Pulmonary receptor for advanced glycation end-products promotes asthma pathogenesis through IL-33 and accumulation of group 2 innate lymphoid cells.
Single nucleotide polymorphisms in the human gene for the receptor for advanced glycation end-products (RAGE) are associated with an increased incidence of asthma. RAGE is highly expressed in the lung and has been reported to play a vital role in the pathogenesis of murine models of asthma/allergic airway inflammation (AAI) by promoting expression of the type 2 cytokines IL-5 and IL-13. IL-5 and IL-13 are prominently secreted by group 2 innate lymphoid cells (ILC2s), which are stimulated by the proallergic cytokine IL-33. We sought to test the hypothesis that pulmonary RAGE is necessary for allergen-induced ILC2 accumulation in the lung. AAI was induced in wild-type and RAGE knockout mice by using IL-33, house dust mite extract, or Alternaria alternata extract. RAGE's lung-specific role in type 2 responses was explored with bone marrow chimeras and induction of gastrointestinal type 2 immune responses. RAGE was found to drive AAI by promoting IL-33 expression in response to allergen and by coordinating the inflammatory response downstream of IL-33. Absence of RAGE impedes pulmonary accumulation of ILC2s in models of AAI. Bone marrow chimera studies suggest that pulmonary parenchymal, but not hematopoietic, RAGE has a central role in promoting AAI. In contrast to the lung, the absence of RAGE does not affect IL-33-induced ILC2 influx in the spleen, type 2 cytokine production in the peritoneum, or mucus hypersecretion in the gastrointestinal tract. For the first time, this study demonstrates that a parenchymal factor, RAGE, mediates lung-specific accumulation of ILC2s.


Systematic bias between blinded independent central review and local assessment: literature review and analyses of 76 phase III randomised controlled trials in 45 688 patients with advanced solid tumour.
Unbiased assessment of tumour response is crucial in randomised controlled trials (RCTs). Blinded independent central review is usually used as a supplemental or monitor to local assessment but is costly. The aim of this study is to investigate whether systematic bias existed in RCTs by comparing the treatment effects of efficacy endpoints between central and local assessments. Literature review, pooling analysis and correlation analysis. PubMed, from 1 January 2010 to 30 June 2017. Eligible articles are phase III RCTs comparing anticancer agents for advanced solid tumours. Additionally, the articles should report objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS) or time to progression (TTP); the treatment effect of these endpoints, OR or HR, should be based on central and local assessments. Of 76 included trials involving 45 688 patients, 17 (22%) trials reported their endpoints with statistically inconsistent inferences (p value lower/higher than the probability of type I error) between central and local assessments; among them, 9 (53%) trials had statistically significant inference based on central assessment. Pooling analysis presented no systematic bias when comparing treatment effects of both assessments (ORR: OR=1.02 (95% CI 0.97 to 1.07), p=0.42, I2=0%; DCR: OR=0.97 (95% CI 0.92 to 1.03), p=0.32, I2=0%); PFS: HR=1.01 (95% CI 0.99 to 1.02), p=0.32, I2=0%; TTP: HR=1.04 (95% CI 0.95 to 1.14), p=0.37, I2=0%), regardless of funding source, mask, region, tumour type, study design, number of enrolled patients, response assessment criteria, primary endpoint and trials with statistically consistent/inconsistent inferences. Correlation analysis also presented no sign of systematic bias between central and local assessments (ORR, DCR, PFS: r>0.90, p<0.01; TTP: r=0.90, p=0.29). No systematic bias could be found between local and central assessments in phase III RCTs on solid tumours. However, statistically inconsistent inferences could be made in many trials between both assessments.


Detection of hepatocellular carcinoma and liver metastases with BR14: a multicenter phase IIA study.
The study was designed primarily to find the optimal dosage range of BR14 contrast-enhanced ultrasonography (CEUS) to detect malignant focal liver lesions. Secondary objectives were the evaluation of the safety profile and comparison with contrast-enhanced MRI (CE MRI). We studied 25 patients (9 females, 16 males, mean age, 66 years) with known hepatocellular carcinoma or liver metastases at 3 centers over a 3-month period. Each patient underwent a baseline examination and at least 3 CEUS examinations with ascending dose levels (0.25 mL; 1.0 mL; 4.0 mL) of BR14. CE MRI was performed 4 weeks before or after the CEUS examination. Dedicated liver maps were used to record the location, size, and type of detected lesions. Examination quality was documented and safety parameters were assessed. The number of lesions detected by BR14 CEUS increased with dosage, whereas the number of missed lesions and the lesion sizes decreased. Despite the increasing contrast enhancement, substantial differences among dosages were not seen for other image quality parameters. No significant changes were noted in safety parameters and no serious adverse events were reported. We conclude that the recommended dose level of BR14 is between 1 mL and 4 mL; at this dosage, lesion detection is comparable to that of CE MRI.


Heteropterys aphrodisiaca infusion reduces the collateral effects of cyclosporine A on the testis.
Cyclosporine A (CsA) is known to have testicular toxicity, leading to male infertility. Stimulant and aphrodisiac properties have been attributed to the plant, Heteropterys aphrodisiaca. Thus, the present work was undertaken to evaluate the association of the drug and the medicinal herb in Wistar rats, applying testicular morphometry and ultrastructure. Twenty-four rats were used, divided into four groups: I, control; II, CsA; III, simultaneous use of CsA and H. aphrodisiaca; IV, H. aphrodisiaca. Daily administration by gavage was carried out, during 56 days, of water (sham), CsA in a dose of 15 mg/kg per day and/or H. aphrodisiaca in a dose of 0.5 ml of the infusion prepared with 25 g of roots/100 ml of boiling water. Increased body weight was observed for all groups, but the animals that received only CsA showed the smallest body weight gain. Morphometry showed increased connective tissue volumetric proportion and decreased Leydig cell volumetric proportion in CsA-treated rats. Using transmission electron microscopy, it was possible to ascertain that CsA caused seminiferous epithelium degeneration, resulting in Sertoli cell vacuolization, abnormal round and elongated spermatids and large accumulation of residual cytoplasm at the epithelium border next to the lumen. Expanded intercellular spaces between germ cells were still observed in H. aphrodisiaca-treated rat testes. The administration of H. aphrodisiaca infusion to CsA-treated rats diminished nearly all the CsA-induced damage to the testis ultrastructure, suggesting that H. aphrodisiaca infusion may be used combined with CsA to reduce CsA-induced injuries in the testis.


Systematic review of the receptor tyrosine kinase superfamily in neuroblastoma pathophysiology.
Neuroblastoma is a devastating disease accounting for 15% of all childhood cancer deaths. Yet, our understanding of key molecular drivers such as receptor tyrosine kinases (RTKs) in this pathology remains poorly clarified. Here, we provide a systematic analysis of the RTK superfamily in the context of neuroblastoma pathogenesis. Statistical correlations for all RTK family members' expression to neuroblastoma patient survival across 10 independent patient cohorts were annotated, synthesized, and ranked using the R2: Genomics Analysis and Visualization Platform. Gene expression of selected members across different cancer cell lines was further analyzed in the Cancer Cell Line Encyclopedia, part of the Cancer Dependency Map portal (depmap portal ( http://depmap.org )). Finally, we provide a detailed literature review for highly ranked candidates. Our analysis defined two subsets of RTKs showing robust associations with either better or worse survival, constituting potential novel players in neuroblastoma pathophysiology, diagnosis, and therapy. We review the available literature regarding the oncogenic functions of these RTKs, their roles in neuroblastoma pathophysiology, and potential utility as therapeutic targets. Our systematic analysis and review of the RTK superfamily in neuroblastoma pathogenesis provides a new resource to guide the research community towards focused efforts investigating signaling pathways that contribute to neuroblastoma tumor establishment, growth, and/or aggressiveness and targeting these druggable molecules in novel therapeutic strategies.


Antiviral effects of phytochemicals against severe acute respiratory syndrome coronavirus 2 and their mechanisms of action: A review.
The worldwide spreading of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has posed a serious threat to health, economic, environmental, and social aspects of human lives. Currently, there are no approved treatments that can effectively block the virus although several existing antimalarial and antiviral agents have been repurposed and allowed use during the pandemic under the emergency use authorization (EUA) status. This review gives an updated overview of the antiviral effects of phytochemicals including alkaloids, flavonoids, and terpenoids against the COVID-19 virus and their mechanisms of action. Search for natural lead molecules against SARS-CoV-2 has been focusing on virtual screening and in vitro studies on phytochemicals that have shown great promise against other coronaviruses such as SARS-CoV. Until now, there is limited data on in vivo investigations to examine the antiviral activity of plants in SARS-CoV-2-infected animal models and the studies were performed using crude extracts. Further experimental and preclinical investigations on the in vivo effects of phytochemicals have to be performed to provide sufficient efficacy and safety data before clinical studies can be performed to develop them into COVID-19 drugs. Phytochemicals are potential sources of new chemical leads for the development of safe and potent anti-SARS-CoV-2 agents.


Biomarkers of Exposure Among "Dual Users" of Tobacco Cigarettes and Electronic Cigarettes in Canada.
"Dual use" refers to the concurrent use of tobacco cigarettes (smoking) and electronic cigarettes (e-cigarettes; vaping). Although dual use is common among e-cigarette users, there is little evidence regarding biomarkers of exposure among dual users and how these change under different conditions of product use. A nonblinded within-subjects crossover experiment was conducted with adult daily dual users (n = 48) in Ontario, Canada. Participants completed three consecutive 7-day periods in which the use of tobacco cigarettes and e-cigarettes was experimentally manipulated, resulting in four study conditions: Dual use, Tobacco cigarette use, E-cigarette use, and No product use. Repeated measures models were used to examine changes in product use and biomarkers of exposure. Compared to dual use, cotinine remained stable when participants exclusively smoked (p = .524), but significantly decreased when they exclusively vaped (p = .027), despite significant increases in e-cigarette consumption (p = .001). Levels of biomarkers of exposure to toxicants, including carbon monoxide (CO), 1-hydroxypyrene (1-HOP), and 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL), were significantly lower when participants exclusively vaped than when they engaged in dual use (CO = -41%, p < .001; 1-HOP = -31%, p = .025; NNAL = -30%, p = .017). Similar findings were observed among participants abstaining from both products as compared to dual use (CO: -26%, p < .001; 1-HOP = -14% [ns]; NNAL = -35%, p = .016). In contrast, levels of biomarkers of exposure increased when participants exclusively smoked as compared to dual use (CO = +21%, p = .029; 1-HOP = +23%, p = .048; NNAL = +8% [ns]). Although dual use may reduce exposure to tobacco smoke constituents to some extent, abstaining from smoking is the most effective way to reduce such exposure. Public health authorities should clearly communicate the relative risk of e-cigarettes and tobacco cigarettes to the general public, focusing on two salient points: (1) e-cigarettes are not harmless, but they are less harmful than tobacco cigarettes; and (2) using e-cigarettes while smoking may not necessarily reduce health risks; therefore, consumers should stop smoking completely to maximize potential health benefits.


