in which CS-US contingency awareness was assessed. A systematic assessment of the methodological quality of the included studies (k = 41) indicated that most studies suffered from methodological limitations (i.e., poor masking procedures, poor awareness measures, researcher degrees of freedom, and trial-order effects), and that higher quality predicted lower odds of studies concluding in favor of contingency unaware fear conditioning. Furthermore, meta-analytic moderation analyses indicated no evidence for a specific set of conditions under which contingency unaware fear conditioning can be observed. Finally, funnel plot asymmetry and p-curve analysis indicated evidence for publication bias. We conclude that there is no convincing evidence for contingency unaware fear conditioning.


Effect of nomifensine on central 5-hydroxytryptamine neurons.
Effects of nomifensine (8-amino-1, 2, 3, 4-tetrahydro-2-methyl-4-phenyl-isoquinoline) (NF), an antidepressant drug which inhibits dopamine uptake, on central serotonergic structures were studied in rats. NF affects of 5-hydroxytryptamine (5-HT) and 5-hydroxyindoleacetic acid levels in the whole brain as well as in the separate rat brain structures. The 5-HT turnover is decreased in the whole brain and the striatum but increased in the midbrain and the hippocamp as judged from experiments with tryptophan hydroxylase inhibitor, alpha-propyldopacetamide. Pretreatment with dopamine-receptor blocking agent, spiperone, antagonized the increase of 5-HT turnover rate in brain regions mentioned above. NF stimulates the hind limb flexor reflex in spinal rat, a preparation regarded as a model for evaluation of drug action on central 5-HT neurons. This stimulatory effect was antogonized by cyproheptadine, by reserpine and imipramine. The obtained results indicate that NF activates central 5-HT neurons both directly and indirectly, via stimulation of dopamine receptors as described previously for other dopamine agonists.


Radiosensitizing effect of estramustine in malignant glioma in vitro and in vivo.
Estramustine-phosphate (EMP), a combination of nornitrogen mustard and 17 beta-estradiol, has been demonstrated to exert specific antiproliferative effects on human glioma cells in vitro. The cytotoxic effect is, at least partially, mediated by inhibiting microtubule function. In this study the combined effect of EMP and radiation was evaluated in the human glioma cell-lines, 251-MG and 105-MG, in vitro, and in the rat glioma BT4C in vitro and in vivo. In all cell-lines an additive effect of EMP and radiation was obtained in vitro. Assuming equal effect of EMP is obtained in subsequent radiation fractions, the cell kill will be increased from 2-3 to 5-10 logs if delivering 30 fractions of 2 Gy combined with EMP. In the BT4C rat model the combined effect was found to be synergistic. Flow cytometry demonstrated an arrest in G2/M phase in all cell-lines after EMP treatment. This block in G2/M phase in addition to the previously demonstrated induction of free oxygen radicals, and the increase of blood flow with an assumed subsequent increase of oxygenation, might provide an explanation for the observed radiosensitizing effect of estramustine.


Reduced heart rate variability in schizophrenia and bipolar disorder compared to healthy controls.
Despite current diagnostic systems distinguishing schizophrenia (SZ) and bipolar disorder (BD) as separate diseases, emerging evidence suggests they share a number of clinical and epidemiological features, such as increased cardiovascular disease (CVD) risk. It is not well understood if poor cardiac autonomic nervous system regulation, which can be indexed non-invasively by the calculation of heart rate variability (HRV), contributes to these common CVD risk factors in both diseases. We calculated HRV in 47 patients with SZ, 33 patients with BD and 212 healthy controls. Measures of symptom severity were also collected from the patient groups. Heart rate variability was significantly reduced in both these disorders in comparison with the healthy participants; however, there were no HRV differences between disorders. Importantly, these reductions were independent of the medication, age or body mass index effects. There was also preliminary evidence that patients with reduced HRV had increased overall and negative psychosis symptom severity regardless of SZ or BD diagnosis. We suggest that HRV may provide a possible biomarker of CVD risk and symptom severity in severe mental illness. Thus, our results highlight the importance of cardiometabolic screening across SZ and bipolar spectrum disorders.


Cardiac versus vascular effects of a new dihydropyridine derivative, CV-4093. In vitro comparison with other calcium antagonists.
The effects of CV-4093, a new dihydropyridine derivative, on isolated cardiovascular tissues were compared with those of several dihydropyridine and non-dihydropyridine calcium antagonists. CV-4093 effectively inhibited the contractions induced in canine femoral arteries by high [K+]0 and Bay K 8644, but incompletely relaxed those induced by norepinephrine. CV-4093, 10(-6) M, abolished the electrically induced slow action potentials in guinea-pig papillary muscles partially depolarized by 25 mM K+ solution and attenuated those induced by isoproterenol, histamine and Bay K 8644. The rank order of potency of dihydropyridine and non-dihydropyridine calcium antagonists in canine femoral arteries and veins precontracted with 120 mM [K+]0 was as follows: nisoldipine greater than nicardipine greater than or equal to nifedipine greater than or equal to CV-4093 greater than verapamil greater than or equal to diltiazem. Nisoldipine was the most potent and CV-4093 was the least potent among these drugs in terms of negative inotropic effect in normally polarized papillary muscles and negative chronotropic effect in right atria of guinea pigs. The rank order of potency for these cardiodepressant actions was nisoldipine greater than or equal to nifedipine greater than nicardipine greater than verapamil greater than diltiazem greater than or equal to CV-4093. The duration of action potential in guinea-pig papillary muscles was shortened by nisoldipine and nifedipine, unchanged by nicardipine and CV-4093 and was slightly prolonged by verapamil and diltiazem. These results suggest that CV-4093 is a calcium antagonist with a highly selective vascular effect and little cardiodepressant action, and could be of value for the treatment of hypertension.


Traumatic events and their relative PTSD burden in Northern Ireland: a consideration of the impact of the 'Troubles'.
Over a 30-year period in its recent history, daily life in Northern Ireland (NI) was characterised by civil violence, colloquially termed as the 'Troubles'. The current report examines exposure to 29 traumatic event types and the associated conditional prevalence of post-traumatic stress disorder (PTSD) among the Northern Ireland population, with a focus on the impact of traumatic events that were characteristic of the NI 'Troubles'. Results presented are based on analysis of data from the Northern Ireland Study of Health and Stress (NISHS). The NISHS is a representative epidemiological study of mental health among the NI adult population (N = 4,340) and part of the World Mental Health Survey Initiative. Perpetration of violence, physical assault by a spouse or partner and private events were the event types associated with the highest conditional prevalence of PTSD. Despite this elevated risk, collectively these events accounted for just 16.8% of the overall public burden of PTSD, given their low prevalence among the general population. Events that were characteristic of civil conflict, including unexpected death of a loved one, witnessing death or a dead body or someone seriously injured and being mugged or threatened with a weapon accounted for the highest proportion of the overall public health burden of PTSD (18.6, 9.4 and 7.8%, respectively). These findings are a feature of the higher prevalence of these events among the general population coupled with their moderate to above average risk of PTSD. Despite the formal end to conflict in NI in 1999, a substantial proportion of the adult population continue to suffer the adverse mental health effects of chronic trauma exposure. Given rates of recovery of PTSD in the absence of evidence-based treatments, it is likely that the legacy of mental ill health associated with conflict, if not adequately addressed, will endure for many years.


Small RNA-directed silencing: the fly finds its inner fission yeast?
Several recent studies demonstrate that piRNAs guide Piwi protein to repress transposon transcription in fly ovaries, much as fission yeast use siRNAs to silence repeat sequences. Still mysterious though is how Piwi targets euchromatic transposons for silencing, but not the specialized heterochromatic loci that produce piRNA precursors.


