Systematic Review and Critical Appraisal of the Evidence Base for Nasoalveolar Molding (NAM).
To critically appraise the body of scientific literature supporting the risks and efficacy of nasoalveolar molding (NAM), specifically in contrast to alternative methods of presurgical infant orthopedics (PSIO) or to treatment without PSIO. Five outcome domains were considered: nasolabial aesthetics; dentoalveolar relationship; midfacial growth; cost and burden of care; and number of anesthetic events. MEDLINE, Embase, and Scopus were queried for articles from the first description of the Grayson-Santiago NAM technique (1993) through December 13, 2021. After the application of inclusionary and exclusionary criteria, selected articles were critically appraised using a systematic framework that included risk of bias assessment using the Cochrane RoB 2.0 and ROBINS-I tools. A total of 88 studies were included. Level-I and -II evidence showed on par or better approximation and alveolar alignment achieved by NAM compared to other PSIO. Level-II and -III evidence showed improved nasolabial aesthetics compared to other PSIOs. Level-II and -III evidence supported no harm to maxillofacial skeletal growth through age 12. Sparse level-III evidence supported a reduced number of labial or nasal revisions following NAM. Level-II and -III evidence showed NAM requiring upfront cost and frequent appointments but reducing caregiver psychosocial burden and reducing long-term costs compared to select alternatives. Many studies carried a high risk of bias. Current evidence supports the overall efficacy of NAM regarding short/mid-term outcomes, with a low risk of negative effects on midfacial growth or dental development. The high risk of bias discovered in many papers underscores the need for robust study design in future research.


Commentary on "Temporal Dynamics of Cerebral Blood Flow During the Acute Course of Severe Subarachnoid Hemorrhage Studied by Bedside Xenon-Enhanced CT".


A comparison of the effects of three positive inotropic agents (amrinone, milrinone and medorinone) on platelet aggregation in human whole blood.
Amrinone, milrinone and medorinone inhibit platelet aggregation in human whole blood. They are particularly potent inhibitors of arachidonic acid induced aggregation, inhibiting by 50% (IC50) at concentrations of 1.5 microM (milrinone), 7.5 microM (medorinone) and 48 microM (amrinone). Each drug was less potent at inhibiting ADP and collagen-induced aggregation. The rank order for inhibition of arachidonic acid - induced aggregation correlated well with the rank order of cyclic AMP phosphodiesterase inhibition for these drugs when compared to the response of a reference cAMP phosphodiesterase inhibitor (CI-930) and a reference cGMP phosphodiesterase inhibitor (M & B 22948). Since inhibition of platelet aggregation in vitro occurred at clinically relevant concentrations, it is evident that these agents have potentially beneficial antithrombotic properties.


Two new compounds from the Hainan Soft Corals Sinularia tumulosa and Sinularia depressa with their anti-inflammatory or cytotoxic activities.
The detailed chemical investigations of the South China Sea soft corals Sinularia tumulosa and Sinularia depressa, yielded two new compounds, namely tumulosterol A (1) and 11'-hydroxy-α-tocopherylquinone (3), along with four related known ones (2, 5-7). Their structures were determined by extensive spectroscopic analysis and comparison with the spectral data previously reported in the literature. In bioassays, compound 1 displayed significant cytotoxic effects against H1975 and MDA-MB-231 cells with IC50 values of 6.0 and 6.3 µM, respectively. In addition, compound 3 exhibited interesting inhibitory effect on lipopolysaccharide (LPS)-induced inflammatory responses in RAW264.7 cells with IC50 value of 9.5 µM.


Plasma exosomes protect against cerebral ischemia/reperfusion injury via exosomal HSP70 mediated suppression of ROS.
Ischemic stroke is the leading cause of severe disability and death worldwide. As the pathogenesis of stroke has not been clearly elucidated and the ability of current therapeutic drugs on crossing the blood-brain barrier (BBB) is extremely low, there is no effective strategy to treat stroke. We aim at investigating the specific advantages of using plasma exosomes (Pla-Exo) for targeting ischemic brain and exploring its underlying mechanism in neuroprotection. Pla-Exo was obtained by a gradient ultracentrifugation of fresh plasma. The quantification of penetrated Pla-Exo through BBB was investigated in vitro BBB model, furthermore, the effects of Pla-Exo and exosomal HSP70 on cerebral ischemia/reperfusion injury were evaluated. Pla-Exo enhanced BBB crossing by specific interaction between Pla-Exo inherited heat shock protein 70 (HSP70) and endothelial Toll-like receptor 4 (TLR4). As expected, Pla-Exo increased HSP70 expression in the ischemic region through the transfer of HSP70, and led to HSP70 mediated suppression of ROS, thus alleviating cerebral ischemia/reperfusion (I/R) injury by attenuating the deterioration of BBB and preventing mitochondria damage. These findings indicated that Pla-Exo can provide protection against ischemia-reperfusion injury via the regulation of HSP70 and it should be further studied as a potential candidate for protection against ischemic injury.


Defining the Values and Quality of Life of Cancer Survivors Following Cytoreductive Surgery and Hyperthermic Intraperitoneal Chemotherapy: An International Survey Study.
Advances in treatment of peritoneal surface malignancies including cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (CRS±HIPEC) have led to long-term survivorship, yet the subsequent quality of life (QOL) and values of these patients are unknown. Survivors were offered surveys via online support groups. Novel items assessed how patients prioritized experience, costs, longevity, and wellbeing. Of the 453 gastrointestinal/hepatobiliary (GI/HPB) surgical patients that responded, 74 underwent CRS±HIPEC and were 54±12 years old, 87% female, and 93% white. Respondents averaged 29 months from diagnosis, with a maximum survival of 20 years. With a moderate level of agreement (W = 39%), rankings of value metrics among respondents were predictable (p < 0.001). Longevity and functional independence were ranked highest; treatment experience and cost of treatment were ranked lowest (p < 0.001). Those who underwent CRS±HIPEC or other GI/HPB surgeries reported the same rank order. QOL in CRS±HIPEC survivors, both mental (M-QOL) (44±13) and physical (P-QOL) (41±11) were lower than in the general population (50±10); p < 0.001. Impairments persisted throughout survivorship, but M-QOL improved over time (p < 0.05). When comparing CRS±HIPEC with other GI/HPB cancer surgery survivors, M-QOL (43±13 versus 43±14, p = 0.85) and P-QOL (40±11 versus 42±12, p = 0.41) were similar. Although CRS±HIPEC survivors experience long-term mental and physical health impairments, they were similar to those experienced by survivors of other GI/HPB cancer surgeries, and their QOL improved significantly throughout survivorship. As CRS±HIPEC survivors prioritize longevity above all other metrics, survival benefit may outweigh a temporary reduction in QOL.


CTRP13 inhibits atherosclerosis via autophagy-lysosome-dependent degradation of CD36.
C1q/tumor necrosis factor-related protein 13 (CTRP13) is a secreted adipokine that can ameliorate abnormal glucose and lipid metabolism. However, the functional role of CTRP13 in the development of atherosclerotic plaques has yet to be described. In this study, we collected blood samples from patients of coronary artery diseases and apolipoprotein E (ApoE)-/- mice that were fed a Western diet for 12 wk to induce atherosclerosis and found that serum CTRP13 level was decreased. En face staining of aortas and aortic sinus in ApoE-/- mice showed that ectopic CTRP13 infusion in vivo dramatically decreased lesion areas, as well as reduced inflammatory responses with less macrophage content. In primary peritoneal macrophages in vitro, CTRP13 supplement reduced oxidized LDL uptake, foam-cell formation, and trapping, together with the suppressed cluster of differentiation 36 (CD36) protein levels. Reduced CD36 protein level was attributed to the autophagy-lysosome-dependent degradation of CD36 at the post-transcriptional level. The blocking of autophagy-lysosome induction could increase CD36 protein level, foam-cell formation, and migration, thus abolishing the protective effects of CTRP13 on atherosclerosis. In summary, these findings define CTRP13 as a novel approach for preventing atherosclerotic plaque formation via modulation of lipid uptake and foam-cell migration.-Wang, C., Xu, W., Liang, M., Huang, D., Huang, K. CTRP13 inhibits atherosclerosis via autophagy-lysosome-dependent degradation of CD36.


[Genetic demographic structure of the Belgorod population: age, ethnicity, education, and occupation].
Data from marriage records of the city of Belgorod for 1960, 1985, and 1995 have been used to determine some parameters of population structure in this city. The coefficients of correlation with respect to age of marriage between spouses in the couples contracting marriages in these years were 0.74, 0.62, and 0.80, respectively. Women of reproductively unfavorable age (under 20 or over 30 years) accounted for 5.5, 0.83, and 19% of all women contracting marriages in these years, respectively. The proportions of interethnic marriages in these years were 16.9, 14.9, and 15.6%, respectively. The percentage of Slavs decreased from 99 to 97% during the 35 years studied, whereas the proportion of Russians insignificantly increased (from 90.4 to 91.4%). The proportion of Caucasian ethnic groups increased by six time (from 0.3 to 1.8%), and that of other non-Slavic ethnic groups increased by almost two times (from 0.7 to 1.2%). The marriage convergence (K) with respect to ethnicity (0.095, 0.106, and 0.090 in 1960, 1985, and 1995, respectively) was lower than that with respect to education (0.296 and 0.350 in 1985 and 1995, respectively) or occupation (0.212 and 0.231 in 1985 and 1995, respectively). The maximum coefficients of ethnically, educationally, and occupationally assortative marriage have been found, respectively, in ethnic minority groups (A' = 20%); in persons with higher and primary education (A' = 37.5 and A' = 49.9%, respectively); and in the military officers/soldiers, engineers, healthcare professionals, and researchers (the respective A' values are 65.6, 32.2, 31.5, and 39.8%).


Effects of captopril and SQ29,852 on anxiety-related behaviours in rodent and marmoset.
The abilities of the ACE inhibitors captopril and SQ29,852 to modify aversive behaviour was compared to the effects of diazepam in the light/dark exploration test in the mouse, the elevated plus maze and social interaction test in the rat, and in anxiety-related behaviours induced by human threat in the marmoset. In the four tests the acute administration of captopril, SQ29,852 and diazepam had the same profiles of action to reduce aversive responding. This was also observed during chronic administration with the three agents in the mouse. However, withdrawal from a chronic treatment with diazepam precipitated a syndrome of increased aversion, whereas withdrawal from treatment with captopril and SQ29,852 was uneventful, values waning to control levels. Withdrawal from treatment with ethanol, nicotine and cocaine also enhanced aversive responding. Treatment with captopril and SQ29,852 antagonised the behavioural consequences of withdrawal from treatment with diazepam and nicotine and SQ29,852 also blocked the consequences of withdrawal from ethanol and cocaine. It is concluded that captopril and SQ29,852 have an anxiolytic profile of action in 3 species, that cessation of treatment is not associated with a withdrawal syndrome, that the ACE inhibitors cross tolerate with diazepam and can antagonise the behavioural consequences of withdrawal from treatment with drugs of abuse.


