Insertion of Cochlear Implant Electrode Array Using the Underwater Technique for Preserving Residual Hearing.
To describe a method of cochlear implantation in which the opening of the cochlea and the electrode array insertion are performed under water (underwater technique). Retrospective patient review. Academic tertiary referral center. Fifteen implantations in children and adult patients with residual hearing at the frequencies 250, 500, and 1000 Hz on the unaided preoperative pure-tone audiometry were included in this study. Cochlear implantation with a conventional full-length electrode, in which the opening of the cochlea and the electrode array insertion are performed after the tympanic cavity was filled with body-temperature Ringer solution. Changes on residual hearing 6 to 8 weeks after surgery and at subsequent follow-up appointments were analyzed. Preservation of residual hearing was defined as measurable postoperative threshold at the frequencies 250, 500, and 1000 Hz. Overall postimplant hearing preservation 6 to 8 weeks after implantation was achieved in 13 of the patients (87%). Subsequent follow-up was performed on average 15.2 months after surgery (range, 7-32) in 14 out of 15 patients. At this late postoperative evaluation preservation of hearing was recorded in nine patients (64%), whereas in the remaining five patients (36%) no residual hearing was measured. The underwater technique offers a reliable nontraumatic method for electrode array insertions during cochlear implantation. The method respects the physiology of the cochlea und minimizes the pressure variations during cochlear opening and implantation.


A model chromatin assembly system. Factors affecting nucleosome spacing.
Poly[d(A-T)].poly[d(A-T)], when reconstituted with chicken erythrocyte core histones and subsequently incubated with sufficient histone H5 in a solution containing polyglutamic acid, forms structures resembling chromatin. H5 induces nucleosome alignment in about two hours at physiological ionic strength and 37 degrees C. The nucleosome spacing and apparent linker heterogeneity in the assembled nucleoprotein are very similar to those in chicken erythrocyte chromatin. Also, condensed chromatin-like fibers on the polynucleotide can be visualized. The binding of one mole of H5 per mole of core octamer is necessary to generate the physiological nucleosome spacing, which remains constant with the addition of more H5. The nucleosome repeat length is not a function of the core histone to poly[d(A-T)] ratio for values lower than the physiological ratio. With increasing ratios, in excess of the physiological value, nucleosome spacing first becomes non-uniform, and then takes on the close packing limit of approximately 165 base-pairs. In addition to eliminating possible base sequence effects on nucleosome positioning, poly[d(A-T)] allows nucleosomes to slide more readily than does DNA, thereby facilitating alignment. Evidence is presented that polyglutamic acid facilitates the nucleosome spacing activity of histone H5, primarily by keeping the nucleoprotein soluble. This model system should be useful for understanding how different repeat lengths arise in chromatin.


Cleavage of DNA containing 5-fluorocytosine or 5-fluorouracil by type II restriction endonucleases.
A systematic study of the cleavage of DNA sequences containing 5-fluorocytosine or 5-fluorouracil by type II restriction endonucleases (REs) was performed and the results compared with the same sequences containing natural pyrimidine bases, uracil or 5-methylcytosine. The results show that some REs recognize fluorine as a hydrogen on cytosine and cleave the corresponding sequences where the presence of m5dC leads to blocking of the cleavage. However, on uracil, the same REs recognize the F as a methyl surrogate and cleave the sequences which are not cleaved if uracil is incorporated instead of thymine. These results are interesting for understanding the recognition of DNA sequences by REs and for manipulation of the specific DNA cutting.


ROS in the local and systemic pathogenesis of COPD.
An imbalance between oxidants and antioxidants is proposed in the pathogenesis of COPD. Potential alterations responsible for an imbalance in oxidant production and intra- and extracellular antioxidant defense systems are discussed with respect to COPD-related changes in the pulmonary compartment. In line with the current view of COPD as a disease with multiple systemic consequences, there is increasing evidence that imbalances in the redox milieu extend beyond the diseased lung in COPD patients. Skeletal muscle dysfunction is often observed in COPD and may result from imbalances in the redox environment of skeletal muscle. Potential triggers of oxidative stress in the muscle compartment include inflammation and hypoxia, and local sources of reactive oxygen and nitrogen species are discussed, as well the mechanisms by which skeletal muscle trophical state, contractility and fatigability may be affected by oxidative stress, resulting in skeletal muscle dysfunction.


Antioxidant p-terphenyl compound, isolated from edible mushroom, Boletopsis leucomelas.
A new acetyl p-terphenyl derivative, boletopsin 15, was isolated from the ethyl acetate extract of fruit bodies of the Basidiomycete Boletopsis leucomelas, together with 4 known compounds. The structures of these compounds were elucidated by spectral analysis as well as by directly comparing the spectral data of the new compound with those of known compounds. The free radical-scavenging activity of the compounds was assayed using the 2,2-diphenyl-1-picrylhydrazyl scavenging method. The results showed that compounds 1 and 2 exhibited significant antioxidant activity (1: EC50 = 2.1 µm and 2: EC50 = 6.6 µm).


Cross-sectional study in Madagascar demonstrates efficacy of virtual mentoring and flipped classroom modifications of neonatal resuscitation programme Helping Babies Breathe.
The Covid-19 pandemic necessitated virtual adaptation of the neonatal resuscitation programme Helping Babies Breathe (HBB). This study assessed one such virtually mentored and flipped classroom modification in Madagascar. A cross-sectional study was performed in September 2021 and May 2022. Healthcare providers were identified by local collaborating organisations. United States-based master trainers collaborated with local trainers on virtually mentored trainings followed by independent trainings. Master trainers were available for consultation via Zoom during the virtual training. A flipped classroom modification and traditional didactic method were compared. Primary outcomes were knowledge and skill acquisition, evaluated by written assessments and objective structured clinical examinations. Overall, 97 providers completed the curriculum. Written assessment scores improved in both training models (traditional-74.8% vs 91.5%, p < 0.001; flipped classroom-89.7% vs 93.6%, p < 0.05). There was no significant difference among written assessment scores (92.8% vs 91.5%, p = 0.62) and significantly higher objective structured clinical examination scores (97.3% vs 89.5%, p < 0.001) for the independent training compared to the virtually mentored training. The virtually mentored HBB training was followed by a successful independent training as measured by participant knowledge and skill acquisition, supporting the efficacy of virtual dissemination.


Mitral valve prolapse syndrome and its association with anxiety and panic States.
Mitral Valve Prolapse Syndrome is one of the most frequent cardiac valvular abnormalities in general population. Mostly the patients remain asymptomatic but a few may suffer from hyperadrenergic panic states, similar to anxiety attacks. In psychiatric practice, a number of physicians have come across this finding during the recent past. Present article deals with two such case illustrations.


Stellate fibrin-fibronectin microclot formation from keratinocytes and fibroblasts stimulated by plasma from patients with psoriasis.
Plasma from patients with active psoriasis has been shown to induce the formation of stellate fibrin-fibronectin microclots in vitro around cultured keratinocytes and fibroblasts. Such a stellate radiation of fibronectin and fibrin was also demonstrated around monocytes from patients with psoriasis. The phenomenon was not observed in healthy subjects but has been found in various disorders.


The need for social support provided by the non-profit cancer societies throughout different phases in the cancer trajectory and its integration into public healthcare.
To describe the phases of the cancer trajectory when social support, in the form of electronic counselling services, as provided by the non-profit cancer societies, is needed, as well as how these services are integrated into the cancer care in public healthcare. In this descriptive qualitative study a purposive sample of patients with cancer (n = 12) were interviewed. The data were content analysed inductively. Social support was needed when emotional well-being was weakened, when the body broke, when the care pathway induced unawareness, and when empowerment needed strengthening. There was no need for social support when well-being was considered in balance. The electronic counselling services were integrated into cancer care by supporting the patient with cancer emotionally, developing the informational expertise of the patient with cancer, expanding the opportunities for support, and supporting public healthcare. Integration required improvements to the actions of the patients and various actors involved in the healthcare system. There was no integration due to the health status of the patient and the sufficiency of the primary support sources. The received social support was not integrated into the actual cancer treatment process of the patient with cancer in the public healthcare system. The phases of support needed in the cancer trajectory as defined by the patient differ from the traditional biomedical phases of treatment.


Effect of increasing doses of aspirin on platelet function as measured by PFA-100 in patients with diabetes.
Platelets of diabetic patients have been reported to be less sensitive to aspirin. The aim of this study is to compare a medium (300 mg) and low (100 mg) dose of aspirin on platelet function in diabetic patients. We have included one hundred and two patients with type 2 diabetes mellitus. Platelet function was measured as closure time (CT) with the Platelet Function Analyzer (PFA)-100 before the administration of aspirin. Initially the patients were given 100 mg aspirin once daily for seven days, and then the measurements were repeated. If the CT exceeded the upper limit of 300 s, the study was terminated. If not, the patients continued the aspirin therapy with a dose of 300 mg daily for another seven days, and the CTs were measured again. After taking 100 mg aspirin, the CT significantly increased from 126+/-29 s to 256+/-66 s (p<0.001). In 68 of 102 (67%) patients, the CT increased to 300 s. In the remaining 34 patients, the baseline CT was 113+/-29, and increased to 170+/-45 s after 100 mg aspirin (p<0.001). In these patients, there was a further increase in the CT from 170+/-45 to 229+/-75 s following 300 mg aspirin (p<0.001). On average, the CT was increased by 60% and 39% following ingestion of 100 and 300 mg aspirin, respectively. CT>300 s were obtained in 15 (44%) of 34 patients after 300 mg aspirin. Although, a daily dose of 100 mg aspirin effectively inhibited platelet function in a majority of diabetics, a considerable proportion of patients showed a greater platelet inhibition with the use of 300 mg aspirin. The PFA-100 closure time may be used to separate those patients who require a higher dose of aspirin to achieve desired antiplatelet effect.


The spontaneously diabetic Wistar rat (the "BB" rat): the significance of transient glycosuria.
A longitudinal study of thirteen rats with transient and intermittent episodes of glycosuria was undertaken, to further characterize the "BB" diabetic syndrome. "Chemical diabetes" (normal fasting glycemia, abnormal GTT) was observed in five rats, accompanied by the same dramatic insulitis previously reported in this syndrome, in two of the three pancreases examined. Progression from "chemical" to overt diabetes occurred in one of these rats. Two other patterns of presentation were observed. Periods of complete remission occurred in four rats with diabetes considered sufficiently severe to warrant previous treatment with insulin. Four additional rats with previous glycosuria (untreated) showed no abnormalities on followup. It is not known whether hyperglycemia accompanied the glycosuria in these rats, and renal glycosuria has not been excluded. Thus, the "BB" diabetic syndrome exists in not only the overt and "chemical" forms, but may also present with transient glycosuria, followed by a variety of subsequent progressions.