Association of long surface appendages with adherence-related functions of the gram-positive species Actinomyces naeslundii.
Electron microscopy of new isolates of gram-positive Actinomyces naeslundii demonstrated long, fragile appendages. Removal of the appendages impaired attachment to epithelial cells and reaggregation, thus implicating them in attachment-related functions.


The involvement of L-gamma-glutamyl-L-cysteinyl-glycine (glutathione/GSH) in the mechanism of redox signaling mediating MAPK(p38)-dependent regulation of pro-inflammatory cytokine production.
Redox regulation of mitogen-activated protein kinase (MAPK(p38))-mediated pro-inflammatory cytokine production is not well characterized in the alveolar epithelium. It was hypothesized that the involvement of the MAPK(p38) pathway in regulating lipopolysaccharide (LPS)-induced tumor necrosis factor (TNF)-alpha and interleukin-6 secretion is redox-sensitive and affected by NAC, an antioxidant and a precursor of glutathione, and L-buthionine-(S,R)-sulfoximine, an irreversible inhibitor of gamma-glutamylcysteine synthetase, the rate-limiting enzyme in GSH biosynthesis. Exposure of fetal alveolar type II epithelial cells to Escherichia coli-derived LPS induced, in a time-dependent manner, the phosphorylation/activation of MAPK(p38) (peak at 15min). In addition, LPS up-regulated the phosphorylation of MAPK(p38) in a dose-dependent manner. The effect of LPS on the MAPK(p38) pathway was associated with the activation of MAPK-activated protein kinase, which phosphorylated the small 27kDa heat-shock protein (Hsp27). LPS induced the phosphorylation of Hsp27 in a time- and dose-dependent manner. Selective blockage of the MAPK(p38) pathway by a pyridinyl-imidazole (SB-203580) abrogated LPS-induced release of TNF-alpha and IL-6. Pre-treatment with NAC reduced LPS-mediated secretion of TNF-alpha and IL-6. Incubation of cells with NAC induced intracellular accumulation of GSH, but reduced the concentration of GSSG. On the other hand, pre-treatment with BSO augmented LPS-mediated secretion of TNF-alpha and IL-6. In addition, BSO induced intracellular accumulation of GSSG, but reduced the concentration of GSH. Whereas NAC blocked the phosphorylation/activation of MAPK(p38), BSO amplified the LPS-mediated effect on MAPK(p38). These results indicated that intracellular redox signaling plays an important role in regulating LPS-induced activation of the MAPK(p38) pathway and MAPK(p38)-mediated regulation of LPS-dependent inflammatory cytokine production in the alveolar epithelium.


Corticosteroids usage and central serous chorioretinopathy: a meta-analysis.
This meta-analysis was conducted to investigate whether usage of corticosteroids was associated with an increased risk of central serous chorioretinopathy by summarizing all available evidence. PubMed, EMBASE, Cochrane Library, and Web of Science databases were searched for all relevant studies published from inception to April 2019. Studies investigating the association between corticosteroids and the risk of central serous chorioretinopathy were included. Six case-control studies were finally included for the meta-analysis after study selection. The results of the analysis showed that there was a significantly higher risk of central serous chorioretinopathy among patients who once used corticosteroids (N = 707) compared with individuals without the usage of corticosteroids (N = 1927) (OR 4.050, 95% CI 2.270 to 7.220, I2 = 59%, P < 0.001). Results were the same for taking corticosteroids orally (OR 1.650, 95% CI 1.510 to 1.810, I2 = 47%, P < 0.001), through injection (OR 1.660, 95% CI 1.440 to 1.910, I2 = 0%, P < 0.001), and through nasal spray (OR 1.910, 95% CI 1.500 to 2.420, I2 = 17%, P < 0.001), but not for inhaled usage (OR 1.340, 95% CI 0.900 to 1.990, I2 = 0%, P = 0.160). In conclusion, this meta-analysis demonstrated that patients with the usage of corticosteroids had an increased risk of central serous chorioretinopathy. Patients who were prescribed with corticosteroids need greater attention to their retina health. Also, all central serous chorioretinopathy (CSC) patients should avoid the use of corticosteroids as much as they possibly can.


Asthma Management in Children.
Asthma is a common, complex heterogeneous disease often beginning in early life and is characterized by reversible airflow obstruction. The phenotypic differences that exist in children with asthma may impact underlying comorbid conditions and pharmacologic treatment choices. Prenatal factors for increased risk of asthma could include maternal diet and the maternal microbiome. Evidence also suggests that postnatal microbial exposures and colonization contribute to the risk of allergic diseases and asthma. After confirming the diagnosis, asthma management in children centers on 3 broad areas: pharmacologic treatment, treatment of underlying comorbidities, and education of the patient and caregivers on the importance of adherence and device technique. Moreover, social determinants of health significantly impact on symptom burden and treatment response.


Current pharmacotherapeutic strategies for Strongyloidiasis and the complications in its treatment.
Strongyloidiasis, an infection caused by the soil-transmitted helminth Strongyloides stercoralis, can lead immunocompromised people to a life-threatening syndrome. We highlight here current and emerging pharmacotherapeutic strategies for strongyloidiasis and discuss treatment protocols according to patient cohort. We searched PubMed and Embase for papers published on this topic between 1990 and May 2022. Ivermectin is the first-line drug, with an estimated efficacy of about 86% and excellent tolerability. Albendazole has a lower efficacy, with usage advised when ivermectin is not available or not recommended. Moxidectin might be a valid alternative to ivermectin, with the advantage of being a dose-independent formulation. The standard dose of ivermectin is 200 µg/kg single dose orally, but multiple doses might be needed in immunosuppressed patients. In the case of hyperinfection, repeated doses are recommended up to 2 weeks after clearance of larvae from biological fluids, with close monitoring and further dosing based on review. Subcutaneous ivermectin is used where there is impaired intestinal absorption/paralytic ileus. In pregnant or lactating women, studies have not identified increased risk with ivermectin use. However, with limited available data, a risk-benefit assessment should be considered for each case.


Neural precursor cell-expressed, developmentally down-regulated 4 (NEDD4) regulates hydrogen peroxide-induced cell proliferation and death through inhibition of Hippo signaling.
E3 ubiquitin ligases are involved in the regulation of oxidative stress-induced cell death. In this study, we investigated the role of neural precursor cell-expressed, developmentally down-regulated protein 4 (NEDD4) in regulation of hydrogen peroxide (H2O2)-induced cell proliferation and apoptosis in human bone marrow-derived stem cells (hBMSCs). Cell proliferation was increased in low doses of H2O2 (10-4 to 10-2 μM), whereas sublethal concentrations of H2O2 (>200 μM) induced apoptosis. A chromatin immunoprecipitation assay identified that recruitment of NF-κB onto the promoter region of NEDD4 mediated H2O2-induced NEDD4 expression. The increase of NEDD4 expression by H2O2 induced translocation of yes-associated protein (YAP) into the nucleus by decreasing the stability of large tumor suppressor kinase (LATS). Thus, the phosphorylation of serine 127 residue of YAP by LATS upstream kinase is decreased and thereby increased the transcriptional activity of YAP. The mRNA expression levels of catalase and manganese superoxide dismutase, which are well-known targets of YAP, were increased by H2O2 treatment but down-regulated by NEDD4 silencing using a specific small interfering RNA targeting NEDD4 (siNEDD4). H2O2-induced scavenging capacity of reactive oxygen species was also decreased by siNEDD4 in hBMSCs. Finally, hBMSC differentiation into osteoblast was decreased by siNEDD4 but reverted by reintroduction of the S127A mutant construction of YAP. Taken together, these results indicate that NEDD4 regulates H2O2-induced alteration of cell status through regulation of the Hippo signaling pathway.-Jeon, S.-A., Kim, D. W., Cho, J.-Y. Neural precursor cell-expressed, developmentally down-regulated 4 (NEDD4) regulates hydrogen peroxide-induced cell proliferation and death through inhibition of Hippo signaling.