Effects of syntactic prominence on eye movements during reading.
Three experiments explored whether patterns of eye movements during reading might help explain syntactic prominence effects that are typically observed using reaction time tasks. Participants read sentences in which target words were in syntactically prominent or syntactically less prominent positions. Across all three experiments, using three types of syntactic prominence manipulations, there were fewer fixations and shorter reading times for words in more prominent positions, indicating that enhanced accessibility of syntactically prominent words is not caused by increased processing time. Rather, syntactic prominence appears to facilitate early encoding/lexical access and sentence integration processes while also, as shown previously, increasing activation of concepts in a comprehender's sentence or discourse representation. We propose that enhanced encoding and sentence integration processes can be attributed to an increase in attentional resources for more prominent concepts, and that this increase derives from readers' immediate sensitivity to informational prominence contours that are signaled by syntax.


Validation of the HULL Score clinical prediction rule for unsuspected pulmonary embolism in ambulatory cancer patients.
Clinical prediction rules (CPRs) developed to predict adverse outcomes of suspected pulmonary embolism (PE) and facilitate outpatient management have limitations in discriminating outcomes for ambulatory cancer patients with unsuspected PE (UPE). The HULL Score CPR uses a 5‑point scoring system incorporating performance status and self-reported new or recently evolving symptoms at UPE diagnosis. It stratifies patients into low, intermediate and high risk for proximate mortality. This study aimed to validate the HULL Score CPR in ambulatory cancer patients with UPE. 282 consecutive patients managed under the UPE-acute oncology service in Hull University Teaching Hospitals NHS Trust were included from January 2015 to March 2020. The primary end-point was all-cause mortality, and outcome measures were proximate mortality for the three risk categories of the HULL Score CPR. 30-day, 90-day and 180-day mortality rates for the whole cohort were 3.4% (n=7), 21.1% (n=43) and 39.2% (n=80), respectively. The HULL Score CPR stratified patients into low-risk (n=100, 35.5%), intermediate-risk (n=95, 33.7%) and high-risk (n=81, 28.7%) categories. Correlation of the risk categories with 30-day mortality (area under the curve (AUC) 0.717, 95% CI 0.522-0.912), 90-day mortality (AUC 0.772, 95% CI 0.707-0.838), 180-day mortality (AUC 0.751, 95% CI 0.692-0.809) and overall survival (AUC 0.749, 95% CI 0.686-0.811) was consistent with the derivation cohort. This study validates the capacity of the HULL Score CPR to stratify proximate mortality risk in ambulatory cancer patients with UPE. The score uses immediately available clinical parameters and is easy to integrate into an acute outpatient oncology setting.


Interferon-gamma induced nitric oxide-mediated apoptosis of anemia of chronic disease in rheumatoid arthritis.
Proinflammatory cytokines play a role in the pathogenesis of anemia of chronic disease (ACD), which is a common cause of anemia in rheumatoid arthritis (RA). Anemia in RA is associated with increased apoptosis of erythroid cells. However, there is unclear information on the mechanism of ACD in the disease. The purpose of this study is to investigate the role of cytokines on nitric oxide-mediated apoptosis in erythroid progenitor cells of ACD in RA patients. Erythroid progenitor cells from healthy subjects and RA patients with ACD were treated with cytokines like interleukin-1β, tumor necrosis factor-α, and interferon-γ at concentrations of 2, 20, and 40 ng/ml for 14 days. Cell viability and cell apoptosis were analyzed by trypan blue staining and flow cytometry, respectively. The results showed that the highest effect of cytokines on reduction cell viability and induction cell apoptosis was found in 20 ng/ml IFN-γ-treated cells of RA patients. In addition, IFN-γ showed significantly increased nitric oxide production and iNOS mRNA expression, which was measured by Griess assay and real-time PCR, respectively. The percentage of cell apoptosis and NO production was reduced after an inducible nitric oxide synthase inhibitor, SMT, treatment. In conclusion, IFN-γ could induce nitric oxide production-mediated apoptosis process, which might be involved in the pathogenesis of ACD in RA patients.


Evaluation of wound healing activities of kefir products.
Kefirs are natural probiotic compounds with antibacterial and anti-inflammatory properties which were tested in experimental burn injury. Kefir gels were prepared from an extract of continuously cultured kefir grains in MRS Broth medium for 24, 48 and 96h. Similar burn injuries were made on dorsal skin surface of 56 rats. After 24h the wounds were infected with Pseudomonas aeruginosa. The infected rats were divided in to 7 groups of 8 rats each. The base gel, silver sulfadiazine ointment, kefir 24h gel, kefir 48h gel, kefir 96h gel and kefir grains 96h gel were applied twice a day. Burn wound area was measured at baseline, one and two weeks. After two weeks the animals in all groups were sacrificed and whole skin wound areas were removed and percentage of epithelization, scar formation, inflammation and angiogenesis were evaluated. Results indicated that at the end of the 2nd week the percentage of wound size were lowest in order of kefir 96h gel<kefir grains 96h gel<kefir 48h gel<kefir 24h gel<silver sulfadiazine 1%<untreated and based gel groups. At the end of the 2nd week the percentage of inflammation was lower and percentage of epithelization and scar formation was higher in order of kefir 96h gel, kefir grains 96h gel, kefir 48h gel, kefir 24h gel, silver sulfadiazine 1%, base gel and untreated groups. In conclusion the kefir gel therapy was an effective therapeutic approach to improve outcomes after severe burn as compared to conventional silver sulfadiazine treatment.


Wee1 kinase alters cyclin E/Cdk2 and promotes apoptosis during the early embryonic development of Xenopus laevis.
The cell cycles of the Xenopus laevis embryo undergo extensive remodeling beginning at the midblastula transition (MBT) of early development. Cell divisions 2-12 consist of rapid cleavages without gap phases or cell cycle checkpoints. Some remodeling events depend upon a critical nucleo-cytoplasmic ratio, whereas others rely on a maternal timer controlled by cyclin E/Cdk2 activity. One key event that occurs at the MBT is the degradation of maternal Wee1, a negative regulator of cyclin-dependent kinase (Cdk) activity. In order to assess the effect of Wee1 on embryonic cell cycle remodeling, Wee1 mRNA was injected into one-cell stage embryos. Overexpression of Wee1 caused cell cycle delay and tyrosine phosphorylation of Cdks prior to the MBT. Furthermore, overexpression of Wee1 disrupted key developmental events that normally occur at the MBT such as the degradation of Cdc25A, cyclin E, and Wee1. Overexpression of Wee1 also resulted in post-MBT apoptosis, tyrosine phosphorylation of Cdks and persistence of cyclin E/Cdk2 activity. To determine whether Cdk2 was required specifically for the survival of the embryo, the cyclin E/Cdk2 inhibitor, Delta34-Xic1, was injected in embryos and also shown to induce apoptosis. Taken together, these data suggest that Wee1 triggers apoptosis through the disruption of the cyclin E/Cdk2 timer. In contrast to Wee1 and Delta34-Xic1, altering Cdks by expression of Chk1 and Chk2 kinases blocks rather than promotes apoptosis and causes premature degradation of Cdc25A. Collectively, these data implicate Cdc25A as a key player in the developmentally regulated program of apoptosis in X. laevis embryos.


Intrapatient variability in theophylline kinetics.
Seven asthmatic children had repeat determinations of theophylline pharmacokinetic measurements over three- to nine-month intervals. Significant intrapatient variability was found in the theophylline clearance and t1/2, which determine the dosage regimen necessary to provide given average, peak, and trough theophylline plasma levels. Repeat clearance values were, on average, 52% different from the original clearances, with a range of -57% to +142%. A single determination of theophylline kinetic measurements in any individual patient cannot be used routinely to predict future theophylline dosage regimens for that patient.


The role of the optic tectum in various visually mediated behaviors of goldfish.
Five visually mediated behaviors were assessed following ablation of one or both lobes of the optic tectum in goldfish. Three of the behaviors disappeared following tectal ablations: optomotor response (swimming with the stripes in a rotating striped drum), food pellet localization and shadow-induced deceleration of respiration. Two of the behaviors persisted following tectal ablation: optokinetic nystagmus (movement of the eyes with the stripes in a rotating striped drum) and dorsal light reflex (tilting of the vertical axis toward the brighter of two laterally placed lights). The unexpected result that lesioned fish tracked the stripes with their eyes, but did not swim after them as normal fish did, suggests that the tectum serves a pre-motor function in addition to its sensory role. In addition, the results demonstrate that selected behaviors can be used to establish whether functional tectal or non-tectal connections are made by regenerating goldfish optic nerves.


Technical-economic and environment benefit analyses of a novel building attached photovoltaic system.
This study proposed a novel building attached photovoltaic (BAPV) system mainly comprised of the PV system, building with household appliances, electric vehicle (EV), and power grid. Effect analyses of four typical factors are conducted, including the number of batteries, PV system supporting type, azimuth, and tilt angles of PV panels. The results show that the BAPV system with 8 batteries, an open PV system supporting type, an azimuth angle of 0°, and a tilt angle of 30.5° is relatively optimal. The operation, economic, and environment benefit performances of the BAPV system are analyzed. The results reveal that the annual effective output electricity of the BAPV system is 58.3 MWh, of which about 20 MWh is consumed by household appliances and EV or stored in batteries, and 38.3 MWh is sold to the power grid. The annual performance ratio of the BAPV system is 82.7%. Based on the annual nominal power generation quantity of the PV system, the effective output electricity occupies about 89%, and the energy loss part occupies 11%. The levelized cost of electricity (LCOE) and cost recovery cycle of the BAPV system are 0.132 yuan/kWh and 8.7 years, respectively. For the whole lifetime, the emission reduction quantities of carbon dioxide, dust, sulfur dioxide, and nitrogen oxide of the BAPV project are 786.3 t, 4.225 t, 7.275 t, and 6.9 t. The results of this study demonstrate the technical and economic feasibilities as well as the acceptable environmental protection performance of the proposed BAPV system, and this paper will contribute to the research and development works of BAPV systems.