Fibromuscular dysplasia: what the radiologist should know: a pictorial review.
Fibromuscular dysplasia (FMD) is an idiopathic, segmentary, non-inflammatory and non-atherosclerotic disease that can affect all layers of both small- and medium-calibre arteries. The prevalence of FMD is estimated between 4 and 6 % in the renal arteries and between 0.3 and 3 % in the cervico-encephalic arteries. FMD most frequently affects the renal, carotid and vertebral arteries, but it can theoretically affect any artery. Radiologists play an important role in the diagnosis of FMD, and good knowledge of FMD's signs will certainly help reduce the delay between the first symptoms and diagnosis. The common string-of-beads aspect is well known, but less common presentations also have to be considered. These less common imaging findings include vascular loops, fusiform vascular ectasia, arterial dissection, aneurysm and subarachnoid haemorrhage. These radiologic presentations should be known by radiologists in order to diagnose possible FMD, particularly when present in young females or when associated with personal or familial hypertension, to reduce the delay between the onset of the first symptom and the final diagnosis. The patients have to be referred to specialised FMD centres for dedicated management. • Fibromuscular dysplasia is not a rare disease. • Radiologists should recognise less common presentations to orient specific management. • Vascular loops, fusiform vascular ectasia and a "string-of-beads" aspect are typical presentations. • Arterial dissection, aneurysm and subarachnoid haemorrhage are less typical radiologic presentations.


[Group-specific antibodies against zearalenone and its metabolites and synthetic analogs].
Formation kinetics, specificity, and analytical potential of polyclonal antibodies raised in rabbits against BSA conjugates of carboxymethyloxime-zearalanone (CMO-ZAN) and carboxymethyloxime-zearalenone (CMO-ZEN). Preparation of the conjugates involved conversion of CMO-ZAN and CMO-ZEN into activated esters and carbodiimide condensation. Two versions of a group-specific enzyme immunoassay (for zearalenone/alpha-zearalenone and zearalanol/alpha-zearalanol) based on heterologous combination of solid-phase antigens are described (sensitivity, 0.01 ng/ml).


Biomass allocation, relative competitive ability and water use efficiency of two dominant species in semiarid Loess Plateau under water stress.
A better understanding of the growth and interspecific competition of native dominant species under water stress should aid in prediction of succession in plant communities. In addition, such research would guide the selection of appropriate conservation and agricultural utilization of plants in semiarid environments that have not been very well characterized. Biomass production and allocation, relative competitive ability and water use efficiency of one C(4) herbaceous grass (Bothriochloa ischaemum) and one C(3) leguminous subshrub (Lespedeza davurica), both important species from the semiarid Loess Plateau of China, were investigated in a pot-cultivation experiment. The experiment was conducted using a replacement series design in which B. ischaemum and L. davurica were grown with twelve plants per pot, in seven combinations of the two species (12:0, 10:2, 8:4, 6:6, 4:8, 2:10, and 0:12). Three levels of water treatments included sufficient water supply (HW), moderate water stress (MW) and severe water stress (LW). These treatments were applied after seedling establishment and remained until the end of the experiment. Biomass production and its partitioning, and transpiration water use efficiency (TWUE) were determined at the end of the experiment. Interspecific competitive indices (competitive ratio (CR), aggressiveness (A) and relative yield total (RYT)) were calculated from the dry weight for shoots, roots and total biomass. Water stress decreased biomass production of both species in monoculture and mixture. The growth of L. davurica was restrained in their mixtures for each water treatment. L. davurica had significantly (P<0.05) greater root:shoot allocation than B. ischaemum for each water treatment and proportion within the replacement series. Aggressiveness (A) values for B. ischaemum with respect to L. davurica were negative only at the proportions of B. ischaemum to L. davurica being 8:4 and 10:2 in LW treatment. B. ischaemum had a significantly (P<0.05) higher CR value under each water treatment, and water stress considerably reduced its relative CR while increased that of L. davurica. RYT values of the two species indicated some degree of resource complimentarity under both water sufficient and deficit conditions. The results suggest that it is advantageous for growing the two species together to maximize biomass production, and the suggested ratio was 10:2 of B. ischaemum to L. davurica because of significantly higher (P<0.05) RYT and TWUE under low water availability condition.


Knowledge of multidrug-resistant tuberculosis amongst Durban University of Technology students in KwaZulu-Natal, South Africa: the need for integrating public health education.
Kwazulu-Natal is the epicenter of South Africa's Multidrug-resistant Tuberculosis (MDR-TB) burden which represents a growing threat to public health. Knowledge and awareness of MDR-TB are crucial for effective management and University students are an important vehicle for knowledge transfer of public health education. This study aimed to evaluate the knowledge of MDR TB and risk factors for transmission, prevention, treatment and control of MDR-TB among Durban University of Technology (DUT) students. This quantitative cross-sectional study was conducted among 150 randomly sampled undergraduate students from 3 faculties and data was collected using a validated questionnaire. While a majority of participants (70.67%) had previous knowledge on TB, only 30.67% knew of MDR-TB. Only 23.49% of students reported knowledge of preventative measures associated with MDR TB. Women had a lower probability of having knowledge of MDR-TB compared to men (OR=0.45; CI:0.22,0.95; p<0.05) and students from the Accounting and Informatics faculty were less likely to believe that MDR-TB was a life-threatening illness (OR=0.24; CI:0.05,1.44; p<0.05) and showed limited knowledge of MDR-TB transmission. This study showed that students lacked knowledge of MDR-TB with respect to risk factors, treatment and prevention, which necessitates intervention strategies at a tertiary level to educate and inform students about MDR-TB.


Effects of dorsolateral prefrontal cortex stimulation on network topological attributes in young individuals with high-level perceived stress: A randomized controlled trial.
Individuals with high-level perceived stress are at higher risk of developing a psychiatric disorder. While repetitive transcranial magnetic stimulation (rTMS) is effective for improving emotional symptoms, there is little evidence of its effect on perceived stress. This randomized sham-controlled trial investigated the effect of rTMS on ameliorating high-level stress and explored the associated changes in brain network activity. Fifty participants with high-level perceived stress were randomly assigned to either the active or sham rTMS group and received 12 active/sham rTMS sessions over four weeks (three per week). Perceived stress score (PSS), Chinese affective scale (CAS) normal and now statuses, and functional network topology were measured. Our results showed greater improvements in PSS and CAS_Normal scores, and reduced path length in the default mode network after active rTMS. Functional activations of the angular gyrus, posterior insula, and prefrontal cortex were also modulated in the active group. There were significant associations between posterior insula efficiency and PSS scores, and between angular efficiency and CAS_Now scores in the active group. These cumulative findings suggest rTMS as a promising intervention for recovery from high-level perceived stress.


Infections and infestations of the gastrointestinal tract. Part 1: bacterial, viral and fungal infections.
The purpose of this article is to review the imaging findings of various infections affecting the gastrointestinal tract. Barium examinations, computed tomography (CT), magnetic resonance imaging (MRI), and ultrasonography all play an important role in the diagnostic workup of gastrointestinal tract infections. Knowledge of differential diagnosis, sites of involvement, and typical imaging features of different infections can help in accurate diagnosis and guide treatment.


Quality of care, risk management, and technology in obstetrics to reduce hospital-based maternal mortality in Senegal and Mali (QUARITE): a cluster-randomised trial.
Maternal mortality is higher in west Africa than in most industrialised countries, so the development and validation of effective interventions is essential. We did a trial to assess the effect of a multifaceted intervention to promote maternity death reviews and onsite training in emergency obstetric care in referral hospitals with high maternal mortality rates in Senegal and Mali. We did a pragmatic cluster-randomised controlled trial, with hospitals as the units of randomisation and patients as the unit of analysis. 46 public first-level and second-level referral hospitals with more than 800 deliveries a year were enrolled, stratified by country and hospital type, and randomly assigned to either the intervention group (n=23) or the control group with no external intervention (n=23). All women who delivered in each of the participating facilities during the baseline and post-intervention periods were included. The intervention, implemented over a period of 2 years at the hospital level, consisted of an initial interactive workshop and quarterly educational clinically-oriented and evidence-based outreach visits focused on maternal death reviews and best practices implementation. The primary outcome was reduction of risk of hospital-based mortality. Analysis was by intention-to-treat and relied on the generalised estimating equations extension of the logistic regression model to account for clustering of women within hospitals. This study is registered with ClinicalTrials.gov, number ISRCTN46950658. 191,167 patients who delivered in the participating hospitals were analysed (95,931 in the intervention groups and 95,236 in the control groups). Overall, mortality reduction in intervention hospitals was significantly higher than in control hospitals (odds ratio [OR] 0·85, 95% CI 0·73-0·98, p=0·0299), but this effect was limited to capital and district hospitals, which mainly acted as first-level referral hospitals in this trial. There was no effect in second-level referral (regional) hospitals outside the capitals (OR 1·02, 95% CI 0·79-1·31, p=0·89). No hospitals were lost to follow-up. Concrete actions were implemented comprehensively to improve quality of care in intervention hospitals. Regular visits by a trained external facilitator and onsite training can provide health-care professionals with the knowledge and confidence to make quality improvement suggestions during audit sessions. Maternal death reviews, combined with best practices implementation, are effective in reducing hospital-based mortality in first-level referral hospitals. Further studies are needed to determine whether the benefits of the intervention are generalisable to second-level referral hospitals. Canadian Institutes of Health Research.


Role of relationship between HbA1c, fibrinogen and HDL-cholesterol on cardiovascular disease in patients with type 2 diabetes mellitus.
To assess the impact of relationship between glycated hemoglobin (HbA(1c)), fibrinogen and HDL-cholesterol (HDL-c) on cardiovascular disease in type 2 diabetes. We investigated i) the relationship of HbA1c, fibrinogen and HDL-c in 375 coronary artery disease (CAD)-negative and 320 CAD-positive diabetic patients and ii) the association between clustering of these three factors and incident major cardiovascular events in 317/320 CAD-positive patients. i) The relationships between HbA1c and both fibrinogen and HDL-c and between HDL-c and fibrinogen were significant only in CAD-positive patients (β = 10.655, p = 0.002; β = -1.056, p = 0.013; β = -1.751, p = 0.000008, respectively); ii) patients with worse-than-median levels of the three factors showed higher risk for major cardiovascular events than others (HR: 2.22, 95%CI = 1.23-4.02, p = 0.008). Both findings were independent of LDL-c, blood pressure or ongoing therapies. Our findings suggest interwoven actions of poor glycemic control, low grade inflammation and low HDL-c on atherosclerotic processes in type 2 diabetes.