Challenges facing the forest industry in relation to seed dormancy and seed quality.
Artificial regeneration of forests through planting requires high quantities of quality seeds for growing vigorous seedlings. These seedlings are raised in nurseries, where germination capacity (GC) and speed are the most important germination parameters. Germination performance is enhanced by prescribing species-specific dormancy-breaking treatments to individual seedlots in bare-root and container nurseries. For most conifer species in British Columbia, the dormancy-breaking treatments and germination conditions have been worked out, but fine-tuning and optimization could improve germination capacity and speed of germination. Implications of inter- and intra-species variations in germination behaviour and seed quality and their influence on the development of unintentional directional selection of specific genotypes are discussed. The potential of molecular and genomics approaches to understand the underlying biology of seed germination-related problems is also discussed.


Purification of a paracrine factor, P-Mod-S, produced by testicular peritubular cells that modulates Sertoli cell function.
A testicular paracrine factor, P-Mod-S, was purified from conditioned medium obtained from serum-free cultures of peritubular cells. Stimulation of testicular transferrin production by cultured Sertoli cells was utilized as a bio-assay for P-Mod-S. A bioactive protein with an apparent molecular weight of 50,000 under physiological conditions was isolated by high pressure size exclusion chromatography. P-Mod-S was found to have an affinity for heparin and bound to a heparin affinity column. Two forms of P-Mod-S were purified with reverse-phase chromatography. The less hydrophobic form was referred to as P-Mod-S (A) and is a 56,000 molecular weight protein. The more hydrophobic form was referred to as P-Mod-S (B) and is a 59,000 molecular weight protein. Purification of P-Mod-S (A) and P-Mod-S (B) from peritubular cell-radiolabeled secreted proteins revealed that both proteins contain radioactivity. This result demonstrates active synthesis and secretion of P-Mod-S by peritubular cells. Although the amino acid composition of the two proteins indicates distinct differences in the content of several amino acids, the relationship of P-Mod-S (A) and P-Mod-S (B) is unknown at present. A greater than 1000-fold increase in the specific activity of P-Mod-S was achieved with the purification procedure utilized. P-Mod-S can account for essentially all the bioactivity present in crude peritubular cell-secreted protein preparations. The effects of the two forms of P-Mod-S on both transferrin and androgen-binding protein production by Sertoli cells was examined. Purified forms of P-Mod-S were found to have a greater effect on Sertoli cell function than any individual regulatory agent previously known to influence the cell, including follicle-stimulating hormone. The significance of peritubular cell-Sertoli cell interactions mediated via P-Mod-S to spermatogenesis and testicular function is discussed, as well as insight provided into general mesenchymal-epithelial cell interactions.


Guinea-pig antisera to bovine insulin and proinsulin were analysed and the association constants and the concentrations of combining sites specific for insulin and for the C-chain were determined. Both antisera contained combining sites with higher (Ak(1) sites) and lower (Ak(2) sites) affinities for the cross-reacting antigens.Antisera produced in response to both insulin and proinsulin had similar concentrations of both the more affine and less affine insulin-specific binding sites. Bovine insulin contaminated with traces of proinsulin did not induce antibodies specific for the C-chain.Antisera to proinsulin contained equal amounts of high affinity binding sites specific for the C-chain and for the insulin part of the molecule. After absorption of the insulin-specific antibodies these sera can be used for the immunoassay of proinsulin.


Mutations of immunoglobulin transmembrane and cytoplasmic domains: effects on intracellular signaling and antigen presentation.
The membrane-bound form of immunoglobulin serves as an antigen-specific receptor for B cells mediating signal transduction and antigen presentation. We have developed an assay that reconstitutes both these physiologic responses with respect to the antigen phosphorylcholine. By introducing specific mutations in the human Ig mu chain gene, we have shown that certain transmembrane residues and the short cytoplasmic domain are crucial for these two activities. Moreover, elimination of a single transmembrane hydroxyl group severely inhibits antigen presentation without affecting signal transduction, suggesting that these two functions are mediated by different protein interactions.


Accumulation and distribution of polycyclic aromatic hydrocarbons in rice (Oryza sativa).
Various tissues of rice plants were sampled from a PAH contaminated site in Tianjin, China at different growth stages of the ripening period and analyzed for PAHs. PAHs were much higher in roots than in the exposed tissues. Grains and internodes accumulated much smaller amounts of PAHs than leaves, hulls or ear axes. No specific gradient trends along roots, stem, ear axes, and grains were observed, suggesting that systematic translocation among them is unlikely. Over the ripening period, PAH concentrations were increased in rice roots and decreased in most above-ground tissues. Significant correlations between PAH and lipid contents can only be observed during full mature stage. The spectra of individual PAH compounds in rice organs including roots were similar to those in air, rather than those in soil. There was also a significant correlation between bioconcentration factor (BCF, plant over air) and octanol/air partitioning coefficient (Koa).


Doppler spectral waveform generation in vitro: an aid to diagnosis of vascular disease.
This paper describes a microcomputer controlled pump which generates pulsatile flows similar to those found in the human peripheral circulation. Continuous wave Doppler ultrasound was used to investigate the flows generated by the pump and the behaviour of diagnostic indices derived from the spectra was examined. Sonograms were recorded from elastic and rigid tubes with various degrees of axisymmetric constriction. Heart rate, stroke volume, severity of vessel constriction, vessel wall elasticity, distal resistance, and systemic peripheral impedance were varied in turn and the resulting Doppler spectra compared. Indices considered were the pulsatility index, spectral broadening index and peck Doppler frequency. In general, the indices lacked the sensitivity to detect low to moderate levels of disease.


Effect of short course chemotherapy on salivary paracetamol elimination.
1. Salivary elimination of paracetamol was studied in six male pulmonary tuberculosis patients on short course chemotherapy. 2. Peak paracetamol concentration showed a steady decrease at the end of first week and continued until the end of the study. 3. The elimination half-life of paracetamol decreased 5 weeks after the therapy with a corresponding increase in the clearance rate. 4. Adjustment of dosage of drugs that are metabolized by the microsomal enzymes may be required in patients on anti-tubercular drug regimen in which rifampicin is included.


A new method for quantification of false lumen thrombosis in aortic dissection using magnetic resonance imaging and a blood pool contrast agent.
False lumen thrombosis after aortic dissection is a major predictor of prognosis. First pass computed tomography (CT) and magnetic resonance (MR) imaging are used routinely, where the image acquisition is timed to the arrival of contrast in the proximal unaffected aorta. Delayed phase imaging is difficult to refine because flow rates in the false lumen are often very slow and highly variable between patients. Blood pool contrast agents bind to albumin and become homogenously distributed in the intravascular circulation, allowing accurate imaging of areas where flow is low. We compared first pass MR and CT with a delayed phase MR acquisition using a blood pool agent to assess whether this more accurately quantified false lumen thrombosis. Patients with medically treated chronic type B aortic dissection and evidence of false lumen thrombosis on previous CT imaging underwent first pass CT, first pass MR, and delayed phase MR with blood pool agent. Absence of false lumen contrast enhancement was quantified to assess the apparent differences in thrombosis. Phase-contrast MR data were also obtained to assess the affect of flow velocity on false lumen contrast enhancement, and direct thrombus MR images were used to confirm the presence of thrombus. Twelve patients were recruited. No difference was seen in apparent thrombus volume between first pass CT and first pass MR imaging (146.9 cm(3) [SD, 88.6] vs 187.6 cm(3) [SD, 136.1], P = .1119; R(2) = .67 [95% confidence interval (CI), r = .46-.95], P = .0012). In all patients, the volume of thrombus derived from first pass acquisitions was greater than the volume derived from delayed phase MR imaging with blood pool agent: first pass CT (paired t test, P = .0007; mean difference = 83.4 cm(3) [95% CI, 44.1-122.6]) and first pass MR (paired t test, P = .0009; mean difference = 124.0 cm(3) [95% CI, 63.2-184.9]). The difference in thrombus volume between first pass and delayed phase MR imaging with blood pool agent correlated significantly with the mean velocity of flow in the false lumen, with lower flow related to a greater difference (R(2) = .61, P = .0028 [95% CI, r = -.94--.37]). Direct thrombus MR images were able to correctly discriminate between thrombus and blood and matched the area of contrast absence on delayed phase MR with blood pool agent images. First pass techniques to assess false lumen thrombosis in aortic dissection consistently overestimate the apparent thrombus volume by five to six times. This has implications for interpretation of cohort studies and clinical trials that use false lumen thrombosis as an outcome measure. We recommend delayed phase MR imaging with a blood pool agent when accurate assessment of false lumen thrombosis is required.


Association of Fitness and Grip Strength With Heart Failure: Findings From the UK Biobank Population-Based Study.
To investigate the associations of objectively measured cardiorespiratory fitness (CRF) and grip strength (GS) with incident heart failure (HF), a clinical syndrome that results in substantial social and economic burden, using UK Biobank data. Of the 502,628 participants recruited into the UK Biobank between April 1, 2007, and December 31, 2010, a total of 374,493 were included in our GS analysis and 57,053 were included in CRF analysis. Associations between CRF and GS and incident HF were investigated using Cox proportional hazard models, with adjustment for known measured confounders. During a mean of 4.1 (range, 2.4-7.1) years, 631 HF events occurred in those with GS data, and 66 HF events occurred in those with CRF data. Higher CRF was associated with 18% lower risk for HF (hazard ratio [HR], 0.82; 95% CI, 0.76-0.88) per 1-metabolic equivalent increment increase and GS was associated with 19% lower incidence of HF risk (HR, 0.81; 95% CI, 0.77-0.86) per 5-kg increment increase. When CRF and GS were standardized, the HR for CRF was 0.50 per 1-SD increment (95% CI, 0.38-0.65), and for GS was 0.65 per 1-SD increment (95% CI, 0.58-0.72). Our data indicate that objective measurements of physical function (GS and CRF) are strongly and independently associated with lower HF incidence. Future studies targeting improving CRF and muscle strength should include HF as an outcome to assess whether these results are causal.