Cost analysis of youth clinic network in Estonia.
Youth-friendly sexual and reproductive health (YFSRH) services for young people have high priority in many countries. Yet, little is known about the actual cost of delivering YFSRH services. This article analyses costs of a fully scaled up national youth clinic network (YCN) in Estonia. It reports; 1) total budget of the YCN during the period 2002-2012, and 2) annual clinic level costs of three youth clinics (YCs) in 2012. The retrospective cost analysis is based on financial and medical records of Estonian Health Insurance Fund (EHIF), Estonian Sexual Health Association (ESHA), National Institute for Health Development and the YCs. The programme level costs are analysed per year, financing source and a portion spent on coordination in 2002-2012. Costs of three YCs are analysed per clinic, expense category, patient and healthcare service in 2012. The total budget of the YCN was €8.38 million and it served 304,000 young patients in 2002-2012. 95% of the total budget was financed by the EHIF. 3.6% was spent on coordination. The YCs in Tallinn, Tartu and Ida-Virumaa had annual budgets of €247,000, €267,000 and €42,000 respectively. In 2012 the three YCs provided YFSRH services to 19,700 patients, excluding sexuality education lessons and internet counselling. The YFSRH services cost €543,000. Consequently, the average cost per patient was €27.76. The largest expense categories were personnel salaries 35% and medical supplies 33%. Cost of the YFSRH services were; STI consultation €54.80, SRH counselling €13.13, contraception consultation €9.32, internet counselling €8.21 and sexuality education lesson €1.52. The Estonian YCN is a positive example for other countries considering or already implementing similar programmes. The cost analyses highlighted the following: Sustainable funding is particularly important, without it the YFSRH services would not have been scaled up and sustained on the national level in Estonia. Investment in professional coordination of the YFSRH services is recommended, and it does not necessarily have to be expensive. Only 3.6% of the total budget of YCN was used for ESHA coordination, which is a small portion especially when taking into account ESHA's substantial contributions to development, training, quality improvements and representation of the YCN.


Localized transient expression of GUS in leaf discs following cocultivation with Agrobacterium.
A chimaeric gene has been constructed that expresses beta-D-glucuronidase (GUS) in transformed plant tissues, but not in bacterial cells. This gene has proved extremely useful for monitoring transformation during the period immediately following gene transfer from Agrobacterium tumefaciens. GUS expression was detectable 2 days after inoculation, peaked at 3-4 days and then declined; if selection was imposed expression increased again after 10-14 days. The extent of transient expression after 4 days correlated well with stable integration as measured by kanamycin resistance, hormone independence, and gall formation. Histochemical staining of inoculated leaf discs confirmed the transient peak of GUS expression 3-4 days after inoculation. The most surprising result was that the blue staining was concentrated in localized zones on the circumference of the disc; within these zones, essentially all the cells appeared to be expressing GUS. We suggest that the frequency of gene transfer from Agrobacterium is extremely high within localized regions of leaf explants, but that the frequency of stable integration is several orders of magnitude lower.


William L. McGuire Memorial Symposium. Estrogen and progestin effects in human breast carcinogenesis.
The influences of estrogen and progestin on human mammary neoplasia are reviewed with a view to identifying what is known about their effects. Estrogens promote growth of established cancer and pharmacological levels of progestins induce remission. In vivo, highest proliferation of histologically normal mammary epithelium occurs in the progestogenic phase of the menstrual cycle or under the progestogenic influence of oral contraceptives. Little additional hard data exist to indicate whether progestins promote or inhibit human mammary carcinogenesis. Effects on proliferation, steroid receptor content and development are discussed together with interpretation of epidemiological data on risk factors that have hormonal components. Progestins may not be the benign or beneficial agents previously supposed, and there are virtually no data to suggest that they are antiestrogenic. It is hypothesized that carcinogenesis may be accompanied by increased sensitivity to estrogen, which provides a growth advantage to the tumor by maximizing use of the low estrogen concentrations encountered in the postmenopausal state.


Medicinal effect and its JP2/RyR2-based mechanism of Smilax glabra flavonoids on angiotensin II-induced hypertrophy model of cardiomyocytes.
Rhizome and root of Smilax glabra Roxb (Liliaceae family) is a widely used traditional Chinese medicine (TCM) named Tu-fu-ling (TFL) for cardiac disease therapy. The TFL flavonoids (TFLF) has been extracted and proven to possess the anti-cardiac hypertrophy effect in our previous reports. Such effect could be mediated by the modulation of intracellular Ca(2+) flux in myocardial cells, in which junctophilin-2 (JP2) and ryanodine receptor 2 (RyR2) play an important role. However, its mechanism of the anti-cardiac hypertrophy effect remains unclarified. 2μmol/L Ang II was applied to induce hypertrophy model of rat primary cardiomyocytes. After treatment of TFLF at 0.25, 0.5 and 1.0mg/ml, the cell size was microscopic measured, and the protein and mRNA expressions of JP2 and RyR2 in cardiomyocytes were estimated by immunofluorescence imaging, ELISA and real-time PCR assay. Obvious hypertrophy of cardiomyocytes was induced by Ang II but reversed by TFLF from 0.5 to 1.0mg/ml. The protein and mRNA expressions of JP2 and RyR2 in cardiomyocytes were also inhibited by Ang II but restored by TFLF at its dose range. Such effect of TFLF was exerted at a dose dependent manner, which was even better than that of verapamil. Our findings may evidence the correlation between JP2/RyR2 and myocardiac hypertrophy, and indicate the JP2/RyR2-mediated anti-hypertrophy mechanism of TFLF for the first time. It deserves to be developed as a promising TCM candidate of new drug for myocardial hypertrophy treatment.


Both ipsilateral and contralateral localized vibratory stimulations modulated pain-related sensory thresholds on the foot in mice and humans.
This study was aimed to investigate the effect of localized vibration on sensory thresholds in mice and humans using a novel quantitative method. The sensory thresholds of 7-week-old male C57BL/6J mice were measured with four sine-wave electrostimulation frequencies (5, 50, 250, and 2,000 Hz) before and after applying 2-minute vibration to the plantar side of the foot in mice. In human participants (16 males and 16 females; mean age, 21.0±0.8 years), the sensory threshold was measured at 50 Hz before and after applying 2-minute and 5-minute vibrations to the dorsal side of the foot. Application of a 2-minute vibration at either the ipsilateral or contralateral side modulated the sensory thresholds elicited by a 5- or 50-Hz right electrostimulation in mice. In human participants, application of a 5-minute vibration at either the ipsilateral or contralateral side modulated the sensory threshold elicited by 50-Hz right electrostimulation, but had no effect on local skin temperature. These results suggest that the right side of pain-related Aδ fibers (50 Hz) or C fibers (5 Hz) was modulated by the localized ipsilateral or contralateral side of vibratory stimuli, respectively, in mice and humans. The ability of contralateral vibration to modify the right sensory thresholds suggests possible involvement of the central nervous system in vibratory modulation.


Publication rates of annual Research Day abstracts in peer-reviewed journals by residents and fellows at a community-based institution - A 10-year review of data and analysis.
Research and publications are becoming increasingly important for residents who want to match into competitive fellowship training programs and fellows looking to optimize career opportunities. Institutional Research Days provide trainees the opportunity to gain presentation experience and feedback about their studies. We evaluated all abstracts that were presented at Ascension Providence Hospital (APH) during Research Day over a 10-year period to determine publication rates of manuscripts in peer-reviewed journals. Research abstracts presented by both residents and fellows during Research Days at APH from 2009 to 2018 were reviewed. Abstracts were classified by type of project, type of presentation, trainee, winners and non-winners, and training program. Winners were defined as abstracts which won first, second and third place awards. Publication of manuscripts was evaluated by searching PubMed and Google Scholar. Fisher's Exact test was used to analyze categorical data and Student's t-test was used to analyze continuous data; p < 0.05 was considered significant. A total of 491 research and case report abstracts were presented by residents and fellows during Research Day over 10 years. For residents, 346 abstracts were presented; 25% (n = 85) were winners. The majority (51%) of winning abstracts were published, but only 26% of non-winning abstracts were published (p < 0.0001). More of both winning research oral (65%) and poster abstracts (61%) were published than non-winning oral (41%) and poster abstracts (22%, p = 0.02 and p = 0.0001, respectively), but publication rates for case reports were similar. The vast majority of published winning oral (88%) and poster abstracts (74%) came from the surgical programs. Fellows presented 145 abstracts; 30% (n = 43) were winners. A slightly higher percentage of winning abstracts (42%) were published compared to non-winning abstracts (32%, p = 0.3). Unlike the residents, the fellows had no significant publication rate differences between winning and non-winning research oral, research poster or case report abstracts, or between medical and non-medical subspecialties. Despite their award-winning presentations, residents and fellows published less than half of these projects and less than a third of non-award-winning projects. However, most publications came from the surgical specialties, indicating the colleagues in the medical specialties were not publishing. Further data are needed to identify factors that can improve a trainee's chances of being published in a peer-reviewed journal.


Motilin and erythromycin-A share a common binding site in the third transmembrane segment of the motilin receptor.
The motilin receptor (MTLR) represents a clinically useful pharmacological target, as agonists binding to the MTLR have gastroprokinetic properties. In order to compare the molecular basis for interaction of the MTLR with motilin and with the non-peptide motilin agonist, erythromycin-A (EM-A), the negatively charged E119 located in the third transmembrane (TM3) region was mutated to D (E119D) and Q (E119Q), respectively, and changes in activity of the mutant receptors were verified. Each mutant receptor was stably transfected in CHO-cells containing the Ca2+ indicator apo-aequorin. Receptor activation in response to motilin, EM-A and their analogues was assessed by Ca2+-luminescense. In the E119Q mutant, the Ca2+ response to motilin and EM-A was abolished while in the E119D mutant it was reduced with 62% (motilin) and 81% (EM-A). The pEC50 values were shifted from 9.65+/-0.03 to 7.41+/-0.09 (motilin) and from 6.63+/-0.12 to 4.60+/-0.07 (EM-A). Acetylation of the N-terminal amine group as in [N-acetyl-Phe]1 mot (1-14), decreased the potency 6.3-fold (WT-MTLR) and 148-fold (E119D). Acetylation of EM-A enol ether induced a more pronounced shift in potency: 7943-fold (WT-MTLR) and 1413-fold (E119D). The comparable loss of affinity of the mutant receptors for motilin and EM-A indicate that these agonists both interact with the TM3 domain of the MTLR. The results with acetylated derivatives support an ionic interaction between E119 of the MTLR with the N+ of the desosamine sugar in EM-A, but not with the N+ of the free amine group in motilin.