The cytokine basis of cachexia and its treatment: are they ready for prime time?
Cachexia is a hypercatabolic condition that is often associated with the terminal stages of many diseases, in which the patient's resting metabolic rate is high and loss of muscle and fat tissue mass occur at an alarming rate. The patient also usually has concurrent anorexia, amplifying the wasting syndrome that is cachexia. The greater the extent of cachexia (regardless of underlying disease), the worse the prognosis. Efforts to treat cachexia over the years have fallen short of satisfactorily reversing the wasting syndrome. This article reviews the pathophysiology of cachexia, enumerating the different pro-inflammatory cytokines that contribute to the syndrome and attempting to illustrate their interwoven pathways. We also review the different treatments that have been explored, as well as the recent literature addressing the use of anti-cytokine therapy to treat cachexia.


Mechanism and origins of regioselectivities of Rh-catalyzed alkenylation of allylbenzenes.
Rhodium-catalyzed alkenylation of allylbenzene derivatives via C-C bond activation provides an unprecedented access to alkenylation products with remarkable regioselectivities. Using DFT calculations, we elucidate the reaction mechanism and the origins of the regioselectivity.


Stress: metaplastic effects in the hippocampus.
Memory impairments, which occur regularly across species as a result of aging, disease and psychological insults (for example, stress), constitute a useful area for investigation into the neurobiological basis of learning and memory. Memory researchers have identified the hippocampus as a crucial brain structure involved in key aspects of memory formation. The most widely accepted putative mechanisms of memory storage in this structure are LTP and LTD. The hippocampus is enriched with receptors for corticosterone (a glucocorticoid hormone released in response to stress) and it plays a role in glucocorticoid negative feedback and, therefore, some hippocampal functioning might be particularly susceptible to stress. In support of this view, stress-induced modifications in learning, synaptic plasticity and endangerment of neurons have been seen in the hippocampus. Stress and glucocorticoids appear to exert a metaplastic effect through the modulation of Ca2+ levels. We propose a synaptic model that provides a conceptual scaffold to structure our understanding of the manifold actions of stress on the hippocampus. Accordingly, we suggest that stress-induced metaplasticity could disrupt Ca2+ homeostasis and thus endanger hippocampal neurons.


The Montreal cognitive assessment as a cognitive screening tool in sickle cell disease: Associations with clinically significant cognitive domains.
Adults with sickle cell disease (SCD) are at risk for cognitive impairment, which causes significant morbidity. Guidelines support routine cognitive screening, but no screening test is validated in this population. We explored the Montreal Cognitive Assessment (MoCA) as a possible screening test in SCD. We administered the MoCA; a literacy test, the Wide Range Achievement Test, fourth edition (WRAT-4); and a health literacy test, the Shortened Test of Functional Health Literacy in Adults (S-TOFHLA) to adults with SCD and gathered clinical variables through chart review. Spearman's rho, Mann-Whitney, and Kruskal-Wallis tests and quantile regression models were used. Among our sample of 49 adults with SCD, the median MoCA score was 25.0 [interquartile range (IQR) 22.0-28.0]. Higher educational attainment was associated with MoCA scores (p = 0.001). In multivariable models, MoCA scores were associated with S-TOFHLA (p = 0.001) and WRAT-4 Reading (p = 0.002) scores, and overt stroke (p = 0.03) at the median. This pilot study adds to the limited literature of cognitive screening tests in adults with SCD and demonstrates a relationship between MoCA scores and measures of literacy and health literacy. The MoCA is a promising option for briefly screening for cognitive impairment in adults with SCD, though further study is needed to confirm its validity.


Folic acid fortification of flour to prevent neural tube defects in Europe - A position statement by the European Board and college of obstetrics and gynaecology (EBCOG).
Neural tube defects are disabling birth defects developing during the very early stages of conception. Children born with spina bifida face significant physical, psychological and social consequences. They may have bowel and urinary dysfunction, and no lower limb muscle control, resulting in lifelong wheelchair use. There is robust evidence that periconceptual folic acid supplementation prevents neural tube defects, when compared with no intervention. However, approximately 40% pregnancies in Europe are unplanned, and women may therefore not be taking prophylactic folic acid at the time of conception. There is evidence that low dose folic acid consumption via flour fortification provides further benefits in prevention of neural tube defects.


POEGMA-based disulfide-containing fluorescent probes for imitating and tracing noninternalization-based intracellular drug delivery.
POEGMA-based disulfide-containing fluorescent probes were designed and synthesized to enable the real-time and quantitative analysis of the (bio)reduction of disulfides within the polymeric backbones in complex redox media and in the presence of cells. This study lights up the way of exploiting bioreduction in the extracellular spaces for the delivery of hydrophobic drugs.


Assembly of CdS nanoparticles in patterned structures by a novel ion-entrapment process in thermally evaporated fatty acid films.
The formation of cadmium sulfide nanoparticle assemblies in a patterned manner on suitable substrates is described. The protocol for realizing such structures comprises the following steps. In the first step, patterned films of a fatty acid are thermally evaporated onto solid supports using suitable masks (e.g., a transmission electron microscope grid). Thereafter, the fatty acid film is immersed in cadmium sulfate solution and Cd2+ ions entrapped in the lipid matrix by electrostatic complexation with the carboxylate ions of the fatty acid molecules. The final step involves reaction of the entrapped Cd2+ ions with Na2S, leading to the in situ generation of cadmium sulfide nanoparticles within the patterned lipid matrix. This approach shows promise for generating patterned nanoparticle assemblies of different chemical compositions.


The dopamine D3 receptor antagonists PG01037, NGB2904, SB277011A, and U99194 reverse ABCG2 transporter-mediated drug resistance in cancer cell lines.
The ATP - binding cassette (ABC) family G2 (ABCG2) transporters are known to produce multidrug resistance (MDR) in cancer, thereby limiting the clinical response to chemotherapy. Molecular modeling data indicated that certain dopamine (DA) D3 receptor antagonists had a significant binding affinity for ABCG2 transporter. Therefore, in this in vitro study, we determined the effect of the D3 receptor antagonists PG01037, NGB2904, SB277011A, and U99194 on MDR resulting from the overexpression of ABCG2 transporters. The D3 receptor antagonists, at concentrations >100 μM, did not significantly affect the viability of H460-MX20, S1M1-80, A549-MX10 or wild type ABCG2 overexpressing (HEK293-R2) cells. However, at concentrations ranging from 0.01 to 10 μM, the D3 receptor antagonists PG01037, NGB2904, SB-277011A, and U99194 significantly increased the efficacy of the anticancer drugs mitoxantrone and doxorubicin in ABCG2-overexpressing MDR cells. Efflux studies indicated that both PG01037 and NGB2904, at a concentration of 5 μM, significantly decreased the efflux of rhodamine 123 from H460-MX20 cells. Interestingly, 5 μM of PG01037 or NGB2904 significantly decreased the expression levels of the ABCG2 protein, suggesting that these compounds inhibit both the function and expression of ABCG2 transporters at non-toxic concentrations.


Structure related to function: prefrontal surface area has an indirect effect on the relationship between amygdala volume and trait neuroticism.
Trait neuroticism refers to individual differences in negative emotional response to threat, frustration, or loss, operationally defined by elevated levels of irritability, anger, sadness, anxiety, worry, hostility, self-consciousness, and vulnerability to mental and physical difficulties. While functional studies have been fairly consistent when identifying regions associated with neuroticism during emotional stimuli, structural imagining studies do not tend to find a relationship between amygdala volume and trait neuroticism. There is a great deal of functional evidence that frontoparietal areas are related to the amygdala, and to emotional reactivity more generally, as a function of their involvement in emotion regulation. Specifically, top-down emotion appraisal and expression appear to involve parts of the dorsolateral and dorsomedial prefrontal cortices, which operate at least in part via the indirect modulation of the amygdala. It was hypothesized that cortical surface area and cortical thickness in regions associated with emotion appraisal/expression and emotional attention (i.e., superior frontal and rostral middle frontal gyri, respectively) would have an indirect effect on the relationship between amygdala volume and self-reported neuroticism (respectively), potentially explaining the inconsistency in the structural literature. In sample of 1106 adults, superior frontal and rostral middle frontal gyri, as parcellated by Freesurfer, were examined as potentially restricting variance in a model of indirect effects, which may elucidate the overall relationship between cortical and subcortical gray matter volume and trait neuroticism. Results indicated that, despite no association between bilateral amygdala volume and trait neuroticism, when right superior frontal surface area was entered into the model of indirect effects, a significant relationship between amygdala volume and trait neuroticism emerged. Two of the three remaining models indicated that cortical surface area had an indirect effect on the relationship between amygdala volume and trait neuroticism. These findings highlight the relationship between structural and functional neuroimaging studies. Specifically, the results indicate that when volume is related to behavior, individual differences in higher-order cortical regions, particularly surface area, may help to better understand the relationship between emotion and subcortical gray matter volume.


Differences in the reported frequencies of some obstetrical interventions in Europe.
Answers to a questionnaire on perinatal practices in countries of the WHO European region revealed rates of operative delivery ranging from about 6 to 24%. When the caesarean section rates were compared with the rates of forceps and vacuum extraction for each country, no systematic trend was found. There was a slight negative correlation between the frequencies of operative delivery and national perinatal mortality rates, but this accounts for only a small amount of the inter-country variation in perinatal mortality rates. The frequencies of induction of labour ranged from 12 to 36% in four countries with reliable national data. Relatively few European countries have population-based statistical data on the frequencies of caesarean section, forceps delivery and vacuum extractions. The national recording of induction of labour is unusual. Considering the medical and psycho-social impact of these procedures, we suggest national or regional monitoring.


Inhibitors of adenosine catabolism improve recovery of dog myocardium after ischemia.
The effects of inhibitors of adenosine catabolism on contractile function and metabolites were assessed during 15 minutes of ischemia followed by 30 minutes of reperfusion in the open-chest dog heart. As compared to sham treatment, pretreatment with erythro-9-(2-hydroxy-3-nonyl)adenine (EHNA) and dipyridamole (DP) protected contractile function during ischemia, and improved recovery of high energy phosphate content and contractile function during reperfusion following ischemia. Testing EHNA and DP in a free-radical generating system indicated both compounds have some scavenging ability, suggesting the effect of EHNA + DP may not be on adenosine nucleotide metabolism alone. Comparison of end diastolic segment lengths to contractile function indicated the results were not affected by changes in preload resulting from peripheral vasodilation.