Using a stable pre-emulsified canola oil system that includes porcine plasma protein hydrolysates and oxidized tannic acid to partially replace pork fat in frankfurters.
The objective of this study was to evaluate the effect of two different forms of canola oil (pure liquid form or a pre-emulsified form that includes porcine plasma protein hydrolysates modified by oxidized tannic acid) used for pork back-fat substitutions on the physico-chemical characteristics of frankfurters. When compared to the control group, partial replacement of pork back-fat using a pre-emulsified canola oil system exhibited excellent water and fat binding capacities, quicker relaxation times and lower amounts of saturated fatty acids (SFAs) (P < .05), as well as increased hardness, gumminess, and chewiness (P < .05) when verified by dynamic rheology analysis. Additionally, higher replacement ratio of pre-emulsified canola oil did significantly decrease the overall acceptability than the control group (P < .05). Our results indicate that pre-emulsified canola oil provided greater improvement with respect to the physical characteristics of partial pork back-fat replaced frankfurters, when compared to pure canola oil inclusion.


Novel adamantyl retinoid-related molecules with POLA1 inhibitory activity.
Atypical retinoids (AR) or retinoid-related molecules (RRMs) represent a promising class of antitumor compounds. Among AR, E-3-(3'-adamantan-1-yl-4'-hydroxybiphenyl-4-yl)acrylic acid (adarotene), has been extensively investigated. In the present work we report the results of our efforts to develop new adarotene-related atypical retinoids endowed also with POLA1 inhibitory activity. The effects of the synthesized compounds on cell growth were determined on a panel of human and hematological cancer cell lines. The most promising compounds showed antitumor activity against several tumor histotypes and increased cytotoxic activity against an adarotene-resistant cell line, compared to the parent molecule. The antitumor activity of a selected compound was evaluated on HT-29 human colon carcinoma and human mesothelioma (MM487) xenografts. Particularly significant was the in vivo activity of the compound as a single agent compared to adarotene and cisplatin, against pleural mesothelioma MM487. No reduction of mice body weight was observed, thus suggesting a higher tolerability with respect to the parent compound adarotene.


Gut flora enhance bacterial clearance in lung through toll-like receptors 4.
The influence of the gut flora on lung inflammatory reaction against bacterial challenge remains undefined. This study was designed to investigate whether gut flora enhances lung defense against E.coli pneumonia through TLR4 signaling. C3H/HeN (WT) mice and C3H/HeJ (TLR4 deficient) mice were treated with antibiotics in drinking water for 4 weeks to deplete gut commensal microflora. At week 3, drinking water was supplemented with lipopolysaccharide (LPS); a ligand for TLR4, to trigger TLRs in intestinal tract. At the end of 4th week, E.coli was injected to trachea to induce E.coli pneumonia. We found that commensal depletion by antibiotic pretreatment before E.coli pneumonia challenge induced a 30% decrease of MPO activity in the lung, a significant decrease of bacterial killing activity of alveolar macrophage, and bacterial counts in C3H/HeN mice but not in C3H/HeJ (TLR4 deficient) mice. LPS, a TLR4 ligand, supplementation during antibiotic pretreatment reversed these effects and decreased E.coli pneumonia-induced mortality in C3H/HeN mice. Furthermore, commensal depletion induced a suppression of NF-κB DNA binding activity and an increase of KC, MIP-2, IL-1β expression in the lung in C3H/HeN mice but not in C3H/HeJ mice. Taken together with that commensal depletion increased E.coli pneumonia-induced mortality and LPS supplementation decreased it, we conclude that gut flora enhances bacterial clearance against E.coli pneumonia through TLR4.


Chemically induced bladder cancer--a sonographic and morphologic description.
Carcinogen-induced bladder cancer in rodents is a key model for evaluation of novel therapies for bladder cancer because of its similarity to the clinical disease. The major drawback of the model is the difficulty in assessing tumor burden in living animals and at necropsy. The objective of this work was to present simple and accurate solutions for this problem. Sixty female Wistar rats were given N-butyl-N-(4-hydroxybutyl) nitrosamine (BBN) at a concentration of 0.05% in the drinking water for 35 weeks. Periodic evaluation of tumorigenesis was done by ultrasonography of the anesthetized animals. The tumor burden was evaluated after killing the rats by weighing the bladder, digital measurement of the tumor dimensions, and histologic examination. Focal urothelial hyperplasia was noted by the 5th BBN week, severe dysplasia by the 15th BBN week, and transitional cell carcinoma from the 20th week on. Carcinoma was seen on digital photographs taken from the 20th week on. Tumors as small as 1 mm could be easily measured. A poor correlation (R2 = 0.33) was found between bladder weight and the digital photographic measurements of small tumors (20th BBN week). However, when larger tumors were considered (30th BBN week), a good correlation was found (R2 = 0.81). Tumor progress in the rat BBN model was accurately monitored by ultrasonography in living animals. Digital measurement of tumor dimensions provided a precise method for evaluation of tumor burden at necropsy.


Acetaminophen-induced nephrotoxicity: pathophysiology, clinical manifestations, and management.
Acetaminophen-induced liver necrosis has been studied extensively, but the extrahepatic manifestations of acetaminophen toxicity are currently not described well in the literature. Renal insufficiency occurs in approximately 1-2% of patients with acetaminophen overdose. The pathophysiology of renal toxicity in acetaminophen poisoning has been attributed to cytochrome P-450 mixed function oxidase isoenzymes present in the kidney, although other mechanisms have been elucidated, including the role of prostaglandin synthetase and N-deacetylase enzymes. Paradoxically, glutathione is considered an important element in the detoxification of acetaminophen and its metabolites; however, its conjugates have been implicated in the formation of nephrotoxic compounds. Acetaminophen-induced renal failure becomes evident after hepatotoxicity in most cases, but can be differentiated from the hepatorenal syndrome, which may complicate fulminant hepatic failure. The role of N-acetylcysteine therapy in the setting of acetaminophen-induced renal failure is unclear. This review will focus on the pathophysiology, clinical features, and management of renal insufficiency in the setting of acute acetaminophen toxicity. A 47-year-old female was found lethargic at home and brought by ambulance to an emergency department. History from family members suggested an inadvertent acetaminophen overdose, and she had last been seen a few hours earlier. She reportedly ingested 18 tablets of 500 mg acetaminophen (APAP) over the previous two days because she had run out of her prescription pain medication. Her past medical history was significant for fibromyalgia, arthritis, and a prior gastric bypass procedure. She had no history of alcohol abuse or renal insufficiency. She was lethargic. Vital signs: BP 128/96 mmHg, pulse 112/min, respirations 32/min; pulse oximetry 98% on 2L nasal cannula oxygen. Laboratory studies: BUN 9 mg/dL, creatinine 0.9 mg/dl, acetaminophen 12 mcg/mL, AST 5409 u/L and ALT 1085 u/L. A urinalysis was negative for blood with trace protein and ketones. A urine drug screen was positive for marijuana and opioid metabolites. At the initial hospital, she was treated with N-acetylcysteine (NAC) orally. Subsequently, she developed fulminant hepatic failure with elevated transaminases, hypoglycemia, and coagulopathy (Tables 1A and 1B). She was transferred to our facility two days after initial presentation for liver transplant evaluation. At that time, her APAP level was 2.0 mg/L. Oral NAC therapy was continued after transfer. The patient's liver function subsequently improved and she ultimately did not require transplantation. She did develop acute renal failure during the course of her hospitalization, with a creatinine of 2.3 mg/dL on transfer, which increased to 8.1 mg/dL nine days later (approximately 11-13 days post-ingestion). Medical toxicology was consulted by the intensive care unit team to address whether this was acetaminophen-induced renal failure and if there was a role for NAC in this setting.