Morphology and microcirculation changes of the optic nerve head between simple high myopia and pathologic myopia.
To investigate morphological and microcirculation changes of optic nerve head (ONH) in simple high myopia (SHM) and pathologic myopia(PM) to evaluate and identify ONH changes in the development of PM. A cross-sectional clinical study was used. Medical records from 193 right eyes of 193 patients with high myopia (HM) were included. Using the Topocon swept source optical coherence tomograph (SS-OCT) and fundus camera to detect the parameters, we have assessed the relative position and size of ONH, tilt and rotation of ONH, angle α (Defined as between retinal temporal arterial vascular arcades was measured from the centre of ONH with 250 pixels' radius), size and type of peripapillary atrophy (PPA), the thickness of peripapillary retinal nerve fiber layer (PRNFL), peripapillary choriodal thickness (PCT) and peripapillary scleral thickness (PST), and peripapillary vessel density (PVD). In addition, subjects were grouped as SHM and PM according to retinopathy, and the above parameters were compared between the two groups. Patients were divided into the SHM group (138 eyes) and the PM group (55 eyes). Paramters like older age, higher diopter and longer axial length (AL) of the PM were compared to SHM (t=-3.585, -8.808, -11.409, all P<0.05). There were no differences in the smallest diameter and area of ONH, rotation angle and ratio, or PST (all P>0.05). The angle α in PM was smaller than that in SHM (t = 2.728, P<0.01). The disc-fovea distance (DFD), the largest diameter, tilt index and ratio, PPA area and radian in PM were larger than in SHM (t=-3.962, Z=-2.525, t=-2.229, Z=-4.303, Z=-2.834, all P<0.05). The superior and inferior PRNFLs in PM were smaller than in SHM (t = 4.172, 4.263, all P<0.01). The temporoinferior PRNFL was the opposite (t=-2.421, P<0.01). The average PCT in PM (93.82 ± 29.96 μm) was smaller than in SHM (108.75 ± 30.70 μm) (P<0.05). The PVD in each direction of PM was smaller than that in SHM (t = 6.398, 4.196, 4.971, 3.267, 5.029, 5.653, 4.202, 5.146, 2.090, all P<0.05). Compared with SHM, the PM patients were older, with higher diopter. Their AL and DFD were longer, the angle α was smaller, the tilt index was more extensive, the PPA area and radian were larger, PCT was generally thinner, and PVD was lower. When the PPA area was bigger than the ONH area, this already indicated the presence of PM. Based on these results, we suggest ophthalmologists and myopia patients pay more attention to ONH's morphology and microcirculation changes as there is a possibility that microcirculatory changes precede morphologic changes.


Two distinct subpopulations of endosomes involved in membrane recycling and transport to lysosomes.
Functionally distinct subpopulations of endosomes involved in targeting internalized material to specific intracellular destinations were resolved as two distinct peaks by free-flow electrophoresis. The less anodally shifted peak contained a population of early endosomes selectively labeled by brief exposures to endocytic tracers or by receptor-bound transferrin. Late endosomes, labeled only after longer periods of internalization, migrated more toward the anode. While both fluid phase and certain receptor-bound markers could be rapidly chased from early to late endosomes, transferrin remained in vesicles comigrating with early endosomes even after prolonged uptake. Thus early and late endosomes are kinetically related but functionally distinct: early endosomes serve as the major site of recycling of membrane and surface receptors and late endosomes are involved in delivery to lysosomes. The subpopulations each contain unique polypeptides not found on the plasma membrane. Thus, endosomes cannot be derived entirely from internalized cell surface components, and may have at least partly independent biosynthetic origins.


Dysregulation of sphingosine 1 phosphate receptor-1 (S1P1) signaling and regulatory lymphocyte-dependent immunosuppression in a model of post-fingolimod MS rebound.
Fingolimod affords protection from MS by sequestering lymphocytes in secondary lymphoid organs via down regulation of their sphingosine 1 phosphate receptor (S1P1). Unexpectedly, accumulating evidence indicates that patients who discontinue fingolimod treatment may be at risk of rehearsal of magnetic resonance (MR) and clinical disease activity, sometimes featuring dramatic rebound. We therefore developed in vivo and in vitro models of post-fingolimod MS rebound to unravel its cellular and molecular mechanisms. The impact of fingolimod withdrawal on T regulatory lymphocytes was also investigated by means of cytofluorimetric analysis and antigen-specific lymphocyte proliferation assays. We show that mice with relapsing-remitting experimental autoimmune encephalomyelitis (EAE) undergo extremely severe, chronic disease rebound upon discontinuation of fingolimod. Remarkably, rebound is preceded by a burst of S1P1 overexpression in lymph node-entrapped lymphocytes that correlates with subsequent massive lymphocyte egress and widespread CNS immune infiltration. Also, consistent with the ability of S1P1 to counteract polarization and function of T regulatory lymphocytes their number and suppression of effector T cells is reduced by fingolimod suspension. Data disclose the first pathogenic mechanisms of post-fingolimod rebound that may be targeted for therapeutic intervention.


The role of blood platelets in nucleoside metabolism: regulation of megakaryocyte development and platelet production.
In higher vertebrates, different types of blood cells develop from common precursors. Mammals are unique in possessing two types of blood cells--erythrocytes and platelets--which lack nuclei. Although platelets display consistent and easily-recognisable morphological and ultrastructural characteristics and show extreme metabolic and functional versatility, they are not true cells, being produced by fragmentation of giant polyploid precursors called megakaryocytes. At present, the physiological mechanisms which regulate megakaryocyte development and platelet production are not well understood. Platelets are actively involved in metabolism of purine derivatives and a significant platelet role in pyrimidine metabolism has also been demonstrated (see previous papers). Here an attempt is made to integrate information about platelet involvement in nucleic acid precursor metabolism with current concepts of haematopoiesis, particularly megakaryocyte development and platelet production. It is concluded (i) that megakaryocytic cells are immediate descendents of haematopoietic stem cells which have become polyploid as a result of genetic damage or metabolic imbalances, (ii) megakaryocytes and platelets are the ultimate regulators of stem cell development because they control the availability of thymidine and (iii) that the production of megakaryocytes and platelets is a physiological safety mechanism which prevents fixation of genetic damage and protects other cells from potentially cytotoxic and genotoxic stimuli.


Easy and Rapid Methods for Human Umbilical Cord Blood-Derived Mesenchymal Stem Cells and Human Umbilical Wharton's Jelly-Derived Mesenchymal Stem Cells.
These protocols describe modified methods that use Ficoll-Paque density gradient for umbilical cord blood-derived mesenchymal stem cells and explant method for Wharton's jelly-derived mesenchymal stem cells. The Ficoll-Paque density gradient method allows to obtain mesenchymal stem cells while eliminating monocytic cells. In this method, precoating the cell culture flasks with fetal bovine serum helps remove the monocytic cells and instruct more pure mesenchymal stem cells. On the other hand, the explant method for Wharton's jelly-derived mesenchymal stem cell is user-friendly and cost-effective than enzymatic methods. In this chapter, we provide a collection of protocols to obtain mesenchymal stem cells from human umbilical cord blood and Wharton's jelly.


Outer-membrane vesicles from Gram-negative bacteria: biogenesis and functions.
Outer-membrane vesicles (OMVs) are spherical buds of the outer membrane filled with periplasmic content and are commonly produced by Gram-negative bacteria. The production of OMVs allows bacteria to interact with their environment, and OMVs have been found to mediate diverse functions, including promoting pathogenesis, enabling bacterial survival during stress conditions and regulating microbial interactions within bacterial communities. Additionally, because of this functional versatility, researchers have begun to explore OMVs as a platform for bioengineering applications. In this Review, we discuss recent advances in the study of OMVs, focusing on new insights into the mechanisms of biogenesis and the functions of these vesicles.


Predicting vertical ground reaction force in rearfoot running: A wavelet neural network model and factor loading.
This study proposed a simple method for selecting input variables by factor loading and inputting these variables into a wavelet neural network (WNN) model to predict vertical ground reaction force (vGRF). The kinematic data and vGRF of 9 rearfoot strikers at 12, 14, and 16 km/h were collected using a motion capture system and an instrumented treadmill. The input variables were screened by factor loading and utilized to predict vGRF with the WNN. Nine kinematic variables were selected, corresponding to nine principal components, mainly focusing on the knee and ankle joints. The prediction results of vGRF were effective and accurate at different speeds, namely, the coefficient of multiple correlation (CMC) > 0.98 (0.984-0.988), the normalized root means square error (NRMSE) < 15% (9.34-11.51%). The NRMSEs of impact force (8.18-10.01%), active force (4.92-7.42%), and peak time (7.16-12.52%) were less than 15%. There was a small number (peak, 4.12-6.18%; time, 4.71-6.76%) exceeding the 95% confidence interval (CI) using the Bland-Altman method. The knee joint was the optimal location for estimating vGRF, followed by the ankle. There were high accuracy and agreement for predicting vGRF with the peak and peak time at 12, 14, and 16 km/h. Therefore, factor loading could be a valid method to screen kinematic variables in artificial neural networks.


Assessing the rabies control and surveillance systems in Brazil: an experience of measures toward bats after the halt of massive vaccination of dogs and cats in Campinas, Sao Paulo.
Bats are less vulnerable to forest fragmentation than any other mammal, and for that reason, some species can disperse to peri-urban or urban areas. Insectivorous bats are abundant in urban areas due to the density of artificial roosts and insects attracted by city lights. Inter-species transmission of the rabies virus between bats can occur, and this is the most probable mechanism of virus circulation in bat populations. Bats can also transmit the rabies virus to other mammal species, like dogs and cats. With the halt of dog and cat vaccination campaigns in 2010, the importance of rabies surveillance in bats has increased in Brazil. A cross-sectional study performed in Campinas, Sao Paulo State, using data from the passive surveillance system for bats showed that rabies-positive bats from the families Molossidae, Phyllostomidae and Vespertilionidae were found in a peri-urban area. In these areas, dog and cat emergency vaccination (vaccination blockage) was recommended after the halt of the massive vaccination campaign in 2010. This control strategy was able to increase the proportion of vaccinated animals around a critical value of 50% and even with a higher probability of infectious contact between bats and dogs or cats in the vaccination blockage areas, no dog or cat rabies case was observed, evidencing the importance of the implementation of strategic rabies control measures in this new epidemiological scenario.


Volatile sulphur compounds and pathways of L-methionine catabolism in Williopsis yeasts.
Volatile sulphur compounds (VSCs) are important to the food industry due to their high potency and presence in many foods. This study assessed for the first time VSC production and pathways of L: -methionine catabolism in yeasts from the genus Williopsis with a view to understanding VSC formation and their potential flavour impact. Five strains of Williopsis saturnus (var. saturnus, var. subsufficiens, var. suavolens, var. sargentensis and var. mrakii) were screened for VSC production in a synthetic medium supplemented with L: -methionine. A diverse range of VSCs were produced including dimethyl disulphide, dimethyl trisulphide, 3-(methylthio)-1-propanal (methional), 3-(methylthio)-1-propanol (methionol), 3-(methylthio)-1-propene, 3-(methylthio)-1-propyl acetate, 3-(methylthio)-1-propanoic acid (methionic acid) and ethyl 3-(methylthio)-1-propanoate, though the production of these VSCs varied between yeast strains. W. saturnus var. saturnus NCYC22 was selected for further studies due to its relatively high VSC production. VSC production was characterised step-wise with yeast strain NCYC22 in coconut cream at different L: -methionine concentrations (0.00-0.20%) and under various inorganic sulphate (0.00-0.20%) and nitrogen (ammonia) supplementation (0.00-0.20%), respectively. Optimal VSC production was obtained with 0.1% of L: -methionine, while supplementation of sulphate had no significant effect. Nitrogen supplementation showed a dramatic inhibitory effect on VSC production. Based on the production of VSCs, the study suggests that the Ehrlich pathway of L: -methionine catabolism is operative in W. saturnus yeasts and can be manipulated by adjusting certain nutrient parameters to control VSC production.