An All-Scale Hierarchical Architecture Induces Colossal Room-Temperature Electrocaloric Effect at Ultralow Electric Field in Polymer Nanocomposites.
Composed of electrocaloric (EC) ceramics and polymers, polymer composites with high EC performances are considered as promising candidates for next-generation all-solid-state cooling devices. Their mass application is limited by the low EC strength, which requires very high operational voltage to induce appreciable temperature change. Here, an all-scale hierarchical architecture is proposed and demonstrated to achieve high EC strength in poly(vinylidene fluoride-trifluoroethylene-chlorofluoroethylene)-based nanocomposites. On the atomic scale, highly polarizable hierarchical interfaces are induced by incorporating BiFeO3 (BFO) nanoparticles in Ba(Zr0.21 Ti0.79 )O3 (BZT) nanofibers (BFO@BZT_nfs); on the microscopic scale, percolation of the interfaces further raises the polarization of the composite nanofibers; on the mesoscopic scale, orthotropic orientation of BFO@BZT_nfs leads to much enhanced breakdown strength of the nanocomposites. As a result, an ultrahigh EC strength of ≈0.22 K m MV-1 is obtained at an ultralow electric field of 75 MV m-1 in nanocomposites filled with the orthotropic composite nanofibers, which is by far the highest value achieved in polymer nanocomposites at a moderate electric field. Results of high-angle annular dark-field scanning transmission electron microscopy, in situ scanning Kelvin probe microscopy characterization, and phase-field simulations all indicate that the much enhanced EC performances can be attributed to the all-scale hierarchical structures of the nanocomposite.


Sensitivity to photoperiod in Aelia acuminata (L.) after adult diapause.
The sensitivity to photoperiod of Aelia acuminata after diapause was proved. In order to reproduce females need a continuous stimulation by a diapause averting photoperiod. If kept under a diapause promoting photoperiod they stop ovipositing after about 3 weeks.


SCFs in the new millennium.
Substrate-specific degradation is a key feature of the ubiquitin proteasome system. Substrate specificity is typically directed by the E3 or ubiquitin ligase; such specificity can be conferred either by ligase modification or expression or conversely via modification of substrates that permit their recognition by a specific E3 ligase. The most well-known example of such complexes are the Cullin-RING ligases (CRLs). CRLs are composed of one of seven cullin-family scaffold proteins; the CRL serves as a scaffold that interacts directly with a RING-domain enzyme (Rbx1/2) through an extensive protein-protein interface within the globular C-terminal domain. At the N terminus, the cullin associates with an adaptor protein through cullin-repeat motifs. This adaptor, in turn, facilitates recruitment of a substrate-specifying factor that recruits the target to be ubiquitylated. The prototypical CRL is the cul1-containing complex, commonly referred to as the Skp1-Cul1-Fbox (SCF) ligase. SCF ligases contribute to the timely destruction of numerous substrates thereby ensuring normal cell growth. The importance of SCF function is highlighted by cancer-specific alterations in either the expression or the function of select F-box substrate-specific adaptors that results in neoplastic conversion. Herein, we discuss the current understanding of SCF function and contribution to cell biology.


Dopamine and octopamine in whole body extracts of the bulb mite.
Using high performance liquid chromatography with electrochemical detection, whole body extracts of the bulb mite, Rhizoglyphus echinopus (Fumouze and Robin), were found to contain the biogenic amines dopamine and octopamine at concentrations of 4.3 +/- 0.6 and 2.3 +/- 1.4 ng g-1 wet weight, respectively. Adrenaline, noradrenaline, tyramine, N-methyldopamine, N-acetyldopamine, and 5-hydroxytryptamine, if present, were below the limits of detectability. This is the initial demonstration of the presence of octopamine in a mite species.


Citric acid promotes disulfide bond formation of whey protein isolate in non-acidic aqueous system.
Impacts of citric acid (CA) treatment under non-acidic conditions (pH 7.0, 8.0 and 9.0) on whey protein isolate (WPI) were examined in this study. Size exclusion chromatography and SDS-PAGE indicated that molecular size and weight of WPI-CA became larger at pH 7.0, 8.0 and 9.0 with CA ranged from 0 to 15 mg/mL, but the protein aggregates disappeared after β-mercaptoethanol was added. The free SH groups of WPI-CA gradually decreased. This could be deduced that CA could promote disulfide bond formation of WPI at the non-acidic pH values. Furthermore, fourier transform infra-red (FTIR) spectroscopy and fluorescence spectroscopy data confirmed the conformational changes of secondary and tertiary structures of CA-modified WPI, respectively. Therefore, these results suggested that disulfide bond formation of WPI occurred at citric acid treatment under non-acidic conditions, being contributed to production of its larger molecular size substances and alteration of its structural characteristics.


Larson-Penston Self-similar Gravitational Collapse.
Using numerical integration, in 1969 Penston (Mon Not R Astr Soc 144:425-448, 1969) and Larson (Mon Not R Astr Soc 145:271-295, 1969) independently discovered a self-similar solution describing the collapse of a self-gravitating asymptotically flat fluid with the isothermal equation of state p = k ϱ , k > 0 , and subject to Newtonian gravity. We rigorously prove the existence of such a Larson-Penston solution.


Innovative community-based initiatives to engage VFR travelers.
This report describes novel initiatives to inform ethnic groups contributing high numbers of VFRs about potential travel risks. Multilingual and culturally appropriate information was distributed to the media (newspaper, radio, web-based, and television), via printed materials (posters, tear sheets and z-cards) and at community festivals to convey simple travel health messages.


MINOCA Phenotypes - A Challenge for Patient-Specific Management.
Myocardial infarction with non-obstructive coronary arteries (MINOCA) is a puzzling clinical phenomenon with an unclear prognosis, characterized by evidence of myocardial infarction (MI) with normal or near-normal coronary arteries on angiography1. Currently, there are no guidelines for management, and many patients are discharged without a determined etiology, often meaning that optimal treatment gets postponed.We report three MINOCA case studies with main pathophysiological cardiac causes, particularly epicardial, microvascular, and non-ischemic, prompting differential management. The patients presented with acute chest pain, troponin raise, and no angiographically significant coronary disease.In this study, we analyzed the etiology, clinical diagnosis, and treatment of MINOCA concerning the relevant literature.MINOCA is considered to be a dynamic working diagnosis, including coronary, myocardial, and non-coronary disorders. Prospective studies and registries are needed to improve patient care and outcome.


Underwater EMR of adenomas of the appendiceal orifice (with video).
EMR of adenomas involving the appendiceal orifice (AO) is controversial because of a high risk of perforation and incomplete resection. We evaluated the feasibility, safety, and outcomes of underwater EMR (UEMR) without submucosal injection for the treatment of adenomas involving the AO. This was a prospective, observational study of a standardized UEMR technique without submucosal injection for adenomas involving the AO in 27 consecutive patients meeting inclusion and exclusion criteria. Surveillance colonoscopy included biopsy sampling of the EMR site and base of the AO. Main outcome measurements include technical success, histology, resection time, adverse events, and follow-up data. Over 42 months, UEMR of adenomas involving the AO (rim, 5 patients; inside, 22 patients) was attempted in 27 consecutive patients. Median adenoma size was 15 mm (range, 8 to 50). UEMR was successful in 24 patients (89%). Four patients were referred to surgery, 3 with UEMR failure because of an inability to exclude the adenoma extending into the appendix at the index procedure and 1 with invasive adenocarcinoma in the UEMR specimen. The median resection time was 3 minutes (range, 1 to 75). Adverse events consisted of postpolypectomy syndrome in 2 patients (7%). There was no perforation, bleeding requiring transfusion, or appendicitis. Final histology was tubular adenoma (7), tubulovillous adenoma (4), sessile serrated adenoma (15), and invasive adenocarcinoma (1). Twenty-one of 23 patients (91%), not referred to surgery, had follow-up colonoscopy with biopsy sampling of the resection site after a median of 29 weeks (range, 12 to 139) after resection. Residual adenoma was found in 2 of 21 patients (10%). On an intention-to-treat basis, UEMR without submucosal injection enabled safe and complete endoscopic resection of AO lesions. Close surveillance for residual or recurrence is warranted. ( NCT01750619.).


Removal of methanol from water by capacitive deionization system combined with functional nanoporous graphene membrane.
In this article, molecular dynamics simulations were used to examine the feasibility of capacitive deionization (CDI) system combined with a functionalized nanoporous graphene (NPG) membrane for removing methanol from water. The radial distribution function of electrode-methanol and methanol-water, the self-diffusion coefficient of methanol and water, the water density near the membrane, the interaction energy between methanol and membrane, the hydrogen bond structure between methanol and water, and the 2D density map of methanol molecules near the membrane under different electric field (EF) (to simulate the effect of capacitance) were examined to evaluate the separation performance of NPG membranes with hydrogen-passivated pores for methanol. The findings show that an EF with appropriate strength can decrease the amount of water molecules near methanol, increase the self-diffusion coefficient of methanol and water, increase hydrophobicity of hydrogenated pores, decrease the interaction between the NPG membrane and methanol, and weaken hydrogen bond interaction between water and methanol molecules. All these findings suggest that an appropriate EF can improve the NPG membrane's permeability to methanol, and verify the feasibility of CDI system combined with hydrogenated NPG membrane to remove methanol from water. This study is expected to propose a potential CDI application technology, and also give a novel idea for the removal of small organic molecules in water by functionalized NPG membrane.


New Physiological Aspects of Brown Adipose Tissue.
Brown adipose tissue is specialised for the generation of heat by non-shivering mechanisms. In rodents, the tissue plays a role in energy balance and the development of obesity, as well as in thermoregulation. Studies using fluorodeoxyglucose positron emission tomography (FDG-PET), together with the identification of uncoupling protein-1, have provided definitive evidence that brown adipose tissue is present in adult humans. Brown fat activity is stimulated by cold exposure, declines with age and is inversely proportional to BMI. This has led to renewed interest in the tissue as a therapeutic target for the treatment of obesity. Brown adipose tissue also plays a role in glucose disposal and triglyceride clearance, implicating it in the metabolic syndrome. A potential mechanism for increasing thermogenesis is by the 'browning' of white adipose depots through the recruitment of the recently identified third type of adipocyte - the brite (or beige) fat cell.