Attenuation reactions in a multiple contaminated aquifer in Bitterfeld (Germany).
Large-scale contaminated sites with multiple contaminants in the groundwater present a challenge to risk assessment and remediation. Attenuation reactions take place in the subsurface and act to contain contaminants, but must be thoroughly investigated on a site-specific basis. Field data from monitoring wells at a contaminated industrial site in Bitterfeld, Germany, are presented and analyzed for evidence of the prevalent biodegradation reactions. The groundwater in the Tertiary aquifer is contaminated with large quantities of chlorinated aliphatic compounds, in addition to chlorobenzenes and BTEX. In this strictly anaerobic environment, geochemical indications for several microbial processes were found, including methanogenesis, sulfate and iron reduction as well as reductive dechlorination of the chlorinated hydrocarbons. Direct evidence for the latter degradation reaction was observed along the flowpath due to the appearance of intermediates and an increase in the degree of dechlorination.


Changes in pelvic tilt following total hip arthroplasty.
It is important to understand chronological changes in pelvic tilt after total hip arthroplasty (THA). In this study, we first investigated changes in pelvic tilt after THA. Second, we determined the correlation between preoperative pelvic tilt and the extent of postoperative changes in the pelvic tilt. Third, we evaluated the effects of changes in pelvic tilt on postoperative function and disability. We examined 149 patients who received primary THA over a follow-up period of 1 year. We compared postoperative changes with the preoperative pelvic tilt on the basis of the anterior pelvic plane (APP) defined by DiGioia and patient demographics. A significant correlation was observed between preoperative APP and the amount of postoperative change in APP, suggesting that patients with severe preoperative pelvic tilt generally experience greater postoperative changes in pelvic tilt. Our data showed that patients with preoperative anterior pelvic tilt generally exhibit posterior changes in pelvic tilt after operation, while patients with preoperative posterior pelvic tilts did not experience significant postoperative changes in pelvic tilt. The 1-year postoperative function scores in patients with preoperative anterior pelvic tilt were lower than those in patients with preoperative posterior pelvic tilt. Pelvic tilt changed by varying degrees following THA. Special attention must be paid when positioning the acetabular component, particularly in patients with severe pelvic tilt prior to surgery. A greater understanding of the postoperative changes in pelvic tilt may improve the outcome of THA.


Pollution gets personal! A first population-based human biomonitoring study in Austria.
Humans are exposed to a broad variety of man-made chemicals. Human biomonitoring (HBM) data reveal the individual body burden irrespective of sources and routes of uptake. A first population-based study was started in Austria in 2008 and was finished at the end of May 2011. This cross sectional study aims at documenting the extent, the distribution and the determinants of human exposure to industrial chemicals as well as proving the feasibility of a representative HBM study. Overall, 150 volunteers (50 families) were selected by stratified random sampling. Exposure to phthalates, trisphosphates, polybrominated diphenyl ethers (PBDE), bisphenol A (along with nonyl- and octyl phenol) and methyl mercury was assessed. Sixteen of 18 PBDE determined were detected above the limit of quantification (LOQ) in blood samples with #153 and #197 the most abundant species. Bisphenol A in urine was measured in a subsample of 25 with only 4 samples found above the LOQ. In 3 of 100 urine samples at least one of 8 trisphosphate compounds assessed was above the LOQ. These first analytical results of the human biomonitoring data show that the body burden of the Austrian population with respect to the assessed compounds is comparable to or even lower than in other European countries. Overall, the study revealed that in order to develop a feasible protocol for representative human biomonitoring studies procedures have to be optimized to allow for non-invasive sampling of body tissues in accordance with the main metabolic pathways. Procedures of participants' recruitment were, however, labor intensive and have to be improved.


Pressure-induced dissociation of brome mosaic virus.
Brome mosaic virus reversibly dissociates into subunits in the pressure range of 600 x 10(5) to 1600 x 10(5) Pa, as demonstrated by studies of the spectral shift of intrinsic fluorescence, of filtration chromatography and of electron microscopy of samples fixed under pressure. Smaller shell particles (T = 1) were detected as intermediates in the dissociation pathway. Dissociation was facilitated by decreasing the concentration, as expected for a multimolecular reaction. The estimated change in volume upon dissociation into 90 dimer particles was -2960 ml/mol. Large increases in the intrinsic fluorescence intensity and in the binding of bis(8-anilinonaphthalene-1-sulfonate) occurred at pressures higher than 1400 x 10(5) Pa. The pressure-dependence profile of the different spectral properties shifted to lower pressures when 5 mM-MgCl2 was included in the buffer or when the pH was raised from 5.5 to 5.9. When the pressure was progressively increased above 1400 x 10(5) Pa, a value that led to 75% dissociation, the capsid subunits lost the ability to reassociate into regular shells and only amorphous aggregates were formed after decompression, as evidenced by both electron microscopy and gel filtration chromatography. The formation of these random aggregates of brome mosaic virus can be explained by a conformational drift of the separated subunits, similar in nature to that found in simpler oligomeric proteins.


Zinc physiology and biochemistry in oocytes and embryos.
The essential role of zinc in embryogenesis was identified through studies of its presence in eggs and embryos, the effects of its deficiency and its role in metallo proteins required for organ development and formation. The Xenopus laevis oocyte zinc content varies during oogenesis. It increases from 3 to 70 ng zinc/oocyte as it progresses from stage I to VI. The oocyte zinc is derived from the maternal liver as part of a metallo-complex with vitellogenin. The latter transports the metal in plasma and into the oocyte. Once internalized, most of the zinc is stored within yolk platelets bound to lipovitellin, one of the processed products of vitellogenin. About 90% of the total zinc is associated with the yolk platelet lipovitellin while the remaining 10% is in a compartment associated with hitherto unknown molecule(s) or organelle(s) of the cytoplasm. The bi-compartmental distribution remains constant throughout embryogenesis since the embryo behaves as a closed system for zinc after fertilization. The yolk platelet zinc is used after the tadpole is hatched while we proposed that the 10% of the zinc in the non-yolk platelet pool is the one used for embryogenesis. It provides zinc to newly synthesized molecules responsible for the development of zinc-dependent organ genesis. Interference with the availability of this zinc by the chelating agent 1,10-phenanthroline results in the development of embryos that lack dorsal organs, including brain, eyes and spinal cord. The extensive teratology is proposed to be due to altered or absent zinc distribution between the cytosolic pool and zinc-transcription factors. The data identify the components of a zinc transport, storage and distribution system in a vertebrate organism.