[Expression and purification of gene transfer vehicle mediated by epidermal growth factor receptor].
To create a gene transfer vehicle for targeting gene therapy of cancer with epidermal growth factor receptor overexpressing. Encoding sequences of the first domain of histone gene (H1) and EGF C-loop (EGFc) were obtained by PCR amplification. These two DNA fragments were ligated by EcoR I site, and cloned and sequenced. E. coli expression vector of the fusion gene was then constructed. The fusion protein H1EGFc was purified by specific band isolation from SDS-PAGE. The molecular weight of purified protein was consistent with the designed request. Its purity reached 94.02%. A fusion protein H1EGFc was expressed and purified.


Genetic modifiers of penetrance to liver endpoints in HFE hemochromatosis: Associations in a large community cohort.
The iron overload condition hereditary hemochromatosis (HH) can cause liver cirrhosis and cancer, diabetes, and arthritis. Males homozygous for the p.C282Y missense mutation in the Homeostatin Iron Regulator (HFE) gene have greatest risk; yet, only a minority develop these conditions. We aimed to determine whether common genetic variants influencing iron levels or liver disease risk in the general population also modify clinical penetrance in HFE p.C282Y and p.H63D carriers. We studied 1294 male and 1596 female UK Biobank HFE p.C282Y homozygous participants of European ancestry with medical records up to 14 years after baseline assessment. Polygenic scores quantified genetic effects of blood iron biomarkers and relevant diseases (identified in the general population). Analyses were also performed in other HFE p.C282Y/p.H63D genotype groups. In male p.C282Y homozygotes, a higher iron polygenic score increased the risk of liver fibrosis or cirrhosis diagnoses (odds ratio for the top 20% of iron polygenic score vs. the bottom 20% = 4.90: 95% confidence intervals, 1.63-14.73; p = 0.005), liver cancer, and osteoarthritis but not diabetes. A liver cirrhosis polygenic score was associated with liver cancer diagnoses. In female p.C282Y homozygotes, the osteoarthritis polygenic score was associated with increased osteoarthritis diagnoses and type-2 diabetes polygenic score with diabetes. However, the iron polygenic score was not robustly associated with diagnoses in p.C282Y female homozygotes or in other p.C282Y/p.H63D genotypes. HFE p.C282Y homozygote penetrance to clinical disease in a large community cohort was partly explained by common genetic variants that influence iron and risks of related diagnoses in the general population, including polygenic scores in HH screening and diagnosis, may help in estimating prognosis and treatment planning.


High-strength and anti-bacterial BSA/carboxymethyl chitosan/silver nanoparticles/calcium alginate composite hydrogel membrane for efficient dye/salt separation.
In order to solve the problems of poor mechanical property, non-antibacterial and low flux of calcium alginate (CaAlg) membrane, silver nanoparticles (AgNPs) were synthesized with bovine serum albumin (BSA) and carboxymethyl chitosan (CMCS) for improving CaAlg membrane in this paper. Meanwhile, the dispersion property of silver nanoparticles and the mechanical property, thermal stability, antibacterial property and filtration efficiency of the composite membrane were explored. The results illustrated CMCS observably strengthened the mechanical property and thermal stability of the composite membrane, and AgNPs endowed the composite membrane with excellent antibacterial property. The flux of the BSA/CMCS/AgNPs/CaAlg composite membrane was raised compared to CaAlg membrane. Finally, the viscose fiber/polyethylene terephthalate fiber (VF-PET) nonwoven fabric was introduced as the support layer to further improve the filtration flux and mechanical property of the composite membrane. VF-PET/BSA/CMCS/AgNPs/CaAlg membrane had a rejection rate of over 99.0 % for dye molecules and <9.0 % for salt ions, while the flux maintained 38.5 L·m-2·h-1. Furthermore, VF-PET/BSA/CMCS/AgNPs/CaAlg membrane also had excellent separation effect on actual dye wastewater. The separation of dye and salt by the membrane mainly depended on the screening mechanism of membrane pore size, rather than adsorption. The composite membrane had an outstanding performance on the separation of dye molecules and inorganic salt ions.


[Cornerstones of quality assurance in medicine in Germany. Important impulse for the situation in treatment of rheumatism].
The recently passed German hospital structure act (Krankenhausstrukturgesetz) stresses the immense importance of quality for the medical care of the population. How can inpatient and outpatient treatment in the field of rheumatology be improved and how can this be assessed? A very important basis for such measurement approaches are quality indicators, i.e. parameters that indicate to what degree a certain level of quality has already been reached or is planned to be reached in the future. The work performed by the German Rheumatism Research Center (DRFZ) and the Association of Rheumatological Acute Clinics (VRA) in Germany has already used certain quality indicators and this topic has been recently described elsewhere. International quality indicators have also been published in recent years, all for rheumatoid arthritis (RA), the most prevalent inflammatory rheumatic disease and are the central subject of this article. This overview of proposed instruments for quality assessment in rheumatology is intended to initiate a broad discussion on the subject of quality of rheumatological care in Germany.


Effects of statins and steroids on coronary artery disease and stroke in patients with interstitial lung disease and pulmonary fibrosis: A general population study.
To determine the effects of statins and steroids on the risk of coronary artery disease (CAD) and stroke in patients with interstitial lung disease and pulmonary fibrosis (ILD-PF). We retrospectively enrolled patients with ILD-PF who were using statins (statin cohort, N = 11,567) and not using statins (nonstatin cohort, N = 26,159). Cox proportional regression was performed to analyze the cumulative incidence of CAD and stroke. Adjusted hazard ratios (aHRs) and 95% confidence intervals (CIs) of CAD and stroke were determined after sex, age, and comorbidities, as well as the use of inhaler corticosteroids (ICSs), oral steroids (OSs), and statins, were controlled for. Compared with those of patients without statin use, the aHRs (95% CIs) of patients with statin use for CAD and ischemic stroke were 0.72 (0.65-0.79) and 0.52 (0.38-0.72), respectively. For patients taking single-use statins but not ICSs/OSs, the aHRs (95% CIs) for CAD and ischemic stroke were 0.72 (0.65-0.79)/0.69 (0.61-0.79) and 0.54 (0.39-0.74)/0.50 (0.32-0.79), respectively. For patients using ICSs/OSs, the aHRs (95% CIs) for CAD and ischemic stroke were 0.71 (0.42-1.18)/0.74 (0.64-0.85) and 0.23 (0.03-1.59)/0.54 (0.35-0.85), respectively. The findings demonstrate that statin use, either alone or in combination with OS use, plays an auxiliary role in the management of CAD and ischemic stroke in patients with ILD-PF.


The prevention and management of viral hepatitis.
In this review we will discuss advances in the primary and secondary prevention of viral hepatitis and the treatment for chronic viral hepatitis.


Daily intakes of manganese, copper, zinc and cadmium by New Zealand women.
1. A total of 179 duplicate diets were collected by twenty-three women consuming their habitual diet. Twelve of the subjects were living in a residential hall for students, the others were living in their own homes or in flats. Collection periods varied from 3 to 21 d. 2. Average daily intakes were: manganese 2-7 mg; copper 1-5 mg for diets not containing liver, 7-6 mg for fifteen diets containing liver; zinc 10-0 mg; cadmium 21 microgram for diets not containing liver, 27 microgram for fifteen diets containing liver. 3. The intakes were compared with values for adults from other countries and with current recommended dietary allowances or estimated minimum requirements. Mn intakes were typical for non-vegeratian Western diets. Cu and Zn intakes may have been marginally low. The intakes of Cd were low. 4. Daily intakes of protein (71 g), fat (83 g), fat (83 g), carbohydrate (224 g) and energy (8-1 MJ) from 129 of the diets were similar to recent values obtained for New Zealand women. 5. Subjects living in the residential hall had higher intakes of all nutrients than subjects living in their own homes or flats.


Infundibulopyelostomy for vascular obstruction of a middle infundibulum.
The syndrome of nephralgia caused by vascular compression of a superior infundibulum of the kidney and its surgical resolution are reported. A case is presented to demonstrate that this syndrome also can involve a middle infundibulum, which can be treated by the same surgical technique.


The effect of micro-environment on luminescence of aequorin: the role of amino acids and explicit water molecules on spectroscopic properties of coelenteramide.
Despite the fact that the luminescence reaction mechanism of aequorin has been intensively investigated, details in luminescence such as the effect of important amino acids residues and explicit water molecules on spectroscopic properties of coelenteramide remain unclear. In this work, the effect of amino acids residues His16, Tyr82, Trp86, Phe113, Trp129, Tyr132, explicit water molecules Wat505 and Wat405 on the spectral properties of CLM(-) has been studied by CAM-B3LYP, TD M06L and TD CAM-B3LYP methods in hydrophobic environment and aqueous solution. In hydrophobic environment, the amino acids or water molecules have no significant effect on the absorption. Tyr82 and Trp86 move close to CLM(-) changes the hydrogen bond network, and thus, the spectral properties is significantly affected by the hydrogen bonds between His16H(+)+Tyr82+Trp86 and CLM(-). Tyr82, Trp86 hydrogen bonding to CLM(-) upshifts the excited energy and helps emission spectra shift to blue region. Therefore, it is concluded that His16H(+)+Tyr82+Trp86 modify the emission spectra. The molecular electrostatic potential indicated that the greater electron density is located at the oxygen atom of 6-p-hydroxyphenyl group of CLM(-), and it facilitates the formation of hydrogen bond with His16H(+)+Tyr82+Trp86. It is a critical condition for the modification of emission spectra. It is expected to help to understand the interactions between emitter and amino acids in the micro environment.


Endometrioid carcinoma of the rectum arising in endometriosis: report of a case.
The case of a patient with an endometrioid carcinoma arising in endometriosis of the rectum is presented. This lesion grossly appeared to be a carcinoma arising from the rectal mucosa until microscopic examination of the specimen was completed. The endometrial implant continued to grow and eventually degenerated into a carcinoma in spite of bilateral salpingoophorectomy. This was believed to be due to maintenance of the patient on diethylstilbestrol. This case is believed to be the ninth reported case of carcinoma arising in an endometrial implant in the colon or rectum.