Evaluation of fast neutron teletherapy for advanced carcinomas of the major salivary glands.
This review analyzes the local control rate of fast neutron beam teletherapy for malignant salivary gland carcinomas compared to conventional photon irradiation at the same institution. Thirty patients with malignant parotid or submaxillary gland tumors were treated with either cobalt-60 (19 patients) or neutrons +/- photons (11 patients). The 19 photon-treated patients were historical controls. No advantage is found for neutrons in patients with tumors less than 3 cm where 100% local control was achieved with either modality. In patients with tumor masses 3-6 cm in size, neutrons demonstrated a possible advantage with a local control rate of 100% (followup, 7-18 months) compared to a control rate of 33% with conventional photon irradiation. Acute treatment-related morbidity was slightly greater in neutron-treated patients, but no long-term complications have been observed to date.


Conditioned fear exacerbates acute morphine dependence.
A variety of physical stressors have been shown to enhance reactivity to opioid drugs. Few studies have examined the effects of nonphysical stressors on opioid drug reactivity. In this regard, it has previously been shown that animals administered morphine in the presence of shock-associated cues demonstrate increases in hypoalgesia relative to nonshock control animals. These findings have typically been viewed as being mediated by the activation of endogenous pain inhibition systems via conditioned fear. In this series, we further examined the nature of these effects by assessing the effects of conditioned fear on acute morphine dependence. Experiment 1 revealed that animals administered 3 mg/kg morphine in the presence of context fear cues demonstrated an enhanced withdrawal response when removed and administered 3 mg/kg naloxone. Because it is known that conditioning effects do not diminish over time, a second experiment examined whether the enhancement of acute dependence by context fear would still be evident 72 h postconditioning. As in Experiment 1, animals administered morphine in a context associated with shock demonstrated an enhancement of acute dependence. Experiment 2b revealed that the shock parameters used in these studies can induce a hypoalgesic response on the test that is opioid mediated. These findings are discussed with regard to the neuroanatomy of fear systems as they relate to the neuropharmacological study of opioid withdrawal.


Imatinib mesylate causes growth deceleration in pediatric patients with chronic myelogenous leukemia.
Imatinib mesylate, a tyrosine kinase inhibitor, is used in the treatment of chronic myelogeneous leukemia (CML). Given its ease of administration and manageable side effects in adults, imatinib mesylate was introduced as therapy for pediatric CML. Recently published case reports describe growth deceleration in children treated with imatinib. This study details the growth phenotype of seven pediatric patients maintained in remission on imatnib mesylate over an extended period of time. This study is a retrospective chart review of pediatric patients with CML at Oregon Health & Science University treated with imatinib. Height, weight, and body mass index (BMI) measurements were collected before and during treatment. Median standard deviation scores (SDS) were analyzed by Wilcoxon Rank-Sum test and Wilcoxon signed rank cohort analysis. Individual patient analysis demonstrated five of seven subjects with a statistically significant decrease in height SDS pre versus during treatment. The whole group analysis showed a trend to significance for difference in median height SDS pre and during treatment (P = 0.078). Bone age was delayed in all four patients in whom bone ages were obtained. IGF-1, IGFBP-3, and thyroid levels during treatment were normal. Four patients experienced an improvement in height SDS during puberty. However, three patients approaching near final adult height failed to achieve genetic height potential determined by mid-parental target height. Growth in children with CML appears to be adversely impacted by imatinib therapy. BMI and IGF-1/IGFBP-3 are maintained during treatment, suggesting a direct effect of imatinib on the growth plate.


Draft Genome Sequence of Bacillus cereus 905, a Plant Growth-Promoting Rhizobacterium of Wheat.
Bacillus cereus 905 is a plant growth-promoting rhizobacterium, isolated from wheat rhizosphere. The draft genome sequence of this strain is 5.39 Mb and harbors 5,412 coding sequences.


Impact of Sex and Obesity on Echocardiographic Parameters in Children and Adolescents.
Subclinical alterations in left ventricular structure and function are detectable in adolescents with hypertension or obesity. However, data on early echocardiographic abnormalities in seemingly healthy children are lacking. Sex differences in cardiac structure and function have been previously reported, but sex-specific reference values are not available. Specifically, the potential interaction of sex and overweight has not been addressed at all. Anthropometric data, blood pressure and exercise tests were obtained in 356 healthy children. Echocardiographic parameters comprised peak early (E) and late (A) mitral inflow Doppler velocities, E/A ratio, tissue Doppler peak velocities of early (e') and late diastolic (a') excursion of mitral/septal annulus and isovolumetric relaxation time (IVRT). Left ventricular mass index (LVMI) and LVMI z-score were calculated. Interaction terms between BMI and sex and stratification by sex were used for analysis. We provide values for echocardiographic parameters for children of two age groups separated by BMI. Overweight/obese children had a significant higher LVMI, lower E/A ratio, higher E/e' ratios and a longer IVRT. For a given BMI in the upper ranges we demonstrated a higher LVMI in girls than in boys, the IVRT extended significantly more in girls than in boys with increasing BMI. There are sex differences in structural and functional echocardiographic parameters in children and adolescents. Our data not only confirms the importance of overweight and obesity, but demonstrates important interactions between sex and overweight. The greater susceptibility of overweight girls toward echocardiographic changes associated with potential long-term functional impairment needs further exploration and follow-up.Trial registration number DRKS00012371; Date 18.08.2017.


Pulmonary artery growth fails to match the increase in body surface area after the Fontan operation.
To evaluate the growth of the pulmonary arteries after a Fontan procedure. Retrospective review. Two paediatric cardiology tertiary care centres. 61 children who underwent a modified Fontan operation and had angiography suitable for assessment of pulmonary artery size before the Fontan procedure and during long term follow up. An atriopulmonary connection (APC) was present in 23 patients (37.7%) and a total cavopulmonary connection (TCPC) was present in 38 (62.3%). Postoperative angiograms were performed 0.5-121 months (median 19 months) after the Fontan operation. Growth of each pulmonary artery measured just before the first branching point. The diameter was expressed as a z score with established nomograms used to standardise for body surface area. The mean change in the preoperative to postoperative z scores of the right pulmonary artery was -1.06 (p = 0.004). The mean change in the preoperative to postoperative z scores of the left pulmonary artery was -0.88 (p = 0.003). Changes in the preoperative to postoperative z scores were more pronounced in the patients undergoing APC than TCPC, especially for the right pulmonary artery. After the Fontan operation, growth of the pulmonary arteries often fails to match the increase in body surface area.


Nuclear magnetic resonance for studying recognition processes between anandamide and cannabinoid receptors.
The understanding of the molecular basis of cannabinoid activity has greatly improved since the discovery of CB1 and CB2 receptors. In this paper, the ligand binding processes between the endogenous cannabimimetic ligand, anandamide (AEA), and the cannabinoid receptors from different parts of rat brain were studied by nuclear magnetic resonance spectroscopy. The NMR approach is based on the comparison of selective (R1(SE)) and non-selective (R1(NS)) proton spin-lattice relaxation rates of the ligand in the presence and absence of macromolecular receptors, as well as R1(NS) and R1(SE) temperature dependency analysis. From these studies, the ligand-receptor binding strength was evaluated on the basis of the calculation of the "affinity index". The derivation of the "affinity index" from chemical equilibrium kinetics for all systems allowed the comparison of the ability of anandamide to interact with cannabinoid receptors present in different brain sectors.


Midwifery care measures in the second stage of labor and reduction of genital tract trauma at birth: a randomized trial.
Genital tract trauma after spontaneous vaginal childbirth is common, and evidence-based prevention measures have not been identified beyond minimizing the use of episiotomy. This study randomized 1211 healthy women in midwifery care at the University of New Mexico teaching hospital to 1 of 3 care measures late in the second stage of labor: 1) warm compresses to the perineal area, 2) massage with lubricant, or 3) no touching of the perineum until crowning of the infant's head. The purpose was to assess whether any of these measures was associated with lower levels of obstetric trauma. After each birth, the clinical midwife recorded demographic, clinical care, and outcome data, including the location and extent of any genital tract trauma. The frequency distribution of genital tract trauma was equal in all three groups. Individual women and their clinicians should decide whether to use these techniques on the basis of maternal comfort and other considerations.


Ipsilateral Quadriceps Tendon-Bone ACL Revision Reconstruction to Address Failed Primary Bone-Patellar Tendon-Bone ACL Reconstruction with Persistent Patellar Bone Defect.
Bone-patellar tendon-bone (BPTB) autograft is a popular graft choice for anterior cruciate ligament reconstruction (ACLR) in active young adults. In case of BPTB ACLR failure, the 3 most popular autograft choices for a revision surgery include contralateral BPTB, contralateral or ipsilateral hamstrings autograft, and contralateral or ipsilateral quadriceps tendon autograft. Quadriceps tendon autograft has been gaining increasing popularity in recent years in this respect, but using quadriceps tendon-bone autograft in the setup of a previous use of ipsilateral BPTB autograft deserves special technical considerations, with emphasis on preserving patellar bone integrity. We describe a technique for performing revision ACLR after failed primary BPTB ACLR by using ipsilateral quadriceps tendon-bone autograft in the setup of persistent distal patellar bone defect. Using this autograft benefits the advantages of highly resilient graft tissue in addition to fast bone-to-bone healing on the femoral side, and it can be an excellent choice in revision reconstruction for surgeons who prefer tendon-bone autograft for highly active young adults and specifically when the patients underwent bilateral primary autologous BPTB ACLRs.


The extent to which melanoma alters tissue-resident dendritic cell function correlates with tumorigenicity.
We have shown that melanoma-derived factors alter the function of differentiated tissue-resident dendritic cells (DC) in a tumorigenicity-dependent manner. Soluble factors, including TGFβ1 and VEGF-A, contributed to dendritic cell dysfunction associated with a highly-aggressive melanoma and conferred a phenotype upon DC likely to favor immune escape and tumor outgrowth.


Inducible expression of RbAp46 activates c-Jun NH2-terminal kinase-dependent apoptosis and suppresses progressive growth of tumor xenografts in nude mice.
The retinoblastoma (Rb) suppressor-associated protein 46 (RbAp46) is a member of the WD-repeat protein family and a component of histone modifying and remodeling complexes. Previously, we demonstrated that RbAp46 inhibits cell growth and suppresses the transformed phenotypes of tumor cell lines. We established a tetracycline-inducible RbAp46 expression system in Saos-2 cells to test the effects of RbAp46 induction on cell growth in vitro and on tumor formation in vivo. We found that inducible expression of RbAp46 activated the c-Jun N-terminal kinase (JNK) signaling pathway and triggered apoptosis in Saos-2 cells. A dominant-negative mutant of JNK1, which can inhibit RbAp46-induced JNK activity, blocked RbAp46-mediated apoptosis. We also found that the induction of RbAp46 expression strongly suppressed the formation of tumors grafted in nude mice and drastically reduced growth of established tumor xenografts. These results revealed a novel proapoptotic activity for RbAp46 via the JNK pathway and demonstrated that induction of RbAp46 expression inhibits progressive growth of tumor grafts in vivo.