Structural and dynamic characterization of the aromatic amino acids of the human immunodeficiency virus type I nucleocapsid protein zinc fingers and their involvement in heterologous tRNA(Phe) binding: a steady-state and time-resolved fluorescence study.
The steady-state and time-resolved fluorescence properties of two zinc-saturated 18-residue synthetic peptides with the amino acid sequence of the NH2-terminal (NCp7 13-30 F16W, where the naturally occurring Phe was replaced by a Trp residue) and the COOH-terminal (NCp7 34-51) zinc finger domains of human immunodeficiency virus type I nucleocapsid protein were investigated. Fluorescence intensity decay of both Trp 16 and Trp 37 residues suggested the existence of two fully solvent-exposed ground-state classes governed by a C = 2.2 equilibrium constant. The lifetimes of Trp 16 classes differed from those of Trp 37 essentially because of differences in nonradiative rate constants. Arrhenius plots of the temperature-dependent nonradiative rate constants suggested that the fluorescence quenchers involved in both classes and in both peptides were different and the collisional rate of these quenchers with the indole ring was very low, probably because of the highly constrained peptide chain conformation. The nature of the ground-state classes was discussed in relation to 1H nuclear magnetic resonance data. Using Trp fluorescence to monitor the interaction of both peptides with tRNA(Phe) we found that a stacking between the indole ring of both Trp residues and the bases of tRNA(Phe) occurred. This stacking constituted the main driving force of the interaction and modified the tRNA(Phe) conformation. Moreover, the binding of both fingers to tRNA(Phe) was noncooperative with similar site size (3 nucleotide residues/peptide), but the affinity of the NH2-terminal finger domain (K = 1.3 (+/- 0.2) 10(5) M-1) in low ionic strength buffer was one order of magnitude larger than the COOH-terminal one due to additional electrostatic interactions involving Lys 14 and/or Arg 29 residues.


Effect of granular activated carbon concentration on the content of organic matter and salt, influencing E. coli activity and survival in fluidized bed disinfection reactor.
Granular activated carbon (GAC) is used in water treatment systems, typically to remove pollutants such as natural organic matter, volatile organic compounds, chlorine, taste, and odor. GAC is also used as a key component of a new technology that combines a fluidized bed reactor with radio frequency electric fields for disinfection. So far, the effects of GAC on bacteria in these fluidized bed reactors are unclear. This paper describes a systematic study of the physico-chemical changes in five microbial media compositions caused by different concentrations (23-350 g/L) of GAC, and the effects of these physico-chemical changes on the metabolic activity and survival of a model microorganism (Escherichia coli YMc10) in a fluidized bed reactor. The chemical adsorption taking place in suspensions with specific GAC changed nutritional, osmotic, and pH conditions in the investigated microbial media (LB, diluted LB, PBS, diluted PBS, and tap water), leading to a decay of the metabolic activity and survival of E. coli. Especially media that are poor in organic and mineral compounds (e.g., PBS) with suspended GAC showed a concentration decay of 3.5 Log CFU/mL E. coli after 6 h. Organic compounds depletion and severe pH variation were enhanced in the presence of higher GAC concentrations.


Short-term oleoyl-estrone treatment affects capacity to manage lipids in rat adipose tissue.
Short-term OE (oleoyl-estrone) treatment causes significant decreases in rat weight mainly due to adipose tissue loss. The aim of this work was to determine if OE treatment affects the expression of genes that regulate lipid metabolism in white adipose tissue. Gene expression in adipose tissue from female treated rats (48 hours) was analysed by hybridization to cDNA arrays and levels of specific mRNAs were determined by real-time PCR. Treatment with OE decreased the expression of 232 genes and up-regulated 75 other genes in mesenteric white adipose tissue. The use of real-time PCR validate that, in mesenteric white adipose tissue, mRNA levels for Lipoprotein Lipase (LPL) were decreased by 52%, those of Fatty Acid Synthase (FAS) by 95%, those of Hormone Sensible Lipase (HSL) by 32%, those of Acetyl CoA Carboxylase (ACC) by 92%, those of Carnitine Palmitoyltransferase 1b (CPT1b) by 45%, and those of Fatty Acid Transport Protein 1 (FATP1) and Adipocyte Fatty Acid Binding Protein (FABP4) by 52% and 49%, respectively. Conversely, Tumour Necrosis Factor (TNFalpha) values showed overexpression (198%). Short-term treatment with OE affects adipose tissue capacity to extract fatty acids from lipoproteins and to deal with fatty acid transport and metabolism.


Correlation between brain tissue and cerebrospinal fluid concentrations of selected compounds in rats with intact and injured blood-brain barrier.
We examined how the concentrations of exogenous compounds (and their metabolites) in rat brain tissue correlate with their concentrations in the cerebrospinal fluid (CSF) (i) when the blood-brain barrier (B-BB) is intact and increasing doses of compounds are administered, and (ii) when the function of the B-BB is impaired and small constant doses are given. The impairment of B-BB function was caused by chlorophenoxyacetic acid herbicides. An excellent linear correlation between brain tissue and CSF concentrations, calculated from 14C activities, was obtained with 14C-p-aminobenzoic acid, 14C-antipyrine, and 14C-sucrose administered in increasing doses (to 320 mg/kg, i.v.) to B-BB-intact animals (r = 0.92 to 0.99, P less than 0.001). After the administration of small, constant, i.v. doses of 14C-methyl-4-chlorophenoxyacetic acid, 14C-2,4-dichlorophenoxyacetic acid, or 14C-p-aminobenzoic acid into B-BB-damaged rats, both brain tissue and CSF radioactivities increased about linearly 10-fold or more when the lesions progressed. A close correlation between brain tissue and CSF radioactivities was calculated with each compound (r = 0.97 to 0.99, P less than 0.001). In tests with small constant amounts of 14C-antipyrine, 14C-sucrose, and 125I-labeled human albumin, however, no marked linear correlation could be drawn. This was due to the fact that these compounds always caused roughly the same 14C activities both in the brain tissue and in CSF, i.e., their cerebral penetration was only slightly or negligibly affected by the B-BB impairment. The results suggest that significant changes in compound penetration into rat brain tissue can be monitored in the CSF.


Differential regulation of the consummatory, motivational and anticipatory aspects of feeding behavior by dopaminergic and opioidergic drugs.
Various aspects of feeding behavior (eg consumption, motivation and anticipation) are regulated by homeostatic and hedonic systems, and are modulated by dopaminergic and opioid brain systems. Here, we have studied the modulation of these aspects of feeding behavior by opioid and dopaminergic neurotransmission while taking into account food palatability and homeostatic state. Foods that varied in palatability were presented to either food sated or food restricted rats following injections of different doses of naloxone, an opioid receptor antagonist, or flupenthixol, a dopaminergic receptor antagonist, in behavioral paradigms that measured different aspects of feeding. Naloxone decreased food intake in a dose-dependent manner in sated rats given access to palatable food, without modifying food intake in food restricted rats. Flupenthixol did not have any effect on food intake. With regard to motivation, which was tested in a straight alley, naloxone increased the latency to reach the food only in sated rats presented with palatable food. Flupenthixol did not modify the latency of any group. Conditioned locomotor activity to repeated food presentation, a measure of anticipation, is expressed only in food restricted rats. Naloxone did not modify anticipatory activity, whereas flupenthixol decreased it only in food restricted rats presented with palatable food. These results reinforce the idea that the opioid system regulates feeding through the modulation of the perceived palatability of food. The dopaminergic system seems to be more important for the regulation of anticipatory activity related to motivationally relevant stimuli.