Utilizing Drift Tube Ion Mobility Spectrometry for the Evaluation of Metabolites and Xenobiotics.
Metabolites and xenobiotics are small molecules with a molecular weight that often falls below 600 Da. Over the last few decades, multiple small molecule databases have been curated listing structures, masses, and fragmentation spectra possible in metabolomic and exposomic measurements. To date only a small portion of the spectra in these databases are experimentally derived due to the high expense of obtaining, synthesizing, and analyzing standards. A vast majority of spectra have thus been created using theoretical programs to fit the available experimental data. The errors associated with theoretical data have however caused problems with current small molecule identifications, and accurate quantitation as searching the databases using just one or two analysis dimensions (i.e., chromatography retention times and mass spectrometry (MS) m/z values) results in numerous annotations for each experimental feature. Additional analysis dimensions are therefore needed to better annotate and identify small molecules. Drift tube ion mobility spectrometry coupled with MS (DTIMS-MS) is a promising technique to address this challenge as it is able to perform rapid structural evaluations of small molecules in complex matrices by assessing the collision cross section values for each in addition to their m/z values. The use of IMS in conjunction with other separation techniques such as gas or liquid chromatography and MS has therefore enabled more accurate identifications for the small molecules present in complex biological and environmental samples. Here, we present a review of relevant parameter considerations for DTIMS application with emphasis on xenobiotics and metabolomics isomer separations.


Inhibition of brain choline acetyltransferase by tetraplatin.
Tetraplatin inhibited choline acetyltransferase (CAT) from rat and bovine brain with I50 values of 13.5 and 40 microM, respectively. At 0.5 mM concentration, tetraplatin exhibited inhibition of the rat brain enzyme by 89%, whereas cisplatin yielded only 18% inhibition. With bovine CAT, tetraplatin showed noncompetitive inhibition with the substrate choline, Km 337 microM, Ki 29 microM, Vmax 2.83 nmoles acetylcholine formed/min/mg protein, and competitive inhibition with the substrate acetyl-CoA, Km 21 microM, Ki 16 microM, Vmax 3.85 nmoles acetylcholine formed/min/mg protein.


Association of the clusterin gene polymorphisms with type 2 diabetes mellitus.
The association of the clusterin (CLU) gene polymorphism (single nucleotide polymorphisms [SNPs] 1-4: rs1532278, rs1532277, rs2279590, and rs2279591, respectively) with type 2 diabetes mellitus was examined using a population of the Funagata study (n [male-female] = 1631 [741:884]; age, 62.0 ± 12.1 years), a Japanese community-based study. Single nucleotide polymorphisms 1 to 3 were significantly associated with hemoglobin A(1c) levels (P = .0154, .0021, and .0006, respectively) and diabetes (.0310, .0170, and .0021, respectively). A case-control association study of SNP 3 with diabetes by multiple logistic regression analysis showed a significant association of genotype AA (the at-risk genotype) with an odds ratio (OR) of 2.33 (P = .0039) independently of age and sex. The association was marginally validated by a study with another Japanese community-based sample, the Takahata Study (n [male-female] = 2.948 [1333:1615]; age, 63.0 ± 10.2 years) (OR, 1.59; P = .0595; χ(2)P = .0264). When the 2 samples were combined, the association became more significant (OR, 1.75; P = .0025). In subjects with the non-at-risk genotypes, the insulin resistance index--homeostasis model assessment of insulin resistance (HOMA-R)--increased significantly (P < .0001) and the insulin secretion index--HOMA-β--appeared to decrease (P = .1803 and .0097, respectively, for the genotypes AG and GG) as the glucose tolerance progressed toward diabetes (normal glucose tolerance to glucose intolerance to diabetes). However, in subjects with the at-risk genotype, HOMA-R and HOMA-β showed a significant increase already in the subjects with normal glucose tolerance (P = .0239 and .0305, respectively); and as the glucose tolerance progressed toward diabetes, HOMA-R stayed approximately the same, whereas HOMA-β decreased significantly (P = .0332). The CLU gene was associated with diabetes, probably through an increase in insulin resistance primarily and through an impairment of insulin secretion secondarily.


Neural Query System: Data-mining from within the NEURON simulator.
We have developed a simulation tool within the NEURON simulator to assist in organization, verification, and analysis of simulations. This tool, denominated Neural Query System (NQS), provides a relational database system, a query function based on the SELECT function of Structured Query Language, and data-mining tools. We show how NQS can be used to organize, manage, verify, and visualize parameters for both single cell and network simulations. We demonstrate an additional use of NQS to organize simulation output and relate outputs to parameters in a network model. The NQS software package is available at http://senselab. med.yale.edu/senselab/SimToolDB.


Novel constrained CCK-B dipeptoid antagonists derived from pipecolic acid.
A new series of 4-substituted pipecolic acid derivatives was prepared and incorporated into dipeptoids. The resulting products behave as moderately potent CCK-B antagonists but their constrained structure and its comparison with structurally related compounds yield valuable information about the conformational requirements for optimal recognition of the CCK-B receptor by antagonists.


Red blood cell washing, nitrite therapy, and antiheme therapies prevent stored red blood cell toxicity after trauma-hemorrhage.
Transfusion of stored red blood cells (RBCs) is associated with increased morbidity and mortality in trauma patients. Pro-oxidant, pro-inflammatory, and nitric oxide (NO) scavenging properties of stored RBCs are thought to underlie this association. In this study we determined the effects of RBC washing and nitrite and antiheme therapy on stored RBC-dependent toxicity in the setting of trauma-induced hemorrhage. A murine (C57BL/6) model of trauma-hemorrhage and resuscitation with 1 or 3 units of RBCs stored for 0-10 days was used. Tested variables included washing RBCs to remove lower MW components that scavenge NO, NO-repletion therapy using nitrite, or mitigation of free heme toxicity by heme scavenging or preventing TLR4 activation. Stored RBC toxicity was determined by assessment of acute lung injury indices (airway edema and inflammation) and survival. Transfusion with 5 day RBCs increased acute lung injury indexed by BAL protein and neutrophil accumulation. Washing 5 day RBCs prior to transfusion did not decrease this injury, whereas nitrite therapy did. Transfusion with 10 day RBCs elicited a more severe injury resulting in ~90% lethality, compared to <15% with 5 day RBCs. Both washing and nitrite therapy significantly protected against 10 day RBC-induced lethality, suggesting that washing may be protective when the injury stimulus is more severe. Finally, a spectral deconvolution assay was developed to simultaneously measure free heme and hemoglobin in stored RBC supernatants, which demonstrated significant increases of both in stored human and mouse RBCs. Transfusion with free heme partially recapitulated the toxicity mediated by stored RBCs. Furthermore, inhibition of TLR4 signaling, which is stimulated by heme, using TAK-242, or hemopexin-dependent sequestration of free heme significantly protected against both 5 day and 10 day mouse RBC-dependent toxicity. These data suggest that RBC washing, nitrite therapy, and/or antiheme and TLR4 strategies may prevent stored RBC toxicities.


An evaluation of the contributions by fresh gas flow rate, carbon dioxide concentration and desflurane partial pressure to carbon monoxide concentration during low fresh gas flows to a circle anaesthetic breathing system.
Numerous in vitro studies have shown that volatile anaesthetics react with desiccated carbon dioxide (CO2) absorbents to produce carbon monoxide (CO). The effects of anaesthetic concentration, fresh gas flow rate, and the hydration of absorbent or the excretion of CO2 by patients on CO production have also been investigated. This work aims to identify the most significant one of these factors on CO concentration in a low-flow anaesthesia system, without control of the hydration of the absorbents. A simulated clinical circle anaesthetic breathing system was used to study the CO concentration under various conditions. Desflurane was used at three different concentrations. Two CO2 flow rates and three fresh gas flow rates were used. The absorbent temperatures and hydration were measured simultaneously. Desflurane degraded to produce CO in the breathing tube, when the CO2 absorbents were not dried beforehand. In this imitation clinical low-flow setting, fresh gas flow affected the CO production more than the CO2 did (31.7% vs. 9.5%). The actual desflurane partial pressure was not a significant factor. The CO2 flow rate explained 18.2% and 54.0% of the variation of the absorbent hydration changes (%) and temperature, respectively. In clinical practice, the CO2 production varies among patients and is uncontrollable, but markedly affects CO production. The only controllable factor is the fresh gas flow rate if the ultimate goal is to reduce the undesirable exposure of patients to CO from the breathing tube according to this bench model without counting the oxygen consumption.


Distribution of basement membrane antigens in cryopreserved early embryonic hearts.
The early embryonic heart is composed of two cylindrical epithelial layers, an inner endothelium and an outer myocardium. The cardiac jelly (CJ), an acellular accumulation of extracellular matrix (ECM), fills the space between the two epithelia. During development of the heart, a portion of the endothelial cells of the atrioventricular (AV) region differentiate into mesenchyme cells in a temporally and spacially specific manner. Although contiguous with those in the AV region, endothelial cells lining the ventricle never form mesenchyme in situ. At present, the mechanisms controlling the biphasic differentiation of the endothelium and the subsequent migration of cardiac mesenchymal cells are poorly understood. Although the CJ lies between two epithelial and is spatially equivalent to a basement membrane (BM), it has not traditionally been considered to be organized into a BM-like structure. The potential significance of this observation to developmental biology lies in the possibility that BM or their individual components (i.e., fibronectin (FN), laminin (LM), type IV collagen, and heparin sulfate proteoglycan (HSPG] may function as the regulatory site of epithelial differentiation and morphogenesis. A cryofixation technique was developed in order to determine the in situ immunohistochemical distribution of the BM components in the CJ. Results indicated that the CJ exists as the fusion between a larger myocardially derived BM having a lamina densa and an extended reticular lamina and an attenuated, endothelial-associated BM composed only of a lamina densa. Except for FN, the individual BM components were not all present during early stages, but instead appeared in a sequential manner, suggesting that all components of an adult-type BM are not required to initiate the assembly of a structural and functional BM during development. In the AV canal and outflow tract (OT), FN appeared as a progressively expanding gradient of material with the greatest density nearer the myocardium.