Thymic stromal lymphopoietin downregulates NME1 expression and promotes invasion in human trophoblasts via the activation of STAT3 signaling pathway.
Our previous study has demonstrated that TSLP induces the invasion of human trophoblasts and plays a role in embryo implantation. The present study is undertaken to explore the mechanism by which TSLP modulates trophoblast invasion. It was revealed that TSLP treatment significantly downregulated NME1 and TIMP1 expression in both human trophoblasts and JEG-3 cells. The stimulatory effect of TSLP on trophoblast invasion was partially inhibited by either STAT3 inhibitor or STAT5 inhibitor. The downregulation of NME1 expression by TSLP was completely abrogated by STAT3 inhibitor. TIMP1 expression was attenuated by NME1 siRNA interference and enhanced by NME1 overexpression in JEG-3 cells. TSLP-stimulated increase in trophoblast invasion was partially attenuated by NME1 overexpression. Our data suggest that TSLP might downregulate NME1 expression via STAT3 signaling pathway, affecting TIMP1 expression in influencing trophoblast invasion. Our studies suggest that further studies on TSLP as a potential therapeutic for recurrent spontaneous abortion are warranted.


Simple methods for generating neural, bone and endodermal cell types from chick embryonic stem cells.
Most work on embryonic stem cell differentiation uses mammalian cells derived from the blastocyst stage and some of the most widely used protocols to induce differentiation involve growing these cells in monolayer culture. Equivalent stem cells can be obtained from embryos of non-mammalian vertebrates, but to date this has only been successful in birds. These cells can contribute to all somatic lineages in chimaeras and can be induced to differentiate into a variety of cell types in vitro via embryoid body formation. However to date there are no reliable methods for differentiating them into descendants from each of the germ layers in monolayer culture, comparable to the protocols used in mammals. Here we describe three simple and reproducible protocols for differentiation of chick embryonic stem cells into mesoderm (bone), endoderm and neuroectoderm (neurons and glia) in monolayer culture. These methods open the way for more direct comparisons of the properties of mammalian and avian embryonic stem cells that may highlight similarities and differences.


Elevated morbidity and mortality in patients with chronic idiopathic hypophosphatemia: a nationwide cohort study.
Chronic idiopathic hypophosphatemia (CIH) induced by X-linked hypophosphatemic rickets or tumor-induced osteomalacia is a rare inherited or acquired disorder. However, due to its rarity, little is known about the epidemiology and natural course of CIH. Therefore, we aimed to identify the prevalence and long-term health outcomes of CIH patients. Using the Korean Health Insurance Review and Assessment claims database, we evaluated the incidence of hypophosphatemia initially diagnosed from 2003 to 2018. After excluding secondary conditions that could change serum phosphorus levels, we identified 154 patients (76 men and 78 women) with non-secondary and non-renal hypophosphatemia. These hypophosphatemic patients were compared at a ratio of 1:10 with age-, sex-, and index-year-matched controls (n = 1,540). In the distribution of age at diagnosis, a large peak was observed in patients aged 1-4 years and small peaks were observed in ages from 40-70 years. The age-standardized incidence rate showed non-statistically significant trend from 0.24 per 1,000,000 persons in 2003 to 0.30 in 2018. Hypophosphatemic patients had a higher risk of any complication (adjusted hazard ratio [aHR], 2.17; 95% confidence interval [CI], 1.67-2.69) including cardiovascular outcomes, chronic kidney disease, hyperparathyroidism, osteoporotic fractures, periodontitis, and depression. Hypophosphatemic patients also had higher risks of mortality and hospitalization than the controls (aHR, 3.26; 95% CI, 1.83-5.81; and aHR, 2.49; 95% CI, 1.97-3.16, respectively). This first nationwide study of CIH in South Korea found a bimodal age distribution and no sex differences among patients. Hypophosphatemic patients had higher risks of complications, mortality, and hospitalization compared to age- and sex-matched controls.


Social and structural housing conditions influence the development of a depressive-like phenotype in the learned helplessness paradigm in male mice.
Structural and social factors are known to play a crucial role in the pathogenesis of depression. Since animal models of depression are a major tool to gain insights into the mechanisms involved in the pathophysiology of this disease it is important not only to exploit but also to be aware of factors that may affect these models. As housing represents a fundamental external factor, which is controversially debated to affect the animals' emotionality, this study aimed to investigate the impact of different social and structural housing conditions on the development of a depressive-like syndrome in the learned helplessness paradigm. Group housing in an impoverished environment led to an increased vulnerability in the learned helplessness paradigm. Groups that were housed enriched, however, were less helpless. Furthermore impoverished conditions did not increase the vulnerability in single housed animals. Regarding emotionality in the animals, basal anxiety was reduced and the exploration was enhanced by group housing and enriched environment. These results suggest that housing conditions significantly influence the outcome of learned helplessness studies.


Double-outlet right ventricle (S,D,D), VSD related to pulmonary artery, and pulmonic stenosis absent. Correction with an intraventricular conduit in infancy.
The case history of a 5-month-old infant with double-outlet right ventricle (S,D,D) ventricular septal defect (VSD) related to the pulmonary artery, and absence of pulmonic stenosis is reported. The anomaly was repaired with an internal intraventricular conduit. This is the youngest infant with this subset of DORV to survive complete repair and the youngest in whom an intraventricular conduit was used. The diagnosis was not suspected preoperatively, and it is fortunate that the intracardiac anatomy permitted this type of repair at this age. The optimal management program for this subset of DORV should be initial pulmonary artery banding with later complete repair.


Low computational-cost cell detection method for calcium imaging data.
The rapid progress of calcium imaging techniques has reached a point where the activity of thousands to tens of thousands of cells can be recorded simultaneously with single-cell resolution in a field-of-view (FOV) of about ten mm2. Consequently, there is a pressing need for developing automatic cell detection methods for large-scale image data. Several research groups have proposed automatic cell detection algorithms. Almost all algorithms can solve large-scale optimization problems for data, including hundreds of cells recorded from a conventional FOV at a resolution of 512 × 512 pixels, but the solution becomes more difficult as the data size increases beyond that. To handle large-scale data acquired with the latest large FOV microscopes, we propose a method called low computational cost cell detection (LCCD) that is based on filtering and thresholding. We compared LCCD with two other methods, constrained non-negative matrix factorization (CNMF) and Suite2P. We found that LCCD makes it possible to detect cells in artificial and actual data showing a high number density of cells within a shorter time and with an accuracy comparable to or better than those of CNMF and Suite2P. Moreover, LCCD succeeded in detecting more than 20,000 active cells from data acquired with the latest microscopy, called FASHIO-2PM, with a FOV of 3.0 mm × 3.0 mm.


Syntax and morphology in Williams syndrome.
Williams syndrome (WS) is a neuro-developmental disorder which is characterized by an unusual fractionation of language abilities and other cognitive functions. We have investigated four cases of English-speaking subjects with WS, and we show that despite their low IQs the WS children's performance on syntactic tasks and on regular inflection is not impaired. Irregular inflection, however, is affected causing many errors. We also report results from studies investigating the same linguistic phenomena in children with specific language impairment. These children exhibit a different pattern of impairment, with relatively poor performance on syntactic tasks and regular inflection. We suggest a linguistic characterization of the morphosyntax in WS according to which WS subjects are impaired in accessing (particular kinds of) information from lexical entries, with their computational system for language appearing to be intact. We interpret the selective impairments found in WS and SLI as supporting the theoretical distinction between a computational system and an associative memory system for language.


The role of membrane protein sulfhydryl groups in hydrogen peroxide-mediated membrane damage in human erythrocytes.
The formation of spectrin-hemoglobin complex following treatment of red cells with hydrogen peroxide (H2O2) has previously been shown to be associated with alterations in cell shape, decreased membrane deformability and increased recognition of modified cells by anti-IgM immunoglobulin in a phagocytic assay by monocytes. Prior treatment with carbon monoxide completely inhibited the H2O2-associated membrane changes, indicating a role for oxidized hemoglobin in the complex formation. Also, in a cell-free system, blockage of sulfhydryl (SH) groups on purified spectrin by N-ethylmaleimide significantly reduced the complex formation, suggesting a role for SH groups of spectrin in crosslinking process. The present study was undertaken to examine the role of SH blockade by N-ethylmaleimide on intact red cells undergoing oxidative damage. Pretreatment of erythrocytes with N-ethylmaleimide at concentrations ranging from 0.1 to 0.2 mM resulted in decreased lipid peroxidation and spectrin hemoglobin crosslinking. Moreover, pretreatment with N-ethylmaleimide resulted in less marked alterations in cell shape and membrane deformability as well as reduced recognition of peroxidized cells by antiglobulin serum. N-Ethylmaleimide treatment had no effect on methemoglobin formation. Studies with 14C-labeled N-ethylmaleimide showed that over 50% of N-ethylmaleimide was incorporated into spectrin. Pretreatment of cells with higher concentrations of N-ethylmaleimide (over 0.2 mM) was associated with membrane dysfunction independent of H2O2. These results imply that blocking of reactive SH groups leads to reduced interaction of spectrin with oxidized globin. These data, along with our prior observations, indicate that SH groups on spectrin play an important role in hemoglobin oxidation-induced formation of spectrin-hemoglobin complex and the resultant deleterious effects on membrane properties.


Halides inhibition of multicopper oxidases studied by FTIR spectroelectrochemistry using azide as an active infrared probe.
An infrared spectroelectrochemical study of Trametes hirsuta laccase and Magnaporthe oryzae bilirubin oxidase has been performed using azide, an inhibitor of multicopper oxidases, as an active infrared probe incorporated into the T2/T3 copper cluster of the enzymes. The redox potential-controlled measurements indicate that N3- stretching IR bands of azide ion bound to the T2/T3 cluster are only detected for the oxidized enzymes, confirming that azide only binds to Cu2+. Moreover, the process of binding/dissociation of azide ion is shown to be reversible. The interaction of halide anions, which also inhibit multicopper oxidases, with the active site of the enzymes was studied by measuring the changes in the azide FTIR bands. Enzymes inhibited by azide respond differently upon addition of fluoride or chloride ions to the sample solution inhibited by azide. Fluoride ions compete with azide for binding at one of the T2/T3 Cu ions, whereas competition from chloride ions is much less evident.