The course of alcoholism. Long-term prognosis in different types.
The disease concept of alcoholism was first introduced into the medical literature by Magnus Huss in 1984. Since that time many authors have attempted to define therapy-related sub-groups of chronic alcoholics but have been unsuccessful until now because alcoholism represents a complex development and becomes apparent in various clinical pictures. As the method of cross-sectional investigations does not seem to be able to produce reliable results, we performed a prospective long-term study of 444 alcoholics. The methodological claims in literature were taken into consideration like selection criteria, programmes and goals of therapy, follow-up rate and time, etc. Careful observation of the pertinent parts of the pathogenetic pathway leading to chronic alcoholism enabled the authors to establish 4 sub-groups of alcoholics relevant for treatment.


Effect of chiral helical force field on molecular helical enantiomers and possible origin of biomolecular homochirality.
Biomolecular homochirality means that the amino acids in proteins, and sugars in nucleic acids, occur in one form: amino acids in L-form and sugars in D-form. So far, the reason why these molecules have such uniform chirality is not known. In this paper, it is suggested that a net natural chiral right-handed helical force field, produced by the Earth's orbital chirality (EOC), could affect the stability of molecular helical enantiomers and make the right-handed helical enantiomers more stable than their left-handed enantiomers, so terrestrial biological systems must select both right-handed helical nucleic acids based on D-sugars, and proteins based on L-amino acids. In given conditions, the maximum energy difference between biomolecular helical enantiomers (deltaEmax=/Eleft-Eright/) caused by the EOC may be calculated theoretically to be in the order: B-DNA > A-RNA > A-DNA >> alpha-protein > beta-protein. Our experimental results strongly supported the hypothesis that the EOC could cause the spontaneous selection and amplification of right-handed helical enantiomers and could be the origin of homochirality on the Earth.


Micellar electrokinetic chromatography-electrospray ionization mass spectrometry for the identification of drug impurities.
Previously, we have presented a system hyphenating continuous micellar electrokinetic chromatography (MEKC) with electrospray ionization mass spectrometry (ESI-MS). Here we evaluate this technique for its applicability in impurity profiling of drugs using galantamine and ipratropium as test samples. A background electrolyte (BGE) of 10mM sodium phosphate (pH 7.5), 12.5-15% acetonitrile and 20mM sodium dodecylsulfate (SDS) was used for the MEKC-MS analysis of a galantamine sample containing a number of related impurities, and a heat-treated solution of ipratropium containing a number of unknown degradation products. MEKC provided efficient separation of all sample constituents. Despite the presence of non-volatile BGEs, all impurities in the galantamine sample could be detected by ESI-MS in their respective extracted ion traces (XICs) with a detection sensitivity in the sub-microg/ml range (full-scan mode). MS/MS detection provided useful product spectra allowing the structural characterization of the respective galantamine impurities. With the MEKC-MS/MS system, two degradation products could be revealed and identified in the heat-stressed ipratropium sample. The presented method shows good potential for the detection and structure elucidation of minor impurities in drug substances.


[The role of radio-inhalation scintigraphy in diagnosing tumors of the main bronchi].
The distribution of inhaled radio preparation has been studied in 7 cases of main bronchus neoplasms and 25 healthy subjects. Patterns of radio aerosols deposition have been followed versus regime of inhalation. Application of said procedure serves to improve the existing methods of radio inhalation scintigraphy as well as diagnostic procedures for tumors of main bronchi which X-ray examination and functional assessment of external respiration fail to detect.


Depiction of vasculature in small hepatocellular carcinoma, and dysplastic nodules evaluated with carbon dioxide ultrasonography and angiography.
To evaluate the vascularity in dysplastic nodules and well-differentiated and moderately to poorly differentiated hepatocellular carcinomas (HCCs) less than 2 cm using carbon-dioxide (CO2) US and angiography. A total of 115 pathologically proven small liver tumors (0.7 approximately 2.0 cm) were included in the study. There were 31 dysplastic nodules, 49 well-differentiated HCCs and 35 moderately to poorly differentiated HCCs. A comparative study of angiography and CO2 US was carried out. Of the dysplastic nodules, 28 out of 31 tumors were hypo- or isovascular at CO2 US. Twenty-seven out of 31 tumors were hypovascular at angiography. Of the well-differentiated HCCs, 38/49 showed hypervascularity at CO2 US while 24/49 tumors were hypervascular at angiography. All moderately to poorly differentiated HCCs showed hypervascularity at CO2 US, compared to 30/35 tumors at angiography. Most of the dysplastic nodules were hypovascular and most of the moderately to poorly differentiated HCCs were hypervascular. The vascularity of well-differentiated HCCs was in between the above tumors. Both CO2 US and angiography were equally effective in demonstrating the vascularities in dysplastic nodules and moderately to poorly differentiated HCCs. CO2 US was significantly superior to angiography when identifying the vascularity in well-differentiated HCCs.


Severe pain as a possible cause of dropped head syndrome that was attenuated after amputation of an ischemic lower limb.
Dropped head syndrome (DHS) is defined as weakness of the neck extensor muscles causing a correctable chin-on-the-chest deformity. Here we report the case of a patient with severe pain from lower leg ischemia showing DHS whose symptoms were attenuated by pain relief after amputation of the severely ischemic lower leg. To our knowledge this is the first report indicating that severe pain can cause DHS. A 64-year-old Asian woman was referred to our department with a 1-month history of DHS. She also suffered from severe right foot pain because of limb ischemia. She began to complain of DHS as her gangrenous foot pain worsened. She had neck pain and difficulty with forward gaze. We found no clinical or laboratory findings of neuromuscular disorder or isolated neck extensor myopathy. We amputated her leg below the knee because of progressive foot gangrene. Her severe foot pain resolved after the surgery and her DHS was attenuated. Severe pain can cause DHS. If a patient with DHS has severe pain in another part of the body, we recommend considering aggressive pain relief as a treatment option.


Magnetic targeting core/shell Fe3O4/Au nanoparticles for magnetic resonance/photoacoustic dual-modal imaging.
This study reports magnetic targeting guided magnetic (MR)/photoacoustic (PA) dual-modal imaging by core/shell Fe3O4/Au nanoparticles. In this work, MR imaging provides time-dependent tumor location, and PA imaging reveals high resolution vasculatures inside the tumor. It is noted that the synthesized Fe3O4/Au nanoparticles exhibited higher r2 value up to 329 mM-1 s-1 than previously reported T2 contrast agents. Furthermore, the Fe3O4/Au NPs are applied as a promising candidate for in vivo MR/PA imaging of tumors by intravenously injection into LNCaP tumor-beared mice. The MR/PA imaging results show a significantly enhanced MR/PA images in the tumor site. The prepared core/shell Fe3O4/Au nanoparticles will be widely applicable in multi-modal imaging.


CHI. Who nose best? Commission for Health Improvement.
CHI is the fastest growing institution in the NHS. It has been generally well accepted by the NHS. Its methodology is a compromise between looking at mechanisms and testing whether they deliver in practice. There is no consistency in the basic data provided in CHI reports. It remains to be seen what effect CHI reports have on improving patient care.