Pulmonary function in technology-dependent children 2 years and older with bronchopulmonary dysplasia.
Somatic and pulmonary growth coincide with resolution of hypoxemia by 2 years of age in most children with bronchopulmonary dysplasia (BPD). However, a distinct subgroup of children with BPD continue to require mechanical ventilation and/or supplemental oxygen beyond 2 years of age. This study tested the hypothesis that indices of pulmonary function would be significantly worse in children with BPD 2 years and older who remained technology-dependent secondary to hypoxemia, compared to those of age-matched children with BPD who were normoxemic. We measured pulmonary mechanics in 21 oxygen- or ventilator-dependent children with BPD 2 years and older (BPDO2 group; mean age+/-SD, 30.2+/-6.5 months) and in 19 children with BPD who had been weaned off mechanical ventilation and supplemental oxygen for at least 6 months (control group; mean age, 30.1+/-5.5 months). Respiratory rate and tidal volume were measured after sedation with chloral hydrate, and dynamic compliance and expiratory conductance were calculated using the esophageal catheter technique. Maximal flow at FRC (V'(maxFRC)) and ratio of forced-to-tidal flows at midtidal volume were obtained by the rapid thoracic compression technique. FRC was determined by nitrogen washout. There were no statistically significant differences in most measured indices of pulmonary mechanics between the BPDO2 and control groups. However, V'(maxFRC)/FRC was higher in controls compared to subjects in the BPDO2 group (0.81+/-0.40 sec(-1) vs. 0.34+/-0.21 sec(-1), P<0.003). We conclude that most indices of pulmonary function in children with BPD 2 years and older do not reflect the need for mechanical ventilation or supplemental oxygen. We speculate that measurements of lung elastic recoil and tests of distribution of ventilation and pulmonary perfusion may be more sensitive in differentiating normoxemic and hypoxemic children with BPD 2 years and older.


Aquatic environmental fates and risks of benzotriazoles, benzothiazoles, and p-phenylenediamines in a catchment providing water to a megacity of China.
Wearing of vehicle parts could release many chemical additives into the environment, such as benzotriazoles (BTRs), benzothiazoles (BTHs), and p-phenylenediamines (PPDs), which are potentially toxic to wildlife and humans. This study investigated the occurrence, source, and risks of BTRs, BTHs, and PPDs in a source catchment providing water to Guangzhou, a megacity in South China, covering groundwater, surface water, and stormwater. The results showed that BTRs and BTHs were predominant in surface water and groundwater. Unexpectedly, the BTR and BTH concentrations were lower in surface water than groundwater in a third of the paired samples. For the first time, 6PPD-quinone, a toxic ozonation product of N-(1,3-dimethylbutyl)-N'-phenyl-1,4-phenylenediamine (6PPD), was extensively detected in source waters. Stormwater decreased the BTR concentrations but increased the 6PPD-quinone concentrations in surface water owing to their affiliation to suspended particles. From natural to urban segments of Liuxi river, a downstream increasing trend in BTR and BTH concentrations was observed, confirming that they are indicative of urban anthropogenic activities. Strong correlations between industrial activities and BTR or BTH concentrations in surface water indicated that industrial activities were their main sources. Six compounds were prioritized as potentially persistent, mobile, and toxic (PMT) chemicals, combing our monitoring results and REACH criterion. This study improves our understanding of the environmental fates and risks of water-soluble tire-wear chemicals, which provides important information for chemical management, and indicates attention should be paid to the risk posed by 6PPD-quinone in the source water.


Gene by environment interaction mouse model reveals a functional role for 5-hydroxymethylcytosine in neurodevelopmental disorders.
Mouse knockouts of Cntnap2 show altered neurodevelopmental behavior, deficits in striatal GABAergic signaling, and a genome-wide disruption of an environmentally sensitive DNA methylation modification (5-hydroxymethylcytosine [5hmC]) in the orthologs of a significant number of genes implicated in human neurodevelopmental disorders. We tested adult Cntnap2 heterozygous mice (Cntnap2 +/-; lacking behavioral or neuropathological abnormalities) subjected to a prenatal stress and found that prenatally stressed Cntnap2 +/- female mice show repetitive behaviors and altered sociability, similar to the homozygote phenotype. Genomic profiling revealed disruptions in hippocampal and striatal 5hmC levels that are correlated to altered transcript levels of genes linked to these phenotypes (e.g., Reln, Dst, Trio, and Epha5). Chromatin immunoprecipitation coupled with high-throughput sequencing and hippocampal nuclear lysate pull-down data indicated that 5hmC abundance alters the binding of the transcription factor CLOCK near the promoters of these genes (e.g., Palld, Gigyf1, and Fry), providing a mechanistic role for 5hmC in gene regulation. Together, these data support gene-by-environment hypotheses for the origins of mental illness and provide a means to identify the elusive factors contributing to complex human diseases.


Shorter Alkyl Chains Enhance Molecular Diffusion and Electron Transfer Kinetics between Photosensitisers and Catalysts in CO2 -Reducing Photocatalytic Liposomes.
Covalent functionalisation with alkyl tails is a common method for supporting molecular catalysts and photosensitisers onto lipid bilayers, but the influence of the alkyl chain length on the photocatalytic performances of the resulting liposomes is not well understood. In this work, we first prepared a series of rhenium-based CO2 -reduction catalysts [Re(4,4'-(Cn H2n+1 )2 -bpy)(CO)3 Cl] (ReCn ; 4,4'-(Cn H2n+1 )2 -bpy=4,4'-dialkyl-2,2'-bipyridine) and ruthenium-based photosensitisers [Ru(bpy)2 (4,4'-(Cn H2n+1 )2 -bpy)](PF6 )2 (RuCn ) with different alkyl chain lengths (n=0, 9, 12, 15, 17, and 19). We then prepared a series of PEGylated DPPC liposomes containing RuCn and ReCn , hereafter noted Cn , to perform photocatalytic CO2 reduction in the presence of sodium ascorbate. The photocatalytic performance of the Cn liposomes was found to depend on the alkyl tail length, as the turnover number for CO (TON) was inversely correlated to the alkyl chain length, with a more than fivefold higher CO production (TON=14.5) for the C9 liposomes, compared to C19 (TON=2.8). Based on immobilisation efficiency quantification, diffusion kinetics, and time-resolved spectroscopy, we identified the main reason for this trend: two types of membrane-bound RuCn species can be found in the membrane, either deeply buried in the bilayer and diffusing slowly, or less buried with much faster diffusion kinetics. Our data suggest that the higher photocatalytic performance of the C9 system is due to the higher fraction of the more mobile and less buried molecular species, which leads to enhanced electron transfer kinetics between RuC9 and ReC9 .


Still births, neonatal deaths and neonatal near miss cases attributable to severe obstetric complications: a prospective cohort study in two referral hospitals in Uganda.
Neonatal near miss cases occur more often than neonatal deaths and could enable a more comprehensive analysis of risk factors, short-term outcomes and prognostic factors in neonates born to mothers with severe obstetric complications. The objective was to assess the incidence, presentation and perinatal outcomes of severe obstetric morbidity in two referral hospitals in Central Uganda. A prospective cohort study was conducted between March 1, 2013 and February 28, 2014, in which all newborns from cases of severe pregnancy and childbirth complications were eligible for inclusion. The obstetric conditions included obstetric haemorrhage, hypertensive disorders, obstructed labour, chorioamnionitis and pregnancy-specific complications such as malaria, anemia and premature rupture of membranes. Still births, neonatal deaths and neonatal near miss cases (defined using criteria that employed clinical features, presence of organ-system dysfunction and management provided to the newborns were compiled). Stratified and multivariate logistic regression analysis was conducted to identify risk factors for perinatal death. Of the 3100 mothers, 192 (6.2%) had abortion complications. Of the remainder, there were 2142 (73.1%) deliveries, from whom the fetal outcomes were 257 (12.0%) still births, 369 (17.2%) neonatal deaths, 786 (36.7%) neonatal near misses and 730 (34.1%) were newborns with no or minimal life threatening complications. Of the 235 babies admitted to the neonatal intensive care unit (NICU), the main reasons for admission were prematurity for 64 (26.8%), birth asphyxia for 59 (23.7%), and grunting respiration for 26 (11.1%). Of the 235 babies, 38 (16.2%) died in the neonatal period, and of these, 16 died in the first 24 hours after admission. Ruptured uterus caused the highest case-specific mortality of 76.8%, and led to 16.9% of all newborn deaths. Across the four groups, there were significant differences in mean birth weight, p = 0.003. Antepartum hemorrhage, ruptured uterus, severe preeclampsia, eclampsia, and the syndrome of Hemolysis, Elevated Liver Enzymes, Low Platelets (HELLP syndrome), led to statistically significant attributable risk of newborn deaths (still birth or neonatal deaths). Development of severe maternal outcomes, the mothers having been referred, and gravidity of 5 or more were significantly associated with newborn deaths.


[Not Available].
Accelerated solvent extraction (ASE) is an alternative sample extraction procedure for fumonisins in corn and corn products. ASE gave results comparable to that of a draft CEN method, but required less extraction time. Furthermore, ASE gave significantly higher quantitative values than another method reported for extraction of fumonisins (Trucksess et al., 1995).


Acid maltase deficiency: treatment of respiratory insufficiency with cuirass respirator.
Three patients with the late-onset form of acid maltase deficiency showed a gradual weakening of proximal limb and trunk muscles leading to severe respiratory insufficiency. Considerable deterioration of pulmonary function occurred owing to a vicious cycle of hypoventilation and exhaustion. Treatment by nocturnal cuirass ventilation with tailor-made shells was successful. The muscle weakness still progressed very slowly but there were no more respiratory problems.


Optimizing the properties of Zodo gum and examining its potential for amino acid binding by periodate oxidation.
In this study, the Zodo gum exudated by Amygdalus scoparia spach underwent the periodate oxidation process for chemical modification and the formation of dialdehyde groups. Modification of the Zodo gum properties was done using the periodate oxidation method, response surface methodology (RSM) and central composite design (CCD), with 4 factors of sodium periodate volume (6.4-19.2 mL), temperature (35-55 °C), pH (3-5) and time (2-4 h). Dialdehyde Zodo gum (DZG) was produced by controlling test variables and measuring some responses including dialdehyde content and efficacy, in addition to evaluating the rheological parameters. Quadratic, linear polynomial equations were then fitted with the insignificant Lack of fit and high R2 to address the relationship between the mentioned variables and responses. Optimal test conditions, including pH = 3.9, T = 43 °C and Time = 3.5 h, were also determined for the production of DZG10, DZG20 and DZG30 samples. The results of 1H-13C NMR, FTIR and determination of the aldehyde content indicated the formation of dialdehyde groups in equilibrium with the dominant hemiacetal form. The AFM study of the DZG30 sample also showed over-oxidation and depolymerization, which could be associated with increased hydrophobic properties and the reduced viscosity. Although the DZG30 sample had the highest amount of the dialdehyde factor group with the tendency to combine with the amino group of proteins, DZG10 and DZG20 samples could be recommended for industrial applications due to the nonoccurrence of overoxidation.


A novel HLA-B allele, B*4093, sharing sequences with B*4006 and B*0702 in an Asian Indian donor.
A new HLA-B allele (B*4093) in a North Indian Hindu donor differing from B*4006 by four nucleotide substitutions in codon 41.1, codon 44.3, codon 45.1 and codon 50.3 has been identified. This novel allele was part of the A*0211-B*4093-Cw*1502-DRB1*15-DQB1*06 HLA haplotype.