Ultrasound-induced destruction of heparin-loaded microbubbles attenuates L-arginine-induced acute pancreatitis.
Acute pancreatitis (AP) involves sudden inflammation caused by abnormal activation of pancreatic enzymes. The mechanisms underlying AP include oxidative stress, high levels of inflammatory mediators and inflammatory cell infiltration. Heparin, a key therapeutic drug, exerts anti-inflammatory, antioxidative, and anticoagulative effects. However, safe and effective drug delivery remains an obstacle. This study is the first to investigate the therapeutic effects of heparin-loaded microbubbles (HPMB) combined with ultrasound (UHPMB) and the role of heparin in acoustic cavitation. The characteristics of the microbubbles, including particle size, concentration, release, stability, and development, were studied. Heparin concentration in the HPMB was measured, and heparin-induced anticoagulation was evaluated. Drug safety was explored using hemolysis and cell viability assessments. The ability of HPMB to alleviate oxidative stress and inflammation were investigated in vitro. L-arginine induces AP in vivo. UHPMB was used for AP treatment. Serum amylase levels were measured and pancreatic architecture and pathological features were evaluated to determine AP severity. In vivo efficacy was evaluated, and the underlying mechanism of heparin action during acoustic cavitation was explored. HPMB was spherical and presented as an emulsion-like solution without aggregation. HPMB was visible and stable and effectively released the drug under ultrasound (US). HPMB and UHPMB led to lower AP severity than in the untreated group. US-targeted microbubble destruction (UTMD) enhanced the therapeutic effect by decreasing oxidative stress and inflammation in AP models without injuring vital organs. UHPMB regulated VEGF/Flt-1 and SOD-1 expression. HPMB can also mitigate oxidative stress and inflammation in H2O2-pretreated cells. UHPMB exhibits a strong ability not only to selectively target pancreatic lesions and release heparin but also to provide efficient protection by inhibiting oxidative stress and inflammation.


Focal nodular hyperplasia of the liver associated with portal vein agenesis: a morphological and immunohistochemical study of one case and review of the literature.
Congenital absence of portal vein (CAPV) is a rare malformation. To our knowledge, sixteen cases are reported in western literature. All the cases are associated with other diseases, cardiac malformations (12/17 patients; 16 plus the present case) and hepatic neoplasms being the most frequent observations. We present the case of a girl with a complex malformative syndrome consisting of multicystic kidney dysplasia, CAPV and nodular tumor-like mass of the liver. Angiography showed that the splenic vein and superior mesenteric vein joined to form a common trunk directly entering the inferior vena cava above the liver. A review of the CAPV cases of the literature and the clinical and pathological features of the hepatic lesion, classified as Focal Nodular Hyperplasia (FNH), are extensively discussed.


Extracorporeal shock wave lithotripsy for the treatment of bulbous urethral stones.
Extracorporeal shock wave lithotripsy was used to treat multiple, large, bulbous urethral calculi in a paraplegic man. Prior attempt at endoscopic extraction was unsuccessful owing to the size and location of the calculi. Two treatments of 3,000 shocks each resulted in fragmentation of the calculi


Definition, diagnosis, and management of COVID-19-associated pulmonary mucormycosis: Delphi consensus statement from the Fungal Infection Study Forum and Academy of Pulmonary Sciences, India.
COVID-19-associated pulmonary mucormycosis (CAPM) remains an underdiagnosed entity. Using a modified Delphi method, we have formulated a consensus statement for the diagnosis and management of CAPM. We selected 26 experts from various disciplines who are involved in managing CAPM. Three rounds of the Delphi process were held to reach consensus (≥70% agreement or disagreement) or dissensus. A consensus was achieved for 84 of the 89 statements. Pulmonary mucormycosis occurring within 3 months of COVID-19 diagnosis was labelled CAPM and classified further as proven, probable, and possible. We recommend flexible bronchoscopy to enable early diagnosis. The experts proposed definitions to categorise dual infections with aspergillosis and mucormycosis in patients with COVID-19. We recommend liposomal amphotericin B (5 mg/kg per day) and early surgery as central to the management of mucormycosis in patients with COVID-19. We recommend response assessment at 4-6 weeks using clinical and imaging parameters. Posaconazole or isavuconazole was recommended as maintenance therapy following initial response, but no consensus was reached for the duration of treatment. In patients with stable or progressive disease, the experts recommended salvage therapy with posaconazole or isavuconazole. CAPM is a rare but under-reported complication of COVID-19. Although we have proposed recommendations for defining, diagnosing, and managing CAPM, more extensive research is required.


Long-term cardiac arrest survivors of the Vienna emergency medical service.
The purpose of this study was to describe the life of survivors after successful resuscitation and to see if there was an association with the type of emergency cardiac care. The 'Utstein-style' data of patients surviving non-traumatic cardiac arrest 24 (14-32) months were prospectively collected. The everyday activities and psychological concerns of patients with a cerebral performance category (CPC) of 1 and 2 using a questionnaire were analyzed. The chi2-square test was used for statistical analysis. The questionnaires of 92 patients (median age 59, IQR 51-68; females 36) were evaluated. Patients enjoy life (84%; n=73), have depression (36%; n=31), consider their survival a 'second chance' (84%; n=73) and fear that they may suffer cardiac arrest again (56%; n = 45). The average quality of life is 7 on a scale from 0 (worst) to 10 (perfect). The majority of cardiac arrest survivors have a satisfactory life. No significant correlation between the type of emergency cardiac care and post cardiac arrest life was found. The fact that there was no association with the type of emergency cardiac care may be due to the narrow selection of patients (CPC 1 and 2), the small number of patients or factors contributing to post cardiac arrest life other than emergency treatment.


New Insights into and Emerging Roles of Animal Models for Neurological Disorders.
Many researchers rely on animal studies to elucidate the mechanisms underlying diverse disease processes and to test the safety of emerging medical interventions [...].


Fabrication, characterization of two nano-composite CuO-ZnO working electrodes for dye-sensitized solar cell.
Two kind of CuO-ZnO nanocomposite working electrodes were synthesized by sol-gel technology and applied in dye-sensitized solar cells (DSSCs). Their characteristics were studied by field emission scanning electron microscopy (FESEM), X-ray diffraction (XRD) and UV-Vis diffuse reflectance spectrum (DRS). CuO-ZnO nanocomposite thin films were prepared doctor blade technique on the fluorine-doped tin oxide (FTO) and used as working electrodes in dye sensitized solar cells (DSSC). Their photovoltaic behavior were compared with standard using D35 dye and an electrolyte containing [Co(bpy)3](PF6)2, [Co(pby)3](PF6)3, LiClO4, and 4-tert-butylpyridine (TBP). The ranges of short-circuit current (JSC) from 0.18 to 0.21 (mA/cm(2)), open-circuit voltage (VOC) from 0.24 to 0.55V, and fill factor from 0.34 to 0.39 were obtained for the DSSCs made using the working electrodes. The efficiency of the working electrodes after the addition of TBL was more than doubled. The light scattering and carrier transport properties of these composites promote the performance of dye-sensitized solar cells (DSSCs).


Habilitation of patients with congenital malformations associated with thalidomide: psychiatric and psychological aspects.
Nearly 100 cases of congenital malformations associated with thalidomide ingestion by the mother have been reported in Canada to the Department of National Health and Welfare. Depression and selfcastigation have been the specific psychiatric reactions noted, particularly in the mother. In most cases it is preferable psychologically for the parents and the child if the child is kept at home rather than placed in an institution. Parents should be fully informed concerning the child's prognosis for future development. Most of the children followed up for about two years showed no intelligence defects. A prosthesis, if required, should be applied early (at three to six months) so that it may become a part of the child's body-image, but it should not interfere with play activities. Assessment by a psychiatrist and a psychologist is indicated at about six months.


Black Lives Matter in Science Engineering and Medicine : Cato T. Laurencin, M.D., Ph.D.: Winner of the 2020 Herbert W. Nickens Award of the Association of American Medical Colleges, Acceptance Remarks.
Addressing racism is key in moving forward as a nation and creating a more equitable environment. Within this paper, Cato T. Laurencin, M.D., Ph.D. describes the critical need to shift from diversity, inclusion, and equity (D.I.E.) to inclusion, diversity, equity, anti-racism, and learning (I.D.E.A.L.).


Prenatal 3- and 4-dimensional ultrasonographic findings of giant fetal nuchal hemangioma.
A precise prenatal diagnosis of hemangioma may be uncertain although a variety of the antenatal appearances on 2-dimensional sonography have been reported. A 27-year-old primigravida was referred at 32 weeks of gestation for evaluation of a fetal nuchal mass. Two-dimensional sonography showed an extracranial mixed echogenic mass (65 x 54 x 59 mm) occupying the posterior neck. Color Doppler imaging revealed intense hypervascularization. Three-dimensional (3D) and 4-dimensional (4D) sonography showed that the mass was lobulated, with a lumpy internal structure. Nuchal hemangioma was further confirmed by clinical examination and postnatal magnetic resonance imaging. The tumor began to regress in size when the infant was 7 months old. Prenatal 3D/4D ultrasound techniques could be considered as complementary diagnostic tools for such a tumor. They have the advantages of providing accurate and inexpensive virtual reality images through more realistic interactions with the virtualized in utero condition.


Differential partitioning of tRNAs between micellar and aqueous phases: a convenient gel filtration method for separation of tRNAs.
Partition coefficients (Kp) of phenylalanine, glutamic acid-II and tyrosine tRNAs between water and micellar cetyltrimethylammonium chloride (CTACl) have been determined to be 5600, 520 and 3100, respectively, by gel filtration on Sephadex G-100-120. Equations for obtaining Kp values from quantitative gel filtration have also been derived. The use of this method for the separation of tRNAs is demonstrated.


Renal expression of parathyroid hormone-related protein (PTHrP) and PTH/PTHrP receptor in a rat model of tubulointerstitial damage.
PTHrP, which appears to act as a growth/differentiation factor in a variety of tissues, is present in the kidney; however, its role is unclear. The expression of PTHrP and the PTH/PTHrP receptor were investigated by reverse transcription-polymerase chain reaction (RT-PCR) and immunohistochemistry in the remnant kidney of uninephrectomized (UNX) rats after protein overloading [1 g/day of bovine serum albumin (BSA)]. Compared with UNX-control rats, proteinuria in BSA-overloaded animals was detected within the first 24 hours and increased during the entire study period (28 days). Kidney examination by light microscopy showed no significant renal lesions at day 1 of BSA treatment, whereas at days 8 and 28, tubular lesions, infiltration of mononuclear cells, and mesangial expansion were observed. PTHrP mRNA expression in the renal cortex was already increased at day 1 (fourfold) and plateaued between days 8 and 28 (12- and 15-fold, respectively) in BSA-overloaded animals compared with UNX-control rats. At day 8, immunohistochemical analysis with two different anti-PTHrP antibodies showed a dramatic increase of PTHrP staining in the damaged proximal and distal tubules from BSA-overloaded rats with respect to UNX-control rats. Moreover, intense PTHrP immunostaining was also observed in glomerular mesangial and endothelial cells in BSA-overloaded rats, but not in the UNX-control rats. A reciprocal decrease of PTH/PTHrP receptor mRNA and immunostaining, without significant changes in the cellular localization (proximal and distal tubule, and glomerular mesangial and epithelial cells) of the PTH/PTHrP receptor positivity was found to occur in the renal cortex of BSA-overloaded rats. At day 8, coinciding with the up-regulation of PTHrP, an increase in the angiotensin converting enzyme and preproendothelin-1 gene expression was observed in the renal cortex of BSA-overloaded rats compared with UNX-control rats. These results indicate that PTHrP can be added to the group of genes that are up-regulated in proximal tubular cells in response to intense proteinuria. Our results, together with previous findings, suggest that the vasoactive hormones angiotensin II and endothelin-1 could participate in the PTHrP production in the renal cortex of BSA-overloaded rats. Further experiments are required to clarify the mechanisms of PTHrP up-regulation and its possible role in the response to renal damage in this animal model.