Remarkable stability of solubilized and delipidated sarcoplasmic reticulum Ca2+-ATPase with tightly bound fluoride and magnesium against detergent-induced denaturation.
Conditions were developed in the absence of Ca(2+) for purification, delipidation, and long term stabilization of octaethylene glycol monododecyl ether (C(12)E(8))-solubilized sarcoplasmic reticulum Ca(2+)-ATPase with tightly bound Mg(2+) and F(-), an analog for the phosphoenzyme intermediate without bound Ca(2+). The Ca(2+)-ATPase activity to monitor denaturation was assessed after treatment with 20 mm Ca(2+) to release tightly bound Mg(2+)/F(-). The purification and delipidation was successfully achieved with Reactive Red-agarose affinity chromatography. The solubilized Mg(2+)/F(-)-bound Ca(2+)-ATPase was very rapidly denatured at pH 8, but was perfectly stabilized at pH 6 against denaturation for over 20 days at 4 degrees C even without exogenously added phospholipid and at a high C(12)E(8)/enzyme weight ratio (10:1). The activity was not restored unless the enzyme was treated with 20 mm Ca(2+), showing that tightly bound Mg(2+)/F(-) was not released during the long term incubation. The perfect stability was attained with or without 0.1 mm dithiothreitol, but inactivation occurred with a half-life of 10 days in the presence of 1 mm dithiothreitol, possibly due to reduction of a specific disulfide bond(s). The remarkable stability is likely conferred by intimate gathering of cytoplasmic domains of Ca(2+)-ATPase molecule induced by tight binding of Mg(2+)/F(-). The present study thus reveals an essential property of the Mg(2+)/F(-)/Ca(2+)-ATPase complex, which will likely provide clues to understanding structure of the Ca(2+)-released form of phosphoenzyme intermediate at an atomic level.


Antibody to blood group glycosyltransferases in a patient transplanted with an ABO incompatible bone marrow.
In the plasma of a blood group B recipient who was transplanted with a blood group O bone marrow, we investigated an antibody to inhibit the activities of blood group A- and B-glycosyltransferases. When B lymphocytes from the patient were transformed with Epstein-Barr virus, a few clones producing antibodies to B-transferase were obtained.


Feasibility & Preliminary Efficacy of Structured Programming and a Parent Intervention to Mitigate Accelerated Summer BMI Gain: A pilot study.
BackgroundThis study assessed initial feasibility and preliminary efficacy of providing children a free summer day camp and a parent intervention to improve self-regulation and mitigate accelerated summer BMI gain.MethodsThis pilot 2x2 factorial randomized control trial used a mixed methods design to evaluate providing children a free summer day camp (SCV), a parent intervention (PI), and the combination of these two strategies (SCV + PI) to mitigate accelerated summer body mass index (BMI) gain. Feasibility (i.e., recruitment capability, retention, compliance, treatment fidelity, acceptability) was examined using means, standard deviations, and percentages for relevant variables. Changes in BMI were estimated using intent-to-treat and post-hoc dose response analyses via multilevel mixed effects regressions.ResultsA total of 89 families participated, with 24 participants randomized to the PI group, 21 randomized to the SCV group, 23 randomized to the SCV + PI group, and 21 randomized to the control. Parents and children found the summer program acceptable but attendance at the summer program and engagement in the PI were low due to COVID-19 and lack of transportation. Intent-to-treat analyses showed no statistically significant difference between groups in summer BMI gain. Post-hoc dose response analyses showed that for each day (0 to 29) of summer programming children attended they gained - 0.009 (95CI= -0.018, -0.001) less in BMI z-score.ConclusionsEngagement in both the SCV and PI was not ideal and was likely due to COVID-19 and lack of transportation. Providing children with structured summer programming to mitigate accelerated summer BMI gain may be an effective strategy. Thus, a larger trial may be warranted, but more work is needed to ensure children attend the programming.Trial registration: The trial reported herein was prospectively registered at clinicaltrials.gov. Trial #:NCT04608188.


Human tissue kallikrein 1 gene delivery inhibits PDGF-BB-induced vascular smooth muscle cells proliferation and upregulates the expressions of p27Kip1 and p2lCip1.
Tissue kallikrein 1 cleaves kininogen substrate to produce vasoactive kinin peptides that have been implicated in inhibiting neointimal hyperplasia in rat carotid arteries after balloon injury. However, its effects on the proliferation, cell cycle and its mechanisms, for example, cyclin-dependent kinase inhibitors, p27(Kip1) and p2l(Cip1) in vascular biology are poorly understood. The objective of this study was to explore the effects of human tissue kallikrein 1 (hTK1) mediated by recombinant adenovirus (Ad-hTK1) on proliferation and cell cycle of vascular smooth muscle cells (VSMCs) derived from spontaneously hypertensive rats induced by platelet-derived growth factor-BB (PDGF-BB) in vitro. The results showed that, within a given multiplicity of infection (MOI) and time, the hTK1 gene delivery inhibited PDGF-BB-stimulating VSMCs growth in a concentration-dependent (20-100 MOI) and time-dependent (2-5 days) manner by cell counting, with a peak inhibition rate at 36.3% at 72 h (P < 0.01). In addition, hTK1 gene delivery significantly suppressed PDGF-BB-induced proliferation of VSMCs by methyl thiazolyl tetrazoliuin assay, and decreased the percentage of cells in the S phase and in DNA synthesis by flow cytometry, with a peak inhibition rate at 30.2 and 36.4%, respectively (P < 0.01). Western blot assay showed that the protein levels of p27(Kip1) and p2l(Cip1) in cells infected with Ad-hTK1 were much more abundant than those in cells only induced by PDGF-BB, with up-modulating rates at 51.8 and 58.7%, respectively (P < 0.001). We also observed that the effects of hTK1 gene delivery in inhibiting VSMCs proliferation, arresting cell cycling in G(0)/G(1) phase and up-regulating the expression of p27(Kip1) and p2l(Cip1) could be blocked by icatibant (Hoe 140), a specific bradykinin B(2) receptor antagonist. Taken together, these results demonstrated that hTK1 overexpressed by recombinant adenovirus potently inhibits VSMCs proliferation that is required for neointimal hyperplasia and restenosis, and may activate p27(Kip1) and p2l(Cip1) signaling pathways via bradykinin B(2) receptor.


Difficulties in the differentiation of chronic inflammatory diseases of the central nervous system--value of cerebrospinal fluid analysis and immunological abnormalities in the diagnosis.
A number of neurological syndromes may be evoked by involvement of the nervous system due to systemic diseases such as lupus erythematodes, sarcoidosis, Behçet's disease and Sjögren's syndrome (SS) and may be confounded with another chronic inflammatory disease which is restricted to the central nervous system, e.g. multiple sclerosis (MS). Because of different treatment strategies, it is important to distinguish between these different autoimmune diseases. Neither clinical signs nor additional analyses such as serological findings or cerebrospinal fluid (CSF) analysis are able to differentiate between the diseases with certainty. Nevertheless, taking all findings together, diagnosis may be possible. Here we compare typical clinical and CSF findings in MS, neurosarcoidosis, neurolupus, neuro-Behçet and nervous system involving SS with special emphasis on those findings allowing differentiation of the respective diseases by reviewing the literature.


A Systematic Review of Adenoid Ameloblastoma: A Newly Recognized Entity.
Recently, a new odontogenic tumor has been described, the so-called adenoid ameloblastoma (AdAM). The aim of this review was to determine the clinical and imaging features of AdAM and to describe its main histopathological findings. The systematic review included published cases with a diagnosis of AdAM in the gnathic bones, which had sufficient clinical, imaging, and histopathological data to confirm its diagnosis. The following histopathological diagnostic criteria were adopted: presence of ameloblastoma-like components, duct-like structures, spiral cellular condensations, and a cribriform architecture. Fifteen articles, corresponding to 30 cases of AdAM, were selected. Most cases affected men (63.3%), with a slight preference for the mandible (16:14) and the posterior region of gnathic bones was the most commonly affected site. The mean age at diagnosis was 40.8 years. Clinically, the lesions usually presented as a swelling (53.3%) and, radiographically, as a well-defined radiolucency (33.4%). Surgical resection (40%) was the most frequently adopted treatment and recurrence occurred in 30% of cases. Microscopic examination showed cribriform areas in most AdAM cases (93.3%); duct-like structures and spiral cellular condensations were seen in 100% of the cases. The small number of reported cases, the existence of erroneous diagnoses, and the adoption of initial conservative management make it difficult to determine whether AdAM has a higher risk of recurrence or more aggressive biological behavior than conventional ameloblastomas.