A Pure-Red Doublet Emission with 90 % Quantum Yield: Stable, Colorless, Iodinated Triphenylmethane Solid.
Red luminescence is found in off-white tris(iodoperchlorophenyl)methane (3I-PTMH ) crystals which is characterized by a high photoluminescence quantum yield (PLQY 91 %) and color purity (CIE coordinates 0.66, 0.34). The emission originates from the doublet excited state of the neutral radical 3I-PTMR , which is spontaneously formed and becomes embedded in the 3I-PTMH matrix. The radical defect can also be deliberately introduced into 3I-PTMH crystals which maintain a high PLQY with up to 4 % radical concentration. The immobilized iodinated radical demonstrates excellent photostability (estimated half-life >1 year under continuous irradiation) and intriguing luminescent lifetime (69 ns). TD-DFT calculations demonstrate that electron-donating iodine atoms accelerate the radiative transition while the rigid halogen-bonded matrix suppresses the nonradiative decay.


Modulation of in vitro erythropoiesis. Studies with euthyroid and hypothyroid dogs.
The interactions of adrenergic agonists and thyroid hormones on the growth of erythroid colony-forming units were studied in cultures of dog marrow before and after the establishment of hypothyroidism. Erythroid colony growth in cultures form euthyroid dogs was enhanced by isoproterenol and other adrenergic agonists having beta 2-receptor specificity. With hypothyroidism, however, this responsiveness was lost, and sensitivity to alpha-agonists, such as phenylephrine and norepinephrine, was acquired. This alteration in receptor specificity appeared to be dependent upon thyroid hormone and was rapidly reversible. Preincubation of marrow cells from hypothyroid animals with thyroid hormone resulted in the reappearance of responsiveness to beta-adrenergic agonists and the loss of sensitivity to alpha-agonists. These findings are in agreement with previous suggestions that beta-adrenergic receptor activity is modulated by thyroid hormone levels and demonstrate that the specificity of adrenergic modulations of erythropoiesis in culture may accurately reflect the thyroid status of the intact animal.


Herbicide propisochlor exposure induces intestinal barrier impairment, microbiota dysbiosis and gut pyroptosis.
Propisochlor is a chloroacetamide herbicide causing liver toxicity and suppressing immunity in human and animal. Although the herbicide has been used for years, the effects of propisochlor on intestinal health remain poorly understood. Hence, the impacts of propisochlor in intestinal health and gut microbiota were analyzed by using molecular approach and bacterial 16S rRNA sequencing. The result showed that the intake of propisochlor in mice impaired gut morphology, reduced expression of tight junction proteins, decreased thickness of mucus layer and activated pyroptosis signaling. Moreover, the exposure of propisochlor in mice led to significant alterations in gut microbial diversity and composition, including an increase of Bacteroidetes and a decrease of Firmicutes. The gut microbiota, such as Parabacteroides, Parasutterella, and Bacteroides, demonstrated a strong negative correlation with the intestinal health. These findings suggested that gut microbiota could play a critical role in the propisochlor-induced pyroptosis.


[The clinical consequences of changes occurring in HCV population during the first weeks of chronic hepatitis C treatment with interferon and ribavirin].
Hepatitis C virus (HCV) is an extremely dangerous human pathogen. It is widespread all over the world and often leads to the development of chronic hepatitis C (CHC), which can eventually result in cirrhosis a hepatocellular carcinoma. The efficiency of the current applied methods of treatment of HCV infection remains unsatisfactory. The main course of development of CHC and of therapeutic problems is the genetic polymorphism of HCV. The conducted analysis of the structure of the virus' population permits are conclude that the degree of diversity it presents is a crucial agent in the prediction of the outcome of IFN and ribavirin therapy.


The induction of ferroptosis by KLF11/NCOA4 axis: the inhibitory role in clear cell renal cell carcinoma.
Ferroptosis is a form of cell death and has great potential application in the treatment of many cancers, including clear cell renal cell carcinoma (ccRCC). Herein, we identified the essential roles of Krüppel-like factor 11 (KLF11) in suppressing the progression of ccRCC. By analyzing mRNA expression data from the Gene Expression Omnibus (GEO) database, we found that KLF11 was a significantly downregulated gene in ccRCC tissues. The results of subsequent functional assays verified that KLF11 played an antiproliferative role in ccRCC cells and xenograft tumors. Furthermore, gene set enrichment analysis indicated that ferroptosis was involved in ccRCC development, and correlation analysis revealed that KLF11 was positively related to ferroptosis drivers. We also found that KLF11 promoted ferroptosis in ccRCC by downregulating the protein expression of ferritin, system xc (-) cystine/glutamate antiporter (xCT), and glutathione peroxidase 4 (GPX4), acting as the inhibitory factors of ferroptosis and increasing the intracellular levels of lipid reactive oxygen species (ROS). As a transcriptional regulator, KLF11 significantly increased the promoter activity of nuclear receptor coactivator 4 (NCOA4), a gene significantly downregulated in ccRCC and whose low expression is associated with poor survival. The characteristics of ccRCC cells caused by KLF11 overexpression were reversed after NCOA4 silencing. In summary, the present study suggests that KLF11 suppresses the progression of ccRCC by increasing NCOA4 transcription. Therefore, the KLF11/NCOA4 axis may serve as a novel therapeutic target for human ccRCC.


Functional polymorphism of -141C Ins/Del in the dopamine D2 receptor gene promoter and schizophrenia.
Several studies showed the density of D2 receptors was elevated in postmortem brains from schizophrenics. Genes which operate at the level of gene activation may be associated with the pathogenesis of schizophrenia. Arinami et al. [(1997) Human Molecular Genetics 6, 577-582] found a polymorphism in the 5'-flanking region of the D2 receptor gene designated as -141C Ins/Del. The promoter activity by luciferase assay of a plasmid containing the -141C Ins allele was higher than in the one containing the -141C Del allele. In addition, the -141C Ins allele frequency was significantly higher in schizophrenics than in control subjects. We replicated the -141C Ins/Del polymorphism in 170 schizophrenics and 121 healthy control subjects. The number of schizophrenics with the -141C Ins/Ins genotype was significantly higher than that of control subjects (P = 0.038). The frequency of the -141C Ins allele was significantly increased in the schizophrenics compared with the control subjects (P = 0.042). The mean age of onset for the patients with -141C Ins/Del was significantly lower than that for the patients with -141C Ins/Ins (P = 0.029). There was no association between the genotype and either positive symptoms or the response to antipsychotic medication. Our results suggest that the -141C Ins/Del polymorphism may affect the susceptibility to schizophrenia.


Do rates of dental wear in extant African great apes inform the time of weaning?
Reconstructing the life histories of extinct hominins remains one of the main foci of paleoanthropological inquiry, as an extended juvenile period impacts the social and cognitive development of species. However, the paucity of hominin remains, the lack of comparative hominoid data, and the destructive nature of many life history approaches have limited our understanding of the relationship between dental development (eruption) and weaning in primates. Alternatively, the rate of dental wear in early-forming teeth has been suggested a good proxy for the timing of weaning. Here we test this hypothesis on an ontogenetic series of Gorilla gorilla gorilla and Pan troglodytes troglodytes, using geographic information systems-based shape descriptors of M1s in relation to the nitrogen (δ15N) and carbon (δ13C) isotope composition of their associated hair. Results show that Gorilla g. gorilla are fully weaned considerably later than Pan t. troglodytes, that is, after M1s had been in full functional occlusion for some time. Yet, throughout ontogeny, gorilla dental wear rates are greater than they are in chimpanzees. This refutes the hypothesis that the rates of wear of early-forming teeth inform the time of weaning (i.e., nutritional independence). Instead, dietary breadth and seasonal variation in resource availability are implicated. This finding has implications for interpreting the hominin fossil record and raises questions about the triggers for, and the mechanisms of, life history change in hominin evolution. As a case in point, commonalities in life history patterns between early hominins and Western lowland gorillas seem to be a means to mitigate the effects of recurrent (i.e., seasonal) resource limitations and-conceivably-to prevent high infant mortality rates. Taken further, difference between hominid life histories are likely to be of degree, not kind.


Low dose quetiapine reverses deficits in contextual and cued fear conditioning in rats with excitotoxin-induced hippocampal neuropathy.
Previous studies have demonstrated that adult rats with excitotoxic lesions of the hippocampus display deficits in memory-related behaviors similar to the memory deficits associated with schizophrenia. In this study, we assessed the sub-chronic effects of quetiapine, risperidone and haloperidol on performance deficits after intracerebroventricular administration of the excitotoxin, kainic acid, using paradigms for contextual and cued fear conditioning and spatial reversal learning in rats. The effects of three doses of quetiapine (5, 10 and 20 mg/kg) and single doses of risperidone (0.5 mg/kg) and haloperidol (0.15 mg/kg) were compared. Quetiapine administration at the lowest dose (5 mg/kg) reversed deficits in contextual and cued fear conditioning, but not deficits in spatial reversal learning, in kainic acid-treated animals. However, the two higher doses of quetiapine, and the single doses of risperidone and haloperidol, did not reverse any of the kainic acid-induced behavioral deficits. These results may be relevant to the effects of quetiapine and other antipsychotic drugs on memory deficits in patients with schizophrenia.


Trochanter migrans: late complications due to displacement of the lesser trochanter in trochanteric fractures.
Complications associated with secondary displacement and migration of the lesser trochanter fragment in trochanteric fractures are rare. The complaints expressed by the patient may be misunderstood and attributed to implant-associated or patient-specific problems likely to occur after surgery. This series illustrates potentially dangerous late complications caused by secondary migration of the lesser trochanter. It may help focus the surgeon's attention on possible functional impairment and severe late complications caused by displacement of the lesser trochanter in trochanteric fractures that require prompt intervention.