A tomato disease identification method based on leaf image automatic labeling algorithm and improved YOLOv5 model.
Tomato is one of the most important vegetables in the world. Timely and accurate identification of tomato disease is a critical way to ensure the quality and yield of tomato production. The convolutional neural network is a crucial means of disease identification. However, this method requires manual annotation of a large amount of image data, which wastes the human cost of scientific research. To simplify the process of disease image labeling and improve the accuracy of tomato disease recognition and the balance of various disease recognition effects, a BC-YOLOv5 tomato disease recognition method is proposed to identify healthy growth and nine types of diseased tomato leaves. In the present study, the YOLOv5 model is improved by designing an automatic tomato leaf image labeling algorithm, using the weighted bi-directional feature pyramid network to change the Neck structure, adding the convolution block attention module, and changing the input channel of the detection layer. Experiments show that the BC-YOLOv5 method has an excellent image annotation effect on tomato leaves, with a pass rate exceeding 95%. Furthermore, compared with existing models, the performance indices of BC-YOLOv5 to identify tomato diseases are the best. BC-YOLOv5 realizes the automatic labeling of tomato leaf images before the start of training. This method not only identifies nine common tomato diseases, but also improve the accuracy of disease identification and have a more balanced identification effect on various diseases. It provides a reliable method for the identification of tomato disease. © 2023 Society of Chemical Industry.


Use of fluorescent dyes as molecular probes for the study of multidrug resistance.
Fluorescence microscopy has shown that 18 different fluorescent dyes, staining various intracellular structures in transformed hamster fibroblasts (DM-15), did not stain or stained weakly multidrug-resistant cells selected from DM-15 by colchicine. Reduced staining by fluorescent dyes was characteristic also of five other tested multidrug-resistant cell lines of hamster and mouse origin, selected by actinomycin D, colcemid, rubomycin, and ruboxyl. The intensity of staining of two revertant cell lines was similar to that of parental sensitive cells. All tested inhibitors of multidrug resistance, including weak detergent, metabolic inhibitors, calcium channel blockers, calmodulin inhibitors, and reserpine, restored normal staining of multidrug-resistant cells. The dyes accumulated in resistant cells in presence of these inhibitors left the cells several minutes after the removal of the inhibitor from the incubation medium. Sensitive cells retained the dyes for several hours. The efflux of the dyes from resistant cells is an active process since it occurred even in the presence of the dyes in the incubation medium. The efflux could be blocked by all tested inhibitors of multidrug resistance and it is possibly a basic mechanism of the reduced staining of resistant cells. These data support the idea that multidrug resistance is based on active nonspecific efflux of the drugs and indicate that the simple procedure of cell staining can be used for the detection of resistant cells and further study of the phenomenon of multidrug resistance.


Binding properties of (+/-)[3H]benidipine hydrochloride to rat heart membranes.
Benidipine is a newly developed slow-onset and long-lasting dihydropyridine calcium antagonist. The kinetics of specific binding of (+/-)[3H]benidipine to the dihydropyridine receptor sites in rat heart membranes were assessed. The dissociation constant (Kd) and the maximal number of binding sites were 0.078 +/- 0.029 nM and 286 +/- 6 fmol/mg of protein, respectively. Association and dissociation rate constants of (+/-)[3H]benidipine binding were 4 and 50 times smaller, respectively, than those of (+/-)[3H]nitrendipine binding. In displacement studies, the decreasing order of potency was benidipine, nisoldipine, nicardipine, nitrendipine, nifedipine, and Bay K 8644. A high stereoselectivity was observed, with Ki values of 0.028 nM in the S-S-(+) isomer and 4.4 nM in the R-R-(-) isomer of this drug. Benidipine had a high affinity for specific binding, with an inhibition constant of 0.084 nM, which was in good agreement with the Kd value stated above. Among the stimulants and blockers of alpha- and beta-adrenergic, cholinergic, histaminergic, dopaminergic, serotonergic, or GABAergic receptors, no drug inhibited or enhanced specific (+/-)[3H]benidipine binding. These binding properties of (+/-)[3H]benidipine may explain its unique slow onset and long-lasting antihypertensive activities.


Hydrolytic depolymerization of hydrolysis lignin: Effects of catalysts and solvents.
Hydrolytic depolymerization of hydrolysis lignin (HL) in water and water-ethanol co-solvent was investigated at 250°C for 1h with 20% (w/v) HL substrate concentration with or without catalyst (H2SO4 or NaOH). The obtained depolymerized HLs (DHLs) were characterized with GPC-UV, FTIR, GC-MS, (1)H NMR and elemental analyzer. In view of the utilization of depolymerized HL (DHL) for the preparation of rigid polyurethane foams/resins un-catalyzed depolymerization of HL employing water-ethanol mixture appeared to be a viable route with high yield of DHL ∼70.5wt.% (SR yield of ∼9.8wt.%) and with Mw as low as ∼1000g/mole with suitable aliphatic (227.1mgKOH/g) and phenolic (215mgKOH/g) hydroxyl numbers. The overall % carbon recovery under the selected best route was ∼87%. Acid catalyzed depolymerization of HL in water and water-ethanol mixture lead to slightly increased Mw. Alkaline hydrolysis helped in reducing Mw in water and opposite trend was observed in water-ethanol mixture.


TikTok use and psychosocial factors among adolescents: Comparisons of non-users, moderate users, and addictive users.
Short-video applications like TikTok are increasingly popular. This study examines the association between short-video application use (SVU) and psychosocial factors in 1,346 adolescents (Mage = 14.97, 51.8% female). 199 non-users and 1147 users (686 moderate users, 461 addictive users) were identified. Results revealed a high prevalence of addictive SVU in the sample. Addictive users exhibited worse mental health conditions than non-users and moderate users, including higher levels of depression, anxiety, stress, loneliness, social anxiety, attention problems, and lower life satisfaction and sleep quality. Addictive users also faced higher academic stress, poorer academic performance, more bullying victimization, worse parental relationships, more negative parenting styles, and lower parental education levels. Moderate users had different family environments than non-users, but no differences in mental health or school performance. Together, these findings suggest that addictive users experience a more disadvantageous situation across mental health, family, and school conditions, while non-users have advantageous family environments. Moderate SVU may not be associated with negative mental health condition or poor school performance. Moderate and addictive SVU should be considered distinct phenomena. Given the psychiatric symptoms present in addictive users of TikTok and similar apps, targeted interventions and treatments are urgently needed.


Correction to: Urinary metabolites of polycyclic aromatic hydrocarbons in pregnant women and their association with a biomarker of oxidative stress.
The correct name of the 1st Author is shown in this paper.


Structure and evolution of the human genes encoding protein C and coagulation factor IX.
Human protein C is a vitamin K-dependent plasma protein that serves as a feedback down-regulator of the coagulation cascade by specifically degrading the protein cofactors VIIIa and Va. The protein C precursor consists of the following domains: leader peptide, "gla" region, two epidermal growth factor segments, and the activation peptide/serine protease. Comparison of amino acid sequences reveals that protein C and factor IX are homologous. A comparison of the genes for protein C and factor IX shows that all seven of the introns within the protein coding regions are in identical positions and correspond to protein structure-function domain boundries. However, the base compositions of the two genes (coding and noncoding regions) are remarkably different: approximately 60% guanine + cytosine (G + C) for protein C versus approximately 40% G + C for factor IX. One possible explanation for this phenomenon is that the factor IX gene (located on the X chromosome) has undergone extensive deoxycytosine methylation and subsequent spontaneous deamination mutagenesis, resulting in a net C to thymine (and G to adenine) transition. This would suggest that the protein C gene may represent a more primitive form of the gene duplication precursor.


Prefrontal working memory activity predicts episodic memory performance: A neuroimaging study.
Working memory (WM) and long term memory (LTM) are different neuropsychological processes, although distinction between these domains is an area of debate. LTM is thought to rely on hippocampal circuitry. Cognitive neuroscience models imply that WM processing may at least partially support LTM within regions of the prefrontal cortex (PFC). We sought to determine the association between PFC based WM processing and LTM in the visuospatial domain. In contrast to prior work, we aimed to query if WM was involved in learning and free recall trials as measured by standard neuropsychological tests of LTM. Forty-three older adults (24 with a diagnosis of amnestic Mild Cognitive Impairment and 19 elderly controls) were included in the analysis. Patients completed a fMRI task of visuospatial maintenance WM in which they were required to match a previously studied complex shape with one of two probes. Extent of activity in the right PFC during the WM task was tabulated for each patient. Hippocampal volume was quantified from T1 scans. On a separate day patients completed neuropsychological testing, including the Brief Visuospatial Memory Test- Revised (BVMT-R), which includes learning trials (total recall), delayed free recall, and recognition. Right PFC activity was associated with performance on BVMT-R total recall and delayed recall. Results from multiple regression showed that PFC activity explained an additional 9 % of the variance in memory performance above right hippocampal volume. These findings suggest that PFC processing that supports WM (including stimuli maintenance, retrieval, and selection) are also involved in LTM learning and recall.