[Role of metaflammation as a systemic manifestation of metabolic diseases].
Visceral obesity as a component of the metabolic syndrome is characterized by systemic and local inflammation, which can be quantified in organs (metaflammation). This process can be regarded as a chronic, sterile, and low-grade state of inflammation without infection, trauma, tumor or autoimmunity. It is caused by an inflammation of the visceral adipose tissue (adipose inflammation or adipoflammation) due to adipocyte hypertrophy and hyperplasia with increased infiltration by monocytes and macrophages. Important is the presence of proinflammatory, so-called polarized M1 macrophages that are induced by interferon gamma (IFN-γ) and lipopolysaccharides (LPS) with secretion of interleukin (IL)-6, tumor necrosis factor (TNF) and IL‑1. In contrast, the anti-inflammatory, so-called polarized M2 macrophages induced by IL‑4 and IL-13 with secretion of IL‑8 and IL-10 decrease. In addition, the secreted adipokine pattern changes from anti-inflammatory to proinflammatory. Adipocyte necrosis, local hypoxia, dysregulated autophagy, activation of inflammasomes, modulation of toll-like receptors, and epigenetic factors play a complex role. This mechanism results in local insulin resistance and subsequently a systemic insulin resistance of peripheral organs as well as a spillover of local mediators of inflammation into the systemic circulation (measured as obesity C‑reactive protein, CRP). The activation of inflammatory signal transduction cascades leads to inhibitory phosphorylation of the insulin signaling pathway and a weakening of the effect of insulin. In parallel, ectopic lipid accumulation occurs in the liver, musculature, pancreas, pericardium and lungs. Diacylglycerol (DAG) activates specific isoforms of protein kinase C (ε in the liver and τ in the musculature), which in turn lead to inhibition of the insulin signaling pathway. Insulin resistance in obesity and type 2 diabetes mellitus is an inflammatory disease. The aim of future translational approaches is an anti-inflammatory, molecularly individualized (precision medicine) treatment in adipose tissue (targeted therapy) and in organs of insulin resistance.


The 3' enhancer CNS2 is a critical regulator of interleukin-4-mediated humoral immunity in follicular helper T cells.
A main role for interleukin-4 (IL-4) is in humoral immunity, and follicular helper CD4(+) T (Tfh) cells may be an intrinsic IL-4 source. Here we demonstrate that conserved noncoding sequence 2 (CNS2) is an essential enhancer element for IL-4 expression in Tfh cells but not in Th2 cells. Mice with a CNS2 deletion had a reduction in IgG1 and IgE production and in IL-4 expression in Tfh cells. Tracking of CNS2 activity via a GFP reporter mouse demonstrated that CNS2-active cells expressed several markers of Tfh cells: CXCR5, PD-1, and ICOS; the transcriptional master regulator Bcl6; and the cytokines IL-21 and IL-4. These CNS2-active cells were mainly localized in B cell follicles and germinal centers. The GFP(+) Tfh cells were derived from GFP(-) naive T cells after in vivo systemic immunization. These results indicate that CNS2 is an essential enhancer element required for IL-4 expression in Tfh cells controlling humoral immunity.


Structure elucidation, in vitro binding studies and ROS-dependent anti-cancer activity of Cu(II) and Zn(II) phthaloylglycinate(phen) complexes against MDA-MB-231 cells.
New mononuclear Cu(II) and Zn(II)-based complexes 1 [Cu(L)2(diimine)HOCH3] and 2 [Zn(L)2(diimine)] have been synthesized as anti-cancer chemotherapeutics targeted to tRNA. The structure elucidation of complexes 1 and 2 was carried out by spectroscopic and single X-ray diffraction studies. In vitro interaction studies of complexes 1 and 2 with ct-DNA/tRNA were performed by employing various biophysical techniques to evaluate and predict their interaction behavior and preferential selectivity at biomolecular therapeutic targets. The corroborative results of the interaction studies demonstrated that complexes 1 and 2 exhibited avid binding propensity via intercalative mode of binding toward ct-DNA/tRNA. Electrophoretic assay revealed that the complexes 1 and 2 were able to promote single- and double-strand cleavage of the plasmid DNA at low micromolar concentrations under physiological conditions in the absence of an additional oxidizing or reducing agent. RNA hydrolysis studies revealed that the complexes 1 and 2 could promote tRNA cleavage in a concentration and time-dependent manner. The cytotoxic potential of complexes 1 and 2 was evaluated against the MDA-MB-231 cell line, which showed that the complexes were able to inhibit the cell growth in a dose-dependent manner. The intracellular ROS production and mitochondrial superoxide anion assay revealed that the complexes 1 and 2 induce a dose-dependent activity, suggesting the involvement of ROS-mediated mitochondrial apoptotic pathway leading to cell death.


Blood Glucose Levels and Mortality in Patients With Sepsis: Dose-Response Analysis of Observational Studies.
We undertook a systematic review and meta-analysis to investigate the relationship between blood glucose levels and mortality in patients with sepsis. Medline and EMBASE were searched from inception to April 8, 2018. Cohort studies or case-control studies reported the association between blood glucose and mortality in patients with sepsis were selected. Study characteristics, baseline characteristics, definition of hyperglycemia, and outcomes of interest were extracted. We performed a dose-response meta-analysis to assess the effect of blood glucose level on mortality. We also conducted meta-analysis for patients with or without diabetes separately. Ten cohort studies involving 26 429 patients were included, of which 5 were prospective studies and 5 retrospective studies. Dose-response analysis showed that the effect of blood glucose on mortality may differ in patients with versus without diabetes. There was a U-shaped relationship for patients with diabetes and a J-shaped relationship for patients without diabetes, with blood glucose at 145 to 155 mg/dL corresponding to lowest mortality both in patients with and without diabetes. Current evidence suggested U-shaped relationship between blood glucose and mortality in all patients irrespective of their diabetes status. Diabetic patients with blood glucose below 145 mg/dL may have poorer prognosis compared to patients without established diabetes.


Kelatorphan potentiates the effect of [Met5]enkephalin in the substantia gelatinosa of the cat spinal cord.
In anaesthetized spinal cats, kelatorphan, an inhibitor of enkephalin degradation, was administered microelectrophoretically while recording the excitation of lumbar dorsal horn neurones by noxious and innocuous peripheral stimuli. When administered near the cell bodies of laminae IV and V neurons, kelatorphan neither altered evoked responses nor potentiated the inhibition by [Met5]enkephalin of these cells. When ejected in the substantia gelatinosa, however, kelatorphan reduced the nociceptive responses of some laminae IV and V neurones, an effect blocked by electrophoretic naloxone. The selective inhibition of nociceptive responses by [Met5]enkephalin administered in the substantia gelatinosa was markedly potentiated by co-administration of kelatorphan, and this effect was also blocked by electrophoretic naloxone. Neurones inhibited by administration of kelatorphan alone in the substantia gelatinosa were excited by administration of naloxone alone at the same site. The results suggest that some dorsal horn neurones are tonically inhibited by an action of opioid peptides in the substantia gelatinosa, and indicate that enzymic degradation limits the action of both exogenous and endogenous enkephalin in this spinal region.