FRET microscopy demonstrates molecular association of non-specific lipid transfer protein (nsL-TP) with fatty acid oxidation enzymes in peroxisomes.
The fate of fluorescently labeled pre-nsL-TP (Cy3-pre-nsL-TP) microinjected into BALB/c 3T3 fibroblasts was investigated by confocal laser scanning microscopy. The protein exhibited a distinct punctate fluorescence pattern and colocalized to a high degree with the immunofluorescence pattern for the peroxisomal enzyme acyl-CoA oxidase. Proteolytic removal of the C-terminal leucine of the putative peroxisomal targeting sequence (AKL) resulted in a diffuse cytosolic fluorescence. These results indicate that microinjected Cy3-pre-nsL-TP is targeted to peroxisomes. The association of nsL-TP with peroxisomal enzymes was investigated in cells by measuring fluorescence resonance energy transfer (FRET) between the microinjected Cy3-pre-nsL-TP and Cy5-labeled antibodies against the peroxisomal enzymes acyl-CoA oxidase, 3-ketoacyl-CoA thiolase, bifunctional enzyme, PMP70 and catalase. The technique of photobleaching digital imaging microscopy (pbDIM), used to quantitate the FRET efficiency on a pixel-by-pixel basis, revealed a specific association of nsL-TP with acyl-CoA oxidase, 3-ketoacyl-CoA thiolase and bifunctional enzyme in the peroxisomes. These observations were corroborated by subjecting a peroxisomal matrix protein fraction to affinity chromatography on Sepharose-immobilized pre-nsL-TP. Acyl-CoA oxidase was retained. These studies provide strong evidence for a role of nsL-TP in the regulation of peroxisomal fatty acid beta-oxidation, e.g. by facilitating the presentation of substrates and/or stabilization of the enzymes.


Adolescent aesthetic athletes: a group at risk for eating pathology?
Previous research shows that leanness- and weight-dependent sports increase the risk of developing disturbed eating behaviour. This study investigated whether adolescent aesthetic athletes (n=68, M=14.6 years), particularly ballet dancers and figure skaters, exhibit more eating pathology compared to the general population. Furthermore, it was investigated whether sport-related factors have explanatory value for the dieting behaviour of aesthetic athletes. To asses eating pathology, reliable and valid self-report questionnaires were used including the Eating Disorder Inventory-II, the Children's Eating Disorder Examination-Questionnaire and the Dutch Eating Behaviour Questionnaire. Results show that female aesthetic athletes show more drive for thinness, features of bulimia, dieting behaviour and concerns about weight and shape compared to female adolescents from the general population. Concerning the explanation of dieting behaviour in aesthetic athletes, both sport-related factors (competition state anxiety) and general risk factors (eating concern) seem to be relevant. These results suggest that female aesthetic athletes show more disturbed eating behaviour and thoughts than female adolescents from the general population and therefore may have an enhanced risk of developing clinical eating disorders.


Oropharyngeal candidiasis in patients treated with beclomethasone dipropionate delivered by metered-dose inhaler alone and with Aerochamber.
We compared the incidence of Candida infection, Candida colonization, and reduction in oral prednisone dose in patients with asthma treated with beclomethasone dipropionate delivered by metered-dose inhaler (MDI) alone and MDI plus Aerochamber. Group M contained 18 patients treated with beclomethasone, four actuations four times a day (672 micrograms/day), delivered by MDI alone. Group A contained 18 patients treated with the same dose of beclomethasone delivered by MDI plus Aerochamber. In group M, four of 18 patients had Candida infection, 12 of 18 patients had Candida colonization, and six of 18 patients were completely removed from oral prednisone. In group A, 0 of 18 patients had Candida infection (p = 0.05), six of 18 patients had Candida colonization (p less than 0.05), and 12 of 18 patients were completely removed from oral prednisone (p less than 0.05). We conclude that beclomethasone delivered by MDI plus Aerochamber is more efficacious in reducing oral prednisone dependency and produces less Candida infection and colonization than beclomethasone delivered by MDI alone.


Aggressive treatment of acute limb ischemia due to thrombosed popliteal aneurysms.
The absence of infra-popliteal runoff in patients with acute limb ischemia and thrombosed popliteal aneurysms carries a high risk of amputation. A combined treatment method involving thrombolysis and surgery is reported. Information regarding six patients was reviewed. Ankle brachial indices and degree of ischemia were recorded. All patients underwent digital subtraction angiography. In five patients thrombus dissolution was achieved using a combination of mechanical and pharmacologic therapy. One patient was judged incapable of withstanding any delay in reperfusion and was treated with isolated limb perfusion using a thrombolytic agent. All patients underwent surgical revascularization. Follow-up (1-3 years) consisted of duplex examinations at 6 months and yearly thereafter. Five patients had no measurable ankle brachial index (ABI), while one patient had an ABI of 0.4. Initial angiography noted all patients to have no runoff in continuity to the pedal arch. Following thrombolytic therapy, an adequate bypass vessel was noted in all cases, with reconstitution of the plantar arch in five patients. Distal revascularizations included one peroneal, and five below knee popliteal arterial bypasses. Fasciotomies were performed in four of the six patients. There were no amputations. One patient developed a persistent foot drop. Two patients developed bypass grafts occlusions; one of which required therapy. The pre-operative use of thrombolytic therapy is a safe and effective method to achieve limb salvage in this patient population. Patients must be capable of withstanding an additional period of ischemia allowing for reconstitution of distal runoff. Isolated limb perfusion is of use when a delay to reperfusion cannot be tolerated.


Fluorescence anisotropy-based structure-switching aptamer assay using a peptide nucleic acid (PNA) probe.
This study describes for the first time the feasibility of using peptide nucleic acids (PNAs) as an alternative to the DNA probes in structure-switching aptamer fluorescence polarisation assays. The effects of experimental parameters such as the length of the PNA strand, the nature of dye and the buffer conditions on the assay performances are first explored using two different methodologies based on the competition between the PNA/aptamer hydribridisation and the target/aptamer complexation. D-ATP can be detected from 1 to 25 μM in a linear range and a detection limit (LOD) of 3 μM can be reached. For this target, this lowers by a factor >5 the LOD reported with conventional DNA-based fluorescent structure switching aptamer-based assays and by a factor 3 the LOD observed with non-competitive fluorescent sensing platform indicating the usefulness of the PNA-based approach.


Elbow arthroscopy in trauma and reconstruction.
Arthroscopy of the elbow has become a valuable adjunct in the evaluation and treatment of elbow trauma and reconstruction. Arthroscopic visualization aids diagnosis and treatment while minimizing surgical trauma. The indications and techniques of elbow arthroscopy continue to expand and evolve. This article demonstrates the use of elbow arthroscopy as it relates to some of the topics in this volume. Arthroscopic setup, portal anatomy, technique, as well as an overview of trauma, loose bodies, bursitis, instability, arthrofibrosis, arthritis, and complications are discussed.


A Spiral Spin-Echo MR Imaging Technique for Improved Flow Artifact Suppression in T1-Weighted Postcontrast Brain Imaging: A Comparison with Cartesian Turbo Spin-Echo.
A challenge with the T1-weighted postcontrast Cartesian spin-echo and turbo spin-echo brain MR imaging is the presence of flow artifacts. Our aim was to develop a rapid 2D spiral spin-echo sequence for T1-weighted MR imaging with minimal flow artifacts and to compare it with a conventional Cartesian 2D turbo spin-echo sequence. T1-weighted brain imaging was performed in 24 pediatric patients. After the administration of intravenous gadolinium contrast agent, a reference Cartesian TSE sequence with a scanning time of 2 minutes 30 seconds was performed, followed by the proposed spiral spin-echo sequence with a scanning time of 1 minutes 18 seconds, with similar spatial resolution and volumetric coverage. The results were reviewed independently and blindly by 3 neuroradiologists. Scores from a 3-point scale were assigned in 3 categories: flow artifact reduction, subjective preference, and lesion conspicuity, if any. The Wilcoxon signed rank test was performed to evaluate the reviewer scores. The t test was used to evaluate the SNR. The Fleiss κ coefficient was calculated to examine interreader agreement. In 23 cases, spiral spin-echo was scored over Cartesian TSE in flow artifact reduction (P < .001). In 21 cases, spiral spin-echo was rated superior in subjective preference (P < .001). Ten patients were identified with lesions, and no statistically significant difference in lesion conspicuity was observed between the 2 sequences. There was no statistically significant difference in SNR between the 2 techniques. The Fleiss κ coefficient was 0.79 (95% confidence interval, 0.65-0.93). The proposed spiral spin-echo pulse sequence provides postcontrast images with minimal flow artifacts at a faster scanning time than its Cartesian TSE counterpart.


Screening the receptorome: an efficient approach for drug discovery and target validation.
The receptorome, comprising at least 5% of the human genome, encodes receptors that mediate the physiological, pathological and therapeutic responses to a vast number of exogenous and endogenous ligands. Not surprisingly, the majority of approved medications target members of the receptorome. Several in silico and physical screening approaches have been devised to mine the receptorome efficiently for the discovery and validation of molecular targets for therapeutic drug discovery. Receptorome screening has also been used to discover, and thereby avoid, the molecular targets responsible for serious and unforeseen drug side effects.


FGF21 is required for protein restriction to extend lifespan and improve metabolic health in male mice.
Dietary protein restriction is increasingly recognized as a unique approach to improve metabolic health, and there is increasing interest in the mechanisms underlying this beneficial effect. Recent work indicates that the hormone FGF21 mediates the metabolic effects of protein restriction in young mice. Here we demonstrate that protein restriction increases lifespan, reduces frailty, lowers body weight and adiposity, improves physical performance, improves glucose tolerance, and alters various metabolic markers within the serum, liver, and adipose tissue of wildtype male mice. Conversely, mice lacking FGF21 fail to exhibit metabolic responses to protein restriction in early life, and in later life exhibit early onset of age-related weight loss, reduced physical performance, increased frailty, and reduced lifespan. These data demonstrate that protein restriction in aging male mice exerts marked beneficial effects on lifespan and metabolic health and that a single metabolic hormone, FGF21, is essential for the anti-aging effect of this dietary intervention.


Monocyte-to-lymphocyte, neutrophil-to-lymphocyte and neutrophil-to-monocyte plus lymphocyte ratios in children with active tuberculosis: A multicentre study.
Higher number of monocytes and neutrophils may correlate with active tuberculosis (TB) in children. However, the few paediatric studies available are limited by the small numbers of children with TB disease or infection included. We calculated the monocyte-to-lymphocyte-ratio (MLR), neutrophil-to-lymphocyte-ratio (NLR) and neutrophil-to-monocyte-plus-lymphocyte-ratio (NMLR) in children with active TB, latent TB infection (LTBI), other infectious and non-infectious conditions and healthy children evaluated in two referral centres in Rome. Overall, 649 children were included (41.8% females, mean age of 5.74 years). MLR, NLR and NMLR values were always significantly higher in patients with TB compared with the other groups (p < 0.001). Considering the entire population with the outcome of TB diagnosis, NMLR, with a cut-off of 1.2, had a sensitivity of 63% and a specificity of 76% (AUC: 0.71 [0.64-0.78]); NLR, with a cut-off of 1.5, had a sensitivity of 61% and a specificity of 79% (AUC: 0.72 [0.65-0.79]); MLR, considering a cut-off of 0.2, was less sensitive (56%) but more specific (82%) with a similar AUC (0.72 [0.65-0.79]). Our study provides further evidence that MLR, NLR and NMLR can serve as first level diagnostics to support the clinical suspicion of TB in children.