Regulation of cytosolic free calcium in rabbit proximal renal tubules.
The relative role of various Ca2+ transport systems in the regulation of Ca2+ cytosolic free Ca2+ concentration was evaluated using rabbit renal proximal tubules. Intracellular compartmentation was evaluated through Ca2+ releases induced by carbonyl cyanide p-trifluoromethoxyphenylhydrazone (FCCP), A23187, and ruthenium red (RR) alone and in combination. In a Ca2+-free solution after 1 h of incubation, FCCP released 43 +/- 4%, A23187 54 +/- 3%, and RR 29 +/- 5% of total cellular Ca2+; in addition, RR inhibited the rate of FCCP-induced release, confirming its mitochondrial origin. In 1 mM Ca2+, the releases were 57 +/- 9%, 70 +/- 5%, and 34 +/- 10%, respectively. Therefore, the mitochondrial Ca2+ content is 20-60 nmol/mg of mitochondrial protein, sufficiently large to effectively buffer cell Ca2+. To evaluate the role of the plasma membrane Na:Ca exchanger, 10(-4) M ouabain was added and caused a slight decline in total cell Ca2+ content and no change in ionized Ca2+ measured by the null-point method, suggesting that the plasmalemmal Na+:Ca2+ exchanger does not play an important role in Ca2+ extrusion. Cytosolic free Ca2+ increased when 100 mM sodium was replaced with equimolar choline or tetramethylammonium. However, tetramethylammonium replacement released 55% of the mitochondrial Ca2+ content by increasing mitochondrial Ca2+ efflux without affecting the Ca2+ influx pathway. These results suggest that Na+ replacements in this tissue increase ionized Ca2+ by increasing mitochondrial Ca2+ efflux and not by inhibition of Na+:Ca2+ exchange at the plasma membrane.


Introduction of d-Glutamate at a Critical Residue of Aβ42 Stabilizes a Prefibrillary Aggregate with Enhanced Toxicity.
The amyloid beta peptide 42 (Aβ42) is an aggregation-prone peptide that plays a pivotal role in Alzheimer's disease. We report that a subtle perturbation to the peptide through a single chirality change at glutamate 22 leads to a pronounced delay in the β-sheet adoption of the peptide. This was accompanied by an attenuated propensity of the peptide to form fibrils, which was correlated with changes at the level of the fibrillary architecture. Strikingly, the incorporation of d-glutamate was found to stabilize a soluble, ordered macromolecular assembly with enhanced cytotoxicity to PC12 cells, highlighting the importance of advanced prefibrillary Aβ aggregates in neurotoxicity.


Effects of CYP2C9*3 and *13 alleles on the pharmacokinetics and pharmacodynamics of glipizide in healthy Korean subjects.
Glipizide is a second-generation sulfonylurea antidiabetic drug. It is principally metabolized to inactive metabolites by genetically polymorphic CYP2C9 enzyme. In this study, we investigated the effects of CYP2C9*3 and *13 variant alleles on the pharmacokinetics and pharmacodynamics of glipizide. Twenty-four healthy Korean volunteers (11 subjects with CYP2C9*1/*1, 8 subjects with CYP2C9*1/*3, and 5 subjects with CYP2C9*1/*13) were recruited for this study. They were administered a single oral dose of glipizide 5 mg. The plasma concentration of glipizide was quantified for pharmacokinetic analysis and plasma glucose and insulin concentrations were measured as pharmacodynamic parameters. The results represented that CYP2C9*3 and *13 alleles significantly affected the pharmacokinetics of glipizide. In subjects with CYP2C9*1/*3 and CYP2C9*1/*13 genotypes, the mean AUC0-∞ were increased by 44.8% and 58.2%, respectively (both P < 0.001), compared to those of subjects with CYP2C9*1/*1 genotype, while effects of glipizide on plasma glucose and insulin levels were not significantly different between CYP2C9 genotype groups. In conclusion, individuals carrying the defective CYP2C9*3 and CYP2C9*13 alleles have markedly elevated plasma concentrations of glipizide compared with CYP2C9*1/*1 wild-type.


Effect of an ionic liquid on the physicochemical properties of chitosan/poly(vinyl alcohol) mixtures.
Mixtures containing two polymers, chitosan (Ch) and poly(vinyl alcohol) (PVA) as well as mixtures with addition of an ionic liquid (IL) 1-butyl-3-methyl-imidazolium chloride (BMIM+Cl-) were prepared via casting from aqueous solutions. The morphology, mechanical and surface properties of Ch/PVA mixture films were characterized by scanning electron microscopy (SEM), atomic force microscopy (AFM), thermogravimetric analysis (TGA), infrared spectroscopy (ATR-FTIR), contact angle measurements and tensile tests. Rheological studies were performed via solutions of pure polymers and their mixtures with and without the addition of an ionic liquid. The viscosity curves of mixtures were found to lie between those of pure components over the entire compositional range. The non-Newtonian index (n) of these mixtures were determined by the power law model indicating shear-thinning behavior with pseudoplasticity increasing with an increasing weight fraction of chitosan. Results obtained from SEM, AFM, contact angle measurements, TGA and infrared spectroscopy (ATR-FTIR) were compared and showed that the addition of an ionic liquid is beneficial to the formation of intermolecular forces and the network structure between the polymer and mixture films, which leads to an improvement in the properties of these materials.


Individually programmable cell stretching microwell arrays actuated by a Braille display.
Cell culture systems are often static and are therefore nonphysiological. In vivo, many cells are exposed to dynamic surroundings that stimulate cellular responses in a process known as mechanotransduction. To recreate this environment, stretchable cell culture substrate systems have been developed, however, these systems are limited by being macroscopic and low throughput. We have developed a device consisting of 24 miniature cell stretching chambers with flexible bottom membranes that are deformed using the computer-controlled, piezoelectrically actuated pins of a Braille display. We have also developed efficient image capture and analysis protocols to quantify morphological responses of the cells to applied strain. Human dermal microvascular endothelial cells (HDMECs) were found to show increasing degrees of alignment and elongation perpendicular to the radial strain in response to cyclic stretch at increasing frequencies of 0.2, 1, and 5 Hz, after 2, 4, and 12h. Mouse myogenic C2C12 cells were also found to align in response to the stretch, while A549 human lung adenocarcinoma epithelial cells did not respond to stretch.


[What are the factors affecting fertility in 2008?].
The number of infertile couples to be cared for in infertility centres is estimated to be between 1 to 6 %. This figure has been rising over the past years. During the 24th annual meeting of the ESHRE (European society of Human Reproduction) in Barcelona, changes in the population of infertile couples have been analysed. The major trend is an increase in women's age but also in men's age when desiring their first child. This mean rise has reached more than two years for women's age, over the past 10 years. The negative influence of the woman's age on fertility, especially after 35 years, is clearly established. However, new data in men suggest that an age higher than 35 years could be linked to an increased rate of miscarriages. The concept of preconceptionnal care in order to detect comorbidities, especially smoking, overweight and diabetes has been emphasized. Furthermore, the influence of current lifestyles on fertility, a potential role of endocrine disrupters, represent new concerns, which are in line with a policy of preventive care of infertility. Lastly, patients undergoing treatment with gonadotoxic drugs represent a 'new" population in fertility clinics. Techniques of testicular and ovarian preservation, especially frozen oocytes, must be disseminated and improved in order to prevent infertility in those patients.


A fluoroscopic burn to a patient's right hand sustained in removing a sewing needle--a 22-year follow-up.
Severe radiation burns to the skin and deeper tissues resulting from diagnostic radiology have fortunately been very rare in the United Kingdom. It is hoped they will now be only of historical or academic interest. For this reason a very severe radiation burn to the right hand of a young woman, caused by prolonged fluoroscopy in removing a metalic foreign body, is described. This resulted in a severe sloughing of the skin of the dorsum of the hand that had to be grafted. Subsequently progressive bone necrosis occurred and the hand has never been fully useful since the accident. It is noteworthy that a surgical assistant also sustained radiation burns to the fingers.


Hyperammonemia increases serotonin 1A receptor expression in both rat hippocampus and a transfected hippocampal cell line, HN2-5.
Hyperammonemia is an important cause of cerebral dysfunction in liver failure. We used two well-established models to induce hyperammonemia in rats, injection of urease and injection of methionine sulfoximine (MSO). Urease gave a 10-fold increase in blood ammonia while MSO, a glutamine synthetase inhibitor, gave a 4-fold increase in blood ammonia with no increase in brain glutamine levels. We observed a 2-fold increase in 5-HT1A receptor (5-HT1A-R) expression ([3H] 8-OH-DPAT binding) in hippocampus, and little change elsewhere, including thalamus in both models, thus eliminating a role for increased glutamine in the receptor induction. In contrast, a 4 to 8-fold increase in 5-HT1A-R mRNA was observed both in hippocampus and thalamus, suggesting some post-transcriptional regulation. In the absence of glutamine, ammonium acetate treatment of a hippocampal cell line which had been engineered to stably express the 5-HT1A-R (HN2-5) gave a 1.5-fold increase in [3H] 8-OH-DPAT binding and a 4-fold increase in the mRNA levels for the 5-HT1A-R. We conclude that the cell line HN2-5 is a good model for studying some of the biochemical sequelae of hyperammonemia and that changes in brain function are not only at the metabolic level, as thought earlier, but can also occur at the transcriptional level.


Effect of intermittent feedback control on robustness of human-like postural control system.
Humans have to acquire postural robustness to maintain stability against internal and external perturbations. Human standing has been recently modelled using an intermittent feedback control. However, the causality inside of the closed-loop postural control system associated with the neural control strategy is still unknown. Here, we examined the effect of intermittent feedback control on postural robustness and of changes in active/passive components on joint coordinative structure. We implemented computer simulation of a quadruple inverted pendulum that is mechanically close to human tiptoe standing. We simulated three pairs of joint viscoelasticity and three choices of neural control strategies for each joint: intermittent, continuous, or passive control. We examined postural robustness for each parameter set by analysing the region of active feedback gain. We found intermittent control at the hip joint was necessary for model stabilisation and model parameters affected the robustness of the pendulum. Joint sways of the pendulum model were partially smaller than or similar to those of experimental data. In conclusion, intermittent feedback control was necessary for the stabilisation of the quadruple inverted pendulum. Also, postural robustness of human-like multi-link standing would be achieved by both passive joint viscoelasticity and neural joint control strategies.


Prevention of Staphylococcus aureus biofilm formation and reduction in established biofilm density using a combination of phage K and modified derivatives.
To investigate the ability of a mixture of phage K and six of its modified derivatives to prevent biofilm formation by Staphylococcus aureus and also to reduce the established biofilm density. The bioluminescence-producing Staph. aureus Xen29 strain was used in the study, and incubation of this strain in static microtitre plates at 37°C for 48 h confirmed its strong biofilm-forming capacity. Subsequently, removal of established biofilms of Staph. aureus Xen29 with the high-titre phage combination was investigated over time periods of 24 h, 48 h and 72 h. Results suggested that these biofilms were eliminated in a time-dependent manner, with biofilm biomass reduction significantly greater after 72 h than after 24-48 h. In addition, initial challenge of Staph. aureus Xen29 with the phage cocktail resulted in the complete inhibition of biofilm formation over a 48-h period with no appearance of phage resistance. In general, our findings demonstrate the potential use of a modified phage combination for the prevention and successful treatment of Staph. aureus biofilms, which are implicated in several antibiotic-resistant infections. This study highlights the first use of phage K for the successful removal and prevention of biofilms of Staph. aureus.