Understanding Oral Prep Interest Among South African Adolescents: The Role of Perceived Parental Support and PrEP Stigma.
We examined oral PrEP interest among adolescents and its association with perceived parental support and PrEP stigma. Cross-sectional data were collected during baseline procedures of the "Our Family Our Future" intervention trial in South Africa. Adolescents (14-16 years) at elevated risk for acquiring HIV and their parents or caregivers were dyadically enrolled from 2018 to 2021. There were 879 complete adolescent-parent dyads. Among adolescents, 27% had heard about PrEP, 67% reported they would want to use PrEP, and 58% thought their parent would want them to use PrEP. Among parents, 33% had heard about PrEP and 85% reported they would want their adolescent to use PrEP. Adolescents who thought their parent would want them to use PrEP were more likely to be interested in PrEP than adolescents who thought their parent would not want them to use PrEP (adjusted prevalence ratio (aPR) = 2.11, 95% CI 1.82, 2.44). Further, adolescents with higher average PrEP stigma scores above the adolescent sample median were less likely to be interested in PrEP than adolescents with lower average PrEP stigma scores (aPR = 0.81, 95% CI 0.72, 0.91). In conclusion, parents were more supportive of their adolescent taking PrEP than adolescents perceived they would be, and perceptions of low parental support and greater PrEP stigma were associated with reduced PrEP interest among adolescents. Interventions should aim to improve adolescent-parent communication around sexual health and effective HIV prevention tools.


Multivariate analysis of risk factors for cisplatin-induced nephrotoxicity in gynecological cancer.
Risk factors for cisplatin-induced nephrotoxicity (CIN) vary by population. This study aimed to assess risk factors for CIN in patients with gynecological cancer. Patients who underwent cisplatin-based chemotherapy for gynecological cancer between January 2009 and December 2015 at Aichi Medical University School of Medicine were included in this study. CIN was defined according to the 'risk, injury, failure, loss, and end-stage kidney disease' (RIFLE) criteria and classified as either risk (Class R) or injury (Class I). Analyses were performed using univariate and multivariate logistic regression models. Among 112 patients enrolled, 30 had CIN. Multivariate analysis revealed that hydration with magnesium (odds ratio [OR], 0.223), history of cisplatin use (OR, 4.420), and hypoalbuminemia (OR, 4.170) were risk factors for Class R, and that frequency of cisplatin administration (OR, 5.620) and hydration with magnesium (OR, 0.216) were risk factors for Class I. This study confirmed that hydration without magnesium, history of cisplatin use, frequency of cisplatin administration, and hypoalbuminemia are significant risk factors for CIN.


Current challenges in the manufacture of clinical-grade autologous whole cell vaccines for hematological malignancies.
Autologous whole cell vaccines use a patient's own tumor cells as a source of antigen to elicit an anti-tumor immune response in vivo. Recently, the authors conducted a systematic review of clinical trials employing these products in hematological cancers that showed a favorable safety profile and trend toward efficacy. However, it was noted that manufacturing challenges limit both the efficacy and clinical implementation of these vaccine products. In the current literature review, the authors sought to define the issues surrounding the manufacture of autologous whole cell products for hematological cancers. The authors describe key factors, including the acquisition, culture, cryopreservation and transduction of malignant cells, that require optimization for further advancement of the field. Furthermore, the authors provide a summary of pre-clinical work that informs how the identified challenges may be overcome. The authors also highlight areas in which future basic research would be of benefit to the field. The goal of this review is to provide a roadmap for investigators seeking to advance the field of autologous cell vaccines as it applies to hematological malignancies.


Learning Extremal Representations with Deep Archetypal Analysis.
Archetypes represent extreme manifestations of a population with respect to specific characteristic traits or features. In linear feature space, archetypes approximate the data convex hull allowing all data points to be expressed as convex mixtures of archetypes. As mixing of archetypes is performed directly on the input data, linear Archetypal Analysis requires additivity of the input, which is a strong assumption unlikely to hold e.g. in case of image data. To address this problem, we propose learning an appropriate latent feature space while simultaneously identifying suitable archetypes. We thus introduce a generative formulation of the linear archetype model, parameterized by neural networks. By introducing the distance-dependent archetype loss, the linear archetype model can be integrated into the latent space of a deep variational information bottleneck and an optimal representation, together with the archetypes, can be learned end-to-end. Moreover, the information bottleneck framework allows for a natural incorporation of arbitrarily complex side information during training. As a consequence, learned archetypes become easily interpretable as they derive their meaning directly from the included side information. Applicability of the proposed method is demonstrated by exploring archetypes of female facial expressions while using multi-rater based emotion scores of these expressions as side information. A second application illustrates the exploration of the chemical space of small organic molecules. By using different kinds of side information we demonstrate how identified archetypes, along with their interpretation, largely depend on the side information provided. The online version contains supplementary material available at 10.1007/s11263-020-01390-3.


Psychometric Properties and Validity of a Multi-dimensional Risk Perception Scale Developed in the Context of a Microbicide Acceptability Study.
Currently available risk perception scales tend to focus on risk behaviors and overall risk (vs partner-specific risk). While these types of assessments may be useful in clinical contexts, they may be inadequate for understanding the relationship between sexual risk and motivations to engage in safer sex or one's willingness to use prevention products during a specific sexual encounter. We present the psychometric evaluation and validation of a scale that includes both general and specific dimensions of sexual risk perception. A one-time, audio computer-assisted self-interview was administered to 531 women aged 18-55 years. Items assessing sexual risk perceptions, both in general and in regards to a specific partner, were examined in the context of a larger study of willingness to use HIV/STD prevention products and preferences for specific product characteristics. Exploratory and confirmatory factor analyses yielded two subscales: general perceived risk and partner-specific perceived risk. Validity analyses demonstrated that the two subscales were related to many sociodemographic and relationship factors. We suggest that this risk perception scale may be useful in research settings where the outcomes of interest are related to motivations to use HIV and STD prevention products and/or product acceptability. Further, we provide specific guidance on how this risk perception scale might be utilized to understand such motivations with one or more specific partners.


Biomonitoring of Mimachlamys varia transplanted to areas impacted by human activities (La Rochelle Marina, France).
The development of human activities on French Atlantic coastlines (La Rochelle) lead to chronic pollution of the environment by organic (pesticides, hydrocarbons, agrochemicals) and inorganic (heavy metals) contaminants. These past years, several regulations have been implemented to preserve coastal environments. The purpose of this study was to perform biomonitoring of bivalve species using an outdoor caging technique. The goal of our work was to assess the impact of harbour's trace elements on the state of health of the marine bivalve Mimachlamys varia. First, various molecular defence biomarkers were measured: SOD (oxidative stress), GST (detoxification process), MDA (lipid peroxidation), and Laccase (immune reaction). Thus, in April 2016, scallops were collected at three caging sites, which differ by their levels of pollution, after transplantation into port areas (fairing, rainwater) and a control site (marsh). Bivalve samples were taken at three sampling dates (D0, D07, D21). Biomarker assays were performed in the digestive glands due to their bioaccumulation properties. The second aim was to explore the impacts of inorganic pollutants placed in environmental harbour's sites. After 21 days, the biomarker response of transplanted bivalves revealed a SOD decrease, Laccase and GST stimulations, higher concentrations in Cu, Fe, As, Co, Mn, Zn, Sn and no significant variation of MDA concentration. Our ecological relevance of biomarker approaches opens interesting perspectives to identify M. varia such as a pertinent marine sentinel species. The several selected biomarkers determined could confirm their ability to appraise the water quality of hydro-systems located in French coastlines, such as port areas.


Chronic treatments with tacrine and (-)-nicotine induce different changes of nicotinic and muscarinic acetylcholine receptors in the brain of aged rat.
The present study evaluated effects of chronic treatment with tacrine and (-)-nicotine for 21 days on nicotinic and muscarinic acetylcholine receptors in the brains of old rats (24-25 months) by receptor autoradiography. The nicotinic receptor (nAChR) binding sites were measured by (-)-[3H]nicotine and [3H]epibatidine, and the muscarinic receptor (mAChR) binding sites by [3H]pirenzepine and [3H]AFDX 384. No change in (-)-[3H]nicotine binding was observed in all of the brain regions analysed following chroinic treatment with tacrine (10 mg/kg). Similarly, the [3H]epibatidine binding was not changed in most of the brain regions analysed except for a few brain regions where a decrease was observed in tacrine treated animals compared to control animals. Chronic treatment with (-)-nicotine (0.45 mg base/kg) significantly increased both (-)-[3H]nicotine and [3H]epibatidine bindings in every brain regions analysed except for the hippocampus when measured by (-)-[3H]nicotine. A significant decrease in [3H]AFDX 384 binding, but not in [3H]pirenzepine binding was observed in all of the brain regions analysed following the treatment with tacrine. These data suggest that chronic treatments with tacrine and (-)-nicotine differentially interfere and regulate the subtypes of nAChRs and mAChRs in the brain of aged rat. These data differ from what have been earlier observed in the brain of young adult rat following tacrine treatment, revealing some dynamic changes in receptor properties in the brain during aging.


The provision of pharmaceutical care in Denmark: a cross-sectional survey.
Pharmaceutical care was a concept initially defined in the early 1990s. It had its roots within clinical pharmacy, in the USA. In Denmark, pharmaceutical care has been part of the professional standards of practice for community pharmacy since 1995. The objective of the present study was to investigate the provision of pharmaceutical care in community practice in Denmark. A focus of the study was the estimation of the frequency of medicine-related problem identification and the process of problem management in the Danish pharmacies. A cross-sectional questionnaire-based survey of all Danish community pharmacies was conducted (n = 288). The variables included: detection and identification of medicine-related problems, goal-setting for solving medicine-related problems, and documentation of efforts to solve these. The response rate was 75.7%. A non-respondent analysis was performed. On average three medicine-related problems per pharmacy were found within the working week prior to the survey. For two-thirds of those cases the type of problem involved was identified. For the other third, goals had been set to resolve the problem. Minimal documentation of these activities was reported. The primary collaborators in problem management were general practitioners and patients. Pharmaceutical care, in its fullest sense, as defined in policy documents in Denmark, was not evident in practice. While some aspects of pharmaceutical care were being performed, almost no documentation of efforts was taking place in community pharmacy.


The fine structure of the basal lamina in the lizard pituitary gland.
A report is presented of the fine structure of the basal lamina of cells bordering sinusoids in the skink pituitary gland. The basal lamina, which also lines the sinusoidal membrane, is made up of two bands, a thin lighter band which runs parallel to the cell membrane, and a much wider, denser, and highly branched band which at certain locations is attached to the thin band. The thick band sends regularly spaced branches into the subjacent connective tissue. In most sections these branches appear as parallel, unbranched bars, but in some locations they interconnect to form a highly complex reticular pattern. It is surmised that the basal lamina of these cells must consist of a highly structured lattice which looks and possibly acts like a sponge mat in absorbing and retaining fluid crossing into and from the cells.