Soluble αKlotho as a candidate for the biomarker of aging.
Although the Klotho gene has been recognized as an aging-suppressor gene, the significance of its soluble product, soluble αKlotho (sKlotho), in aging remains to be elucidated. To address this issue, we conducted a single-centered cross-sectional study in a region with a high prevalence of aging. We compared sKlotho levels with the patient characteristics from medical records and laboratory measurements, including fibroblast growth factor 23 (FGF23), intact parathyroid hormone, activated vitamin D3 and factors associated with mineral bone metabolism, in 52 outpatients with a mean age of 78.2 years. Serum sKlotho levels significantly decreased with age, but were not associated with the stage of chronic kidney disease (CKD). Serum FGF23 levels increased as CKD stages advanced, but were not associated with aging. Univariate analyses revealed that sKlotho levels positively correlated with glomerular filtration rate, and negatively with age and serum levels of FGF23 and phosphorus. In a multivariable linear regression analysis, sKlotho significantly correlated with aging and lower FGF23 levels. Only osteoporosis affected sKlotho and FGF23 levels among the various complications and patient status including medication. In summary, serum sKlotho levels inversely correlated with age and FGF23, and were significantly reduced in patients with osteoporosis. sKlotho may serve as a biomarker of aging independent of renal function.


Hypersensitivity reactions related to oxaliplatin (OHP).
Patients treated with platinum compounds are subject to hypersensitivity reactions. Our study has highlighted the reactions related to oxaliplatin (OHP) infusion. One hundred and twenty-four patients affected by advanced colorectal cancer were treated with different schedules containing OHP, at the Institute of Haematology and Medical Oncology 'L. and A. Seragnoli' of Bologna and at the Medical Oncology Division of Livorno Hospital. Seventeen patients (13%) showed hypersensitivity reactions after a few minutes from the start of the OHP infusion. Usually, these reactions were seen after 2-17 exposures to OHP (Mean+/-s.e.: 9.4+/-1.07). No patient experienced allergic reactions at his/her first OHP infusion. Eight patients developed a mild reaction consisting of flushing and swelling of the face and hands, itching, sweating and lachrymation. The remaining nine patients showed a moderate-severe reaction with dyspnoea, wheezing, laryngospasm, psycho-motor agitation, tachycardia, precordial pain, diffuse erythema, itching and sweating. Six patients out of 17 were re-exposed to the drug with premedication of steroids and all except one developed the hypersensitivity reaction again. The cumulative dose, the time of exposure to OHP and the clinical features are variable and unpredictable. The risk of developing hypersensitivity reactions in patients treated with a short infusion of OHP cannot be underestimated.


Teleprehabilitation during COVID-19 pandemic: the essentials of "what" and "how".
In view of the COVID-19 pandemic and recent global events, the healthcare system and its services have been negatively affected, contributing towards extensive surgical backlogs. Oncological surgical candidates have been the most impacted by these changes and recommended self-isolation practices, which could result in emotional distress, sedentary behavior, and poor lifestyle habits. Preoperative supportive intervention, prehabilitation, has been proven to improve patients' functional status and clinical trajectories. Presently, there is a critical need for prehabilitation to optimize patient health, as they experience extended wait times. However, in-hospital delivery may not be an ideal approach due to public health and safety measures. Telehealth is a field of research and practice, which has grown and evolved significantly in the last two decades, allowing for the remote delivery of health services. Therefore, the current commentary addresses the different modalities of telehealth delivery in perspective of their known feasibility and potential application in prehabilitation.


New drug approvals for 2019: Synthesis and clinical applications.
48 new drugs including 38 chemical entities (33 new chemical entities, 3 new diagnostic agents, and 2 payloads of antibody drug conjugates) and 10 biologics were approved by the U.S. Food and Drug Administration (FDA) during 2019. These marketed new drugs represent privileged structures and novel action of mechanism, and thus can be served as leads to discover new drugs with the similar biological targets and improved therapeutic efficacy. This review aims to provide an overview regarding the synthetic approaches of 33 new chemical entities approved by the FDA in 2019 and their clinical applications.


Heart Failure in Rural Communities.
Patients with chronic heart failure (CHF) living in rural areas face an increased risk of adverse cardiovascular events. Even in countries with universal access to health care, rural areas are characteristically underserved, with reduced health care providers supply, greater distance to health care centers, decreased physician density with higher reliance on generalists, and high health care staff turnover. On the other hand, patient-related characteristics vary widely among published data. This review describes the epidemiology of CHF in rural or remote settings, organizational and patient-related factors involved in cardiovascular outcomes, and the role of interventions to improve rural health care.


A rapid review of machine learning approaches for telemedicine in the scope of COVID-19.
The COVID-19 pandemic has rapidly spread around the world. The rapid transmission of the virus is a threat that hinders the ability to contain the disease propagation. The pandemic forced widespread conversion of in-person to virtual care delivery through telemedicine. Given this gap, this article aims at providing a literature review of machine learning-based telemedicine applications to mitigate COVID-19. A rapid review of the literature was conducted in six electronic databases published from 2015 through 2020. The process of data extraction was documented using a PRISMA flowchart for inclusion and exclusion of studies. As a result, the literature search identified 1.733 articles, from which 16 articles were included in the review. We developed an updated taxonomy and identified challenges, open questions, and current data types. Our taxonomy and discussion contribute with a significant degree of coverage from subjects related to the use of machine learning to improve telemedicine in response to the COVID-19 pandemic. The evidence identified by this rapid review suggests that machine learning, in combination with telemedicine, can provide a strategy to control outbreaks by providing smart triage of patients and remote monitoring. Also, the use of telemedicine during future outbreaks could be further explored and refined.


Update on Flat and Papillary Urothelial Lesions: Genitourinary Pathology Society Consensus Recommendations.
The reporting recommendations on "flat and papillary urothelial neoplasia," published in 2 position articles by the Genitourinary Pathology Society in July 2021, was a collective contribution of 38 multidisciplinary experts aiming to clarify nomenclature, classification of flat and papillary urothelial neoplasia and controversial issues. In this review, we discuss some of these recommendations including nomenclature, practical approaches, and their importance for clinical practice.


'Otorrhagia'. A symptom of posterior auricular artery aneurysm.
There are many reports regarding aneurysms of the external carotid artery and its branches, but the case presented in this paper, of an aneurysm of the posterior auricular artery, is a unique one.


Thermodynamic study of Cu2+ binding to the DAHK and GHK peptides by isothermal titration calorimetry (ITC) with the weaker competitor glycine.
The peptides Asp-Ala-His-Lys (DAHK) and Gly-His-Lys (GHK) are naturally occurring Cu(II)-chelating motifs in human serum and cerebrospinal fluid. Here, the sensitive thermodynamic technique isothermal titration calorimetry was used to study the energetics of Cu(II) binding to DAHK and GHK peptides in the presence of the weaker ligand glycine as a competitor. DAHK and GHK bind Cu(II) predominantly in a 1:1 stoichiometry with conditional dissociation constants [i.e., at pH 7.4, in the absence of the competing chelators glycine and 2-(4-(2-hydroxyethyl)-1-piperazinyl)ethanesulfonic acid buffer] of 2.6 ± 0.4 × 10(-14) M and 7.0 ± 1.0 × 10(-14) M, respectively. Furthermore, the apparent ΔH values were measured and the number of protons released upon Cu(II) binding was determined by performing experiments in different buffers. This allowed us to determine the conditional ΔG, ΔH, and ΔS, i.e., corrected for the contributions of the weaker ligand glycine and the buffer at pH 7.4. We found that the entropic and enthalpic contributions to the Cu(II) binding to GHK and DAHK are distinct, with a enthalpic contribution for GHK. The thermodynamic parameters obtained correspond well to those in the literature obtained by other techniques, suggesting that the use of the weaker ligand glycine as a competitor in isothermal titration calorimetry provides accurate data for Cu(II) binding to high-affinity peptides, which cannot be accurately determined without the use of a competitor ligand.


Guide for paediatric radiotherapy procedures.
A third of children with cancer receive radiotherapy as part of their initial treatment, which represents 800 paediatric irradiations per year in France carried out in 15 specialized centres approved on the recommendations of the French national cancer institute in decreasing order of frequency, the types of cancer that require irradiation are: brain tumours, neuroblastomas, Ewing's sarcomas, Hodgkin's lymphomas, soft tissue sarcomas including rhabdomyosarcomas, and nephroblastomas. The treatment guidelines follow the recommendations of the French society for childhood cancers (SFCE) or the French and European prospective protocols. The therapeutic indications, the technical and/and ballistic choices of complex cases are frequently discussed during bimonthly paediatric radiotherapy technical web-conferences. All cancers combined, overall survival being 80%, long-term toxicity logically becomes an important concern, making the preparation of treatments complex. The irradiation methods include all the techniques currently available: 3D conformational irradiation, intensity modulation radiation therapy, irradiation under normal or hypofractionated stereotaxic conditions, brachytherapy and proton therapy. We present the update of the recommendations of the French society for radiation oncology on the indications, the technical methods of realization and the organisation and the specificities of paediatric radiation oncology.


Extracellular Vesicles from Sporothrix Yeast Cells.
Sporotrichosis is an emerging deep mycosis and a public health concern in Brazil. This mycosis is caused by the traumatic inoculation of several species of Sporothrix from nature. However, when cats transmit the disease to humans as zoonotic transmission, severe extracutaneous manifestations are observed. Therefore, effective control of the disease requires the engagement of host receptors by pathogen-derived molecules to stimulate the immune response. In this context, extracellular vesicles from Sporothrix sp contribute to intracellular communication with host cells. In addition, however, extracellular vesicles may contribute to the spread of this fungus via delivering molecules such as proteins, nucleic acids, and lipids. Thus, understanding mechanisms behind extracellular vesicles related to Sporothrix may provide us with a way to understand and identify its capacity to manipulate the host immune system and spread the infection.