Uncovering the microbiota in renal cell carcinoma tissue using 16S rRNA gene sequencing.
Increasing evidence indicates an important role of microbiota in cancer development and progression, while little is known about the correlation between microbiota and renal cell carcinoma (RCC). Thus, we performed this study to profile the intratumoral microbiota possibly associated with RCC. Paired RCC and adjacent normal tissue samples were collected from 24 patients with RCC. V3-V4 variable region of microbial 16S rRNA gene was sequenced using Illumina MiSeq. Sequencing reads were processed using QIIME. Differentially abundant bacterial taxa between groups were identified by LEfSe, and their potential functions were inferred by PICRUSt. Decreased species diversity was presented in RCC tissues (Simpson index, P = 0.0340), and the composition of the bacterial community in RCC tissues was significantly distinct from that in normal tissues (unweighted UniFrac distance, P = 0.026; weighted UniFrac distance, P = 0.017). Compared with normal tissues, 25 taxa increased and 47 reduced taxa were identified in RCC tissues. Among these taxa, the class Chloroplast (AUC = 0.91, P < 0.0001) and the order Streptophyta (AUC = 0.89, P < 0.0001) showed high indication accuracy to discriminate RCC tissues from normal tissues. Furthermore, nine altered pathways were identified in RCC tissues to reveal the potential microbial function. Our results have uncovered the presence of distinct microbiota in RCC and adjacent normal tissues and provided a better understanding of the possible role of the intratumoral microbiota in RCC. Further studies are required to confirm our results and determine the real correlation between microbiota and RCC.


The use of the terrestrial snails of the genera Megalobulimus and Thaumastus as representatives of the atmospheric carbon reservoir.
In Brazilian archaeological shellmounds, many species of land snails are found abundantly distributed throughout the occupational layers, forming a contextualized set of samples within the sites and offering a potential alternative to the use of charcoal for radiocarbon dating analyses. In order to confirm the effectiveness of this alternative, one needs to prove that the mollusk shells reflect the atmospheric carbon isotopic concentration in the same way charcoal does. In this study, 18 terrestrial mollusk shells with known collection dates from 1948 to 2004 AD, around the nuclear bombs period, were radiocarbon dated. The obtained dates fit the SH1-2 bomb curve within less than 15 years range, showing that certain species from the Thaumastus and Megalobulimus genera are reliable representatives of the atmospheric carbon isotopic ratio and can, therefore, be used to date archaeological sites in South America.


The accelerator, the brake, and the terrain: associations of reward-related eating, self-regulation, and the home food environment with diet quality during pregnancy and postpartum in the pregnancy eating attributes study (PEAS) cohort.
Neurobehavioral factors, including reward-related eating and self-regulation, in conjunction with the food environment, may influence dietary behaviors. However, these constructs have not been examined in pregnancy and postpartum, a time of changing appetite and eating behaviors, and when dietary intake has implications for maternal and child health. This study examined associations of reward-related eating, self-regulation, and the home food environment with pregnancy and postpartum diet quality. Participants in the Pregnancy Eating Attributes Study observational cohort were enrolled at ≤12 weeks gestation and followed through one-year postpartum. Pregnancy and postpartum Healthy Eating Index-2015 (HEI-total), and adequacy and moderation scores, respectively, were calculated by pooling 24-h diet recalls administered each trimester and during 2, 6, and 12 months postpartum. Participants completed four measures of reward-related eating - Modified Yale Food Addiction Scale (mYFAS), Power of Food Scale (PFS), Multiple Choice Procedure (MCP), and Reinforcing Value of Food Questionnaire (RVFQ); two measures of self-regulation - Barratt Impulsiveness Scale (BIS) and Delay of Gratification Inventory (DGI); and a Home Food Inventory (HFI), yielding obesogenic (OBES) and fruit/vegetables (FV) scores. Linear regression analyses estimated associations of reward-related eating, self-regulation, and home food environment with diet quality during pregnancy and postpartum, adjusting for sociodemographic characteristics. Pregnancy HEI-total was inversely associated with PFS (β = - 0.14 ± 0.05, p = 0.009), mYFAS(β = - 0.14 ± 0.06, p = 0.02), 2 of the 5 RVFQ indices, MCP (β = - 0.14 ± 0.05, p = 0.01), and DGI food subscale (β = 0.23 ± 0.05, p < 0.001), but associations of postpartum HEI-total with reward-related eating measures and self-regulation were small and not statistically significant. Pregnancy and postpartum HEI-total were associated inversely with HFI-OBES (β = - 0.17 ± 0.06, p = 0.004 and β = - 0.19 ± 0.07, p = 0.006, respectively), and positively with HFI-FV (β = 0.21 ± 0.05, p < 0.001 and β = 0.17 ± 0.06, p = 0.009, respectively). Associations of poorer diet quality with greater reward-related eating during pregnancy but not postpartum suggests the need to better understand differences in the determinants of eating behaviors and approaches to circumvent or moderate reward-related eating to facilitate more optimal diet quality across this critical period. Clinicaltrials.gov . URL - Registration ID - NCT02217462 . Date of registration - August 13, 2014.


Simultaneous diffusion-weighted magnetic resonance images and brain blood perfusion scintigraphy for a transient lesion in the splenium of the corpus callosum.
A transient lesion in the splenium of the corpus callosum is a rare disease and its pathogenesis is unclear. We performed simultaneous diffusion-weighted magnetic resonance images and brain blood perfusion scintigraphy for a transient lesion in the splenium of the corpus callosum. This transient lesion showed hyperintensity on the diffusion-weighted images and hypointensity on the apparent diffusion coefficient map. However, normal blood perfusion was observed on brain blood perfusion scintigraphy. Transient axonal or intramyelinic edema might be a cause of the transient lesion in the splenium of the corpus callosum.


Identification of the forms of cytochrome P-450 induced in rat liver by 2-acetylaminofluorene using immunoblotting and partial purification.
The amounts of 5 different forms of cytochrome P-450 in liver microsomes from rats treated with 2-acetylaminofluorene were determined and compared with the corresponding patterns in microsomes from control, 3-methylcholanthrene- and phenobarbital-treated animals. 2-Acetylaminofluorene was found to increase the amount of cytochromes P-450b + e 10-fold and of cytochrome P-450d 3-fold, while there was a 54% increase in the level of cytochrome P-450 PB/PCN-E. Cytochrome P-450c was increased from a level too low to detect (less than 0.001 pmol/mg protein) to 0.019 pmol/mg protein. These findings were also confirmed by partial purification of cytochromes P-450b + e and c after 2-acetylaminofluorene treatment.


Host-pathogen interactions in natural populations of Linum marginale and Melampsora lini : III. Influence of pathogen epidemics on host survivorship and flower production.
The epidemiology of rust caused by the fungus Melampsora lini and the effects of infection by this pathogen on its host, the herbaceous perennial Linum marginale, were determined in the field and in garden experiments. There was considerable natural variability in disease levels over the four years (1986-1989) of the study. In two years (1986, 1989) major rust epidemics occurred. In the field, the main effect of disease was to reduce survivorship during the winter following infection. Plants which were heavily infected during the 1986 or 1989 growing seasons had reduced survivorship relative to more lightly infected plants. Melampsora lini infections did not appear to affect survivorship in either 1987 or 1988. Flowering was correlated with environmental factors and the number of stems a plant possessed. A severe drought in 1987 completely inhibited flowering. In the other three years the number of flowers produced by a plant was strongly positively correlated with the number of stems it possessed. Disease levels had no consistent effect on flowering. Controlled garden experiments were also used to examine the response of seedlings and adult plants to infection. These showed that both the timing and severity of disease appears to determine the effect of M. lini infections on L. marginale. Early, severe infection reduced growing season and overwintering survivorship as well as capsule production. However, plants in the field were most often infected only after flowering had begun, and the predominant effect of infection was a reduction in overwintering survivorship. The high variability in disease levels from year to year and the deferred nature of the effect of the rust on its host have significant implications for the design of experiments aimed at assessing the role of diseases in plant communities.


Protocol of a randomised phase III clinical trial of sequential capecitabine or 5-fluorouracil plus bevacizumab (Cape/5-FU-Bmab) to capecitabine or 5-fluorouracil plus oxaliplatin plus bevacizumab (CapeOX/mFOLFOX6-Bmab) versus combination CapeOX/mFOLFOX6-Bmab in advanced colorectal cancer: the C-cubed (C3) study.
Results from several randomised trials suggest that the sequential use of cytotoxic agents in patients with metastatic colorectal cancer (mCRC) has the potential to improve overall survival compared with combination chemotherapy. This study is designed to investigate whether sequential treatment with bevacizumab-based first-line treatment with oxaliplatin is superior to combination treatment of mCRC. The C-cubed (C(3)) study is a two-arm, multicentre, open-label, randomised phase III trial in Japan comparing the efficacy and safety of sequential capecitabine or 5-fluorouracil plus bevacizumab (Cape/5-FU-Bmab) with escalation to capecitabine or 5-fluorouracil plus oxaliplatin plus bevacizumab (CapeOX/mFOLFOX6-Bmab) versus combination CapeOX/mFOLFOX6-Bmab as the first-line treatment of mCRC. In the sequential arm (Arm A: oxaliplatin 'wait-and-go'), treatment escalation from Cape/5-FU-Bmab to CapeOX/mFOLFOX6-Bmab is recommended in the case of progressive disease. In the combination arm (Arm B: oxaliplatin 'stop-and-go'), de-escalation from CapeOX/mFOLFOX6-Bmab to Cape/5-FU-Bmab is possible after 12 weeks of treatment. Re-escalation to CapeOX/mFOLFOX6-Bmab after progressive disease is considered only for patients who received de-escalation of oxaliplatin after 12 weeks of treatment not caused by oxaliplatin-associated toxicity. A target sample size of 304 evaluable patients is considered sufficient to validate an expected HR for time to failure of strategy of the sequential approach 'wait-and-go' compared to the combination approach 'stop-and go' with 80% power and 2-sided 5% α in case of a true HR<0.69. This study is conducted according to the standards of Good Clinical Practice and in compliance with the Declaration of Helsinki 2013 and local regulations, and has been submitted and approved by the Ethical Committee of the Non-Profit Organization MINS Institutional Review Board. The protocol and the trial results, even inconclusive, will be presented at international oncology congresses and published in peer-reviewed journals. UMIN000015405, Pre-results.


Vesicle tethers promoting fusion machinery assembly.
In a recent issue of the Journal of Cell Biology, Shorter et al. demonstrate that p115, a vesicle tethering protein, binds specific SNAREs, key components of the membrane fusion machinery, and uncover that this interaction promotes the assembly of the fusion machinery.