[Results of carrier screening and prenatal diagnosis for FMR1 gene in 819 cases].
To determine the carrier rate of Fragile X mental retardation 1 gene (FMR1) mutants in women with a history of adverse pregnancy or childbirth, and to provide prenatal diagnosis for the carriers. Peripheral blood samples were collected from women with a history of adverse pregnancy or childbirth, and the FMR1 gene cytosine-guanine-guanine repeat number (CGG)n was determined by triple-repeat primer polymerase chain reaction (TP-PCR) combined with capillary electrophoresis. Prenatal diagnosis was provided for the carriers during pregnancy. Among 819 samples, 9 gray zone repeats carriers and 10 premutation carriers were detected, which gave a prevalence of 1 in 91 and 1 in 82, respectively, with a total prevalence of 1 in 43. Prenatal diagnosis was provided during 7 pregnancies for 6 carriers. A female fetus with premutation (n = 30/57) and an affected male fetus with full mutation (n = 336) were detected. FMR1 gene testing in women with a history of adverse pregnancy or childbirth can facilitate genetic counseling and reproductive guidance for carriers of gray zone repeats and premutations. Prenatal diagnosis for carriers of premutation can facilitate reduction of the birth of children with fragile X syndrome.


Reduced sound-evoked and resting-state BOLD fMRI connectivity in tinnitus.
The exact neurophysiological basis of chronic tinnitus, which affects 10-15% of the population, remains unknown and is controversial at many levels. It is an open question whether phantom sound perception results from increased central neural gain or not, a crucial question for any future therapeutic intervention strategies for tinnitus. We performed a comprehensive study of mild hearing-impaired participants with and without tinnitus, excluding participants with co-occurrences of hyperacusis. A right-hemisphere correlation between tinnitus loudness and auditory perceptual difficulty was observed in the tinnitus group, independent of differences in hearing thresholds. This correlation was linked to reduced and delayed sound-induced suprathreshold auditory brain responses (ABR wave V) in the tinnitus group, suggesting subsided rather than exaggerated central neural responsiveness. When anatomically predefined auditory regions of interest were analysed for altered sound-evoked BOLD fMRI activity, it became evident that subcortical and cortical auditory regions and regions involved in sound detection (posterior insula, hippocampus), responded with reduced BOLD activity in the tinnitus group, emphasizing reduced, rather than increased, central neural gain. Regarding previous findings of evoked BOLD activity being linked to positive connectivities at rest, we additionally analysed r-fcMRI responses in anatomically predefined auditory regions and regions associated with sound detection. A profound reduction in positive interhemispheric connections of homologous auditory brain regions and a decline in the positive connectivities between lower auditory brainstem regions and regions involved in sound detection (hippocampus, posterior insula) were observed in the tinnitus group. The finding went hand-in-hand with the emotional (amygdala, anterior insula) and temporofrontal/stress-regulating regions (prefrontal cortex, inferior frontal gyrus) that were no longer positively connected with auditory cortex regions in the tinnitus group but were instead positively connected to lower-level auditory brainstem regions. Delayed sound processing, reduced sound-evoked BOLD fMRI activity and altered r-fcMRI in the auditory midbrain correlated in the tinnitus group and showed right hemisphere dominance as did tinnitus loudness and perceptual difficulty. The findings suggest that reduced central neural gain in the auditory stream may lead to phantom perception through a failure to energize attentional/stress-regulating networks for contextualization of auditory-specific information. Reduced auditory-specific information flow in tinnitus has until now escaped detection in humans, as low-level auditory brain regions were previously omitted from neuroimaging studies. German Clinical Trials Register DRKS0006332.


2,2,2-Trifluoroethylation of Styrenes with Concomitant Introduction of a Hydroxyl Group from Molecular Oxygen by Photoredox Catalysis Activated by Visible Light.
The visible-light-induced photoredox difunctionalization reactions of styrenes with 1,1,1-trifluoro-2-iodoethane under an oxygen atmosphere in the presence of water give γ-trifluoromethyl alcohols. In this radical reaction, the oxygen atom in the product originates from molecular oxygen, and water is shown to be important to promote the reaction.


Identification of two regions of the human glucocorticoid receptor hormone binding domain that block activation.
The steroid-binding domain of the human glucocorticoid receptor has a dominant, negative influence over the activity of the remainder of the molecule. We have determined sequences within this domain that are responsible for this inhibition by creating truncations and internal deletions which remove part or all of the ligand-binding domain. Two apparently unrelated sequences within this region are shown to block the ability to stimulate transcription when fused to the carboxyl terminus of a functional, hormone-independent receptor derivative. These results support the possibility of two distinct protein-binding sites within the steroid-binding domain.


Feeding effects of melanocortin ligands--a historical perspective.
The process of energy homeostasis is a highly regulated process involving interacting signals between a variety of anorexigenic and orexigenic peptides, proteins and signaling molecules. The melanocortin system is an important component of this complex regulatory network. Involvement of the melanocortin pathway in the control of food intake and body weight regulation has been studied extensively in the past two decades. Previous studies that involve central administration of melanocortin molecules and examination of molecules that effect food intake in melanocortin knockout (KO) mice (MC3R, MC4R, POMC, AGRP and NPY) have been examined. In this review, we have summarized feeding studies that have resulted in the recognition of the melanocortin system as a major contributor to the complex neuroendocrine system regulating energy homeostasis.


The value of dynamic imaging for standardization of abdominal ultrasonography.
Digital video recording of dynamic images is a potential way to improve the reproducibility of abdominal ultrasonography (US). Static US and dynamic US were compared using contrast-enhanced computed tomography (CE-CT) as a reference standard, and the value of stored video images was verified. The subjects were 120 individuals who had undergone CE-CT ≤1 month before undergoing US. After static US, dynamic US was carried out according to the Scanning Procedure for Abdominal Ultrasonography described in this paper, and records of 30 separate scans were saved on digital video discs (DVD) as individual video files for interpretation. The findings from static US and dynamic US were compared. With respect to the abdominal US signs covered in this evaluation, dynamic US achieved a detection rate equivalent to or better than that of static US. Detection rates were significantly more frequent on dynamic US for: enlarged hepatic hilum lymph nodes (P < 0.001); gallbladder wall thickness (P < 0.01); cystic lesions of the liver, bright liver, and splenomegaly (P < 0.05). Dynamic US is a valuable tool because it enables repeated evaluation of target organs with playback speed adjustment.


Biotransformation of T-2 toxin and diacetoxyscirpenol in the isolated perfused rat liver.
Twelve metabolites of T-2 toxin and two metabolites of DAS have been detected by GLC-MS in the perfusate of isolated rat livers. Less than 50% of the administered dose was recovered in the perfusate. However, preliminary results of the analysis of bile show that considerable amounts of T-2 toxin and DAS were excreted mainly as glucuronide conjugates. The concurrence of the data reported here with the results of in vivo studies indicate that the isolaged perfused rat liver system is suitable in studying the metabolism of trichothecence mycotoxins.


Communicating Benefit and Risk Information in Direct-to-Consumer Print Advertisements: A Randomized Study.
Previous research demonstrated that providing qualitative and quantitative information in a "drug facts box" may help individuals understand prescription drug information in print-based direct-to-consumer advertisements. The authors sought to determine whether qualitative, quantitative, or a combination thereof best communicates benefit and risk information. To replicate and extend previous research, the authors used simple quantitative drug information. A randomized controlled study was conducted with 5067 Internet panelists with heartburn. Participants viewed a drug facts box with benefit and risk information that varied the presence or absence of qualitative summaries and absolute frequencies, percentages, and absolute differences. Measures included knowledge of drug benefits and risks, perceptions, and intentions. Providing absolute frequencies and percentages most improved participants' drug knowledge and affected perceptions and intentions. The study findings suggest that, for simple drug information, adding absolute frequencies and percentages to direct-to-consumer advertisements may benefit consumers. Absolute differences and qualitative labels may not be needed.


Lead exposure lowers the set point for food consumption and growth in weanling rats.
Lead (Pb) depresses growth in infants and young children. Our earlier studies using a weanling rat model of Pb exposure suggest that this Pb effect is due to depression of appetite. In the present study we examined whether this depression of appetite is consistent with a down-regulation of the appetite "set point" as described using dietary manipulations following either lesions of certain hypothalamic regions or 2,3,7,8-tetrachlorodibenzo-p-dioxin exposure. Two types of dietary manipulations were employed: (a) consumatory response to hyperalimentation (force-feeding), and (b) consumatory and growth response during the catch-up period following food restriction. In the hyperalimentation experiments, food intake was determined (a) with and without force-feeding, and (b) without Pb and with Pb administered either orally or systemically. Pb exposure reduced food consumption compared to controls. Force-feeding of a liquid diet further reduced food consumption, but only to the level that maintained total caloric intake at, or close to, the level of Pb animals not force-fed. In the food-restriction experiments, weanling rats had their food intake restricted for 4 days and then were provided free access to food, at which time one subgroup of these animals was exposed to Pb. Catch-up of previously food-restricted animals, in terms of food consumption and growth, was the same in the first 2 days, regardless of whether Pb was administered. During the next 10 days, the food intake and growth of the non-Pb-exposed, food-restricted animals gradually converged on the previously free-fed, non-Pb-exposed animals, whereas the food-restricted. Pb-exposed animals converged on the growth-depressed, previously free-fed Pb-exposed animals. All these responses to dietary manipulations are consistent with a reduced set point for appetite rather than with a nonspecific effect of Pb, e.g., aversion to food or general malaise.


EGFR/FOXO3A/LXR-α Axis Promotes Prostate Cancer Proliferation and Metastasis and Dual-Targeting LXR-α/EGFR Shows Synthetic Lethality.
Prostate cancer is the second leading cause of cancer-related death in men. Early prostate cancer has a high 5-year survival rate. However, the five-year survival rate is low in progressive prostate cancer, which manifests as bone metastasis. The EGF receptor overexpression increases during disease progression and in the development of castration-resistant disease, and may be a potential therapeutic target. Liver X receptors (LXRs) are ligand-dependent nuclear receptor transcription factors and consist of two subtypes, LXR-α and LXR-β, which can inhibit tumor growth in various cancer cells. We revealed that LXR-α, but not LXR-β, was reduced in prostate cancer tissues compared with adjacent normal tissues. LXRs' agonist GW3965 enhanced the inhibitory action of LXR-α on the proliferation and metastasis of prostate cancer cells. Furthermore, our results support the notion that LXR-α is regulated by the EGFR/AKT/FOXO3A pathway. As an EGFR inhibitor, Afatinib could weaken AKT activation and increase the expression level of FOXO3A in prostate cancer. In addition, we indicated that the combination of Afatinib and GW3965 simultaneously increased and activated LXR-α, which led to an increase of tumor suppressors, and eventually inhibited tumor progression. Therefore, the combination of EGFR inhibitor and LXRs agonist may become a potential treatment strategy for prostate cancer, especially metastatic prostate cancer.