31P-nuclear magnetic resonance spectroscopy in vivo of six human melanoma xenograft lines: tumour bioenergetic status and blood supply.
Six human melanoma xenograft lines grown s.c. in BALB/c-nu/nu mice were subjected to 31P-nuclear magnetic resonance (31P-NMR) spectroscopy in vivo. The following resonances were detected: phosphomonoesters (PME), inorganic phosphate (Pi), phosphodiesters (PDE), phosphocreatine (PCr) and nucleoside triphosphate gamma, alpha and beta (NTP gamma, alpha and beta). The main purpose of the work was to search for possible relationships between 31P-NMR resonance ratios and tumour pH on the one hand and blood supply per viable tumour cell on the other. The latter parameter was measured by using the 86Rb uptake method. Tumour bioenergetic status [the (PCr + NTP beta)/Pi resonance ratio], tumour pH and blood supply per viable tumour cell decreased with increasing tumour volume for five of the six xenograft lines. The decrease in tumour bioenergetic status was due to a decrease in the (PCr + NTP beta)/total resonance ratio as well as an increase in the Pi/total resonance ratio. The decrease in the (PCr + NTP beta)/total resonance ratio was mainly a consequence of a decrease in the PCr/total resonance ratio for two lines and mainly a consequence of a decrease in the NTP beta/total resonance ratio for three lines. The magnitude of the decrease in the (PCr + NTP beta)/total resonance ratio and the magnitude of the decrease in tumour pH were correlated to the magnitude of the decrease in blood supply per viable tumour cell. Tumour pH decreased with decreasing tumour bioenergetic status, and the magnitude of this decrease was larger for the tumour lines showing a high than for those showing a low blood supply per viable tumour cell. No correlations across the tumour lines were found between tumour pH and tumour bioenergetic status or any other resonance ratio on the one hand and blood supply per viable tumour cell on the other. The differences in the 31P-NMR spectrum between the tumour lines were probably caused by differences in the intrinsic biochemical properties of the tumour cells rather than by the differences in blood supply per viable tumour cell. Biochemical properties of particular importance included rate of respiration, glycolytic capacity and tolerance to hypoxic stress. On the other hand, tumour bioenergetic status and tumour pH were correlated to blood supply per viable tumour cell within individual tumour lines. These observations suggest that 31P-NMR spectroscopy may be developed to be a clinically useful method for monitoring tumour blood supply and parameters related to tumour blood supply during and after physiological intervention and tumour treatment. However, clinically useful parameters for prediction of tumour treatment resistance caused by insufficient blood supply can probably not be derived from a single 31P-NMR spectrum since correlations across tumour lines were not detected; additional information is needed.


The effect of soya consumption on inflammatory biomarkers: a systematic review and meta-analysis of clinical trials.
Inflammation is a major cause of chronic diseases. Several studies have investigated the effects of soya intake on inflammatory biomarkers; however, the results are equivocal. The aim of this study was to conduct a systematic review and meta-analysis of clinical trials that evaluated the effect of soya consumption on inflammatory biomarkers. Medline, Scopus, ISI Web of Science and Google Scholar were systematically searched, up to and including May 2020, for clinical trials that evaluated the effects of soya and soya products on TNF-α, IL-6, IL-2, IL-1β and interferon γ (IFN-γ) in adults. A random effects method was used to calculate overall effects, and subgroup analyses were performed to discern probable sources of inter-study heterogeneity. A total of twenty-eight clinical trials were included. Although soya consumption reduced TNF-α (Hedges' g = -0·28; 95 % CI -0·49, -0·07), it had no significant effect on IL-6 (Hedges' g = 0·07, 95 % CI -0·14, 0·28), IL-2 (mean difference (MD) = -1·38 pg/ml; 95 % CI -3·07, 0·31), IL-1β (MD = -0·02 pg/ml; 95 % CI -0·08, 0·03) and IFN-γ (MD = 1685·82 pg/ml; 95 % CI -1604·86, 4976·50). Subgroup analysis illustrated a reduction in TNF-α in parallel designed studies, at dosages ≥100 mg of isoflavones, and in unhealthy subjects. The present study showed that high doses of isoflavones in unhealthy subjects may yield beneficial effects on TNF-α.


Sticking Around: Short-Range Activity of Wnt Ligands.
Wnt ligands are secreted lipid-modified proteins that are essential for development and homeostasis. Published recently in Nature, Farin et al. (2016) report that Wnt3 acts at a short distance during growth of mouse intestinal organoids, suggesting that Wnt proteins remain membrane-bound to activate signaling at a short range from their source.


Calcitonin gene-related peptide (CGRP) and capsaicin-induced stimulation of heart contractile rate and force.
The effects of calcitonin gene-related peptide (CGRP) on guinea-pig heart contractility were investigated in vitro in relation to the response of capsaicin and noradrenaline (NA). Synthetic rat CGRP (greater than 10(-8) M) caused a long-lasting, positive inotropic and chronotropic effect on the spontaneously beating right atrium. The response to CGRP mimicked the effects of capsaicin and was resistant to beta-adrenoceptor blockade using metoprolol. Furthermore, CGRP did not change basal efflux or the release of 3H-NA induced by transmural nerve stimulation, suggesting an action independent of sympathetic mechanisms. Mepyramine and cimetidine did not reduce the response to CGRP. After tachyphylaxis to the effects of CGRP (5 X 10(-7) M) which developed within 15-20 min, the positive inotropic and chronotropic atrial response to capsaicin was abolished. The effects of NA, however, were not influenced by CGRP tachyphylaxis. In the isolated perfused whole heart, CGRP had more pronounced stimulatory effects on ventricular contractile rate than on force compared to NA. The CGRP response was resistant to metoprolol and still present in capsaicin-pretreated animals. Capsaicin caused a slight initial inhibition of ventricular contractility, which was followed by a marked stimulatory action. As for CGRP, the cardioexcitatory response to capsaicin was more pronounced on rate than on force. The stimulatory responses to capsaicin were absent 2 weeks after systemic capsaicin pretreatment. In conclusion, CGRP mimics the non-adrenergic, cardioexcitatory effects of capsaicin, and the capsaicin response is absent after CGRP tachyphylaxis.(ABSTRACT TRUNCATED AT 250 WORDS)


Macromorphological findings in cases of death in water: a critical view on "drowning signs".
Death in water is a challenging issue in forensic pathology since from natural death to homicide all circumstances of death in water are conceivable. Therefore, the correct interpretation of all abnormal autopsy findings is important. In order to determine a death by drowning, numerous internal and external signs of drowning are already described. However, these are supposed to be influenced by various factors reducing their significance and evidence. Moreover, the autopsy of water corpses often reveals further pathological findings that should not be underestimated for determining the cause of death. The aim of this study was to set frequencies of the observed drowning signs in context to the forensic literature and to identify possible influencing factors. In this study, we observed that pathological organ changes of the cardiovascular system were significantly more common in corpses after shortened (atypical) drowning processes than in classical drowned victims. Furthermore only a complete formation of external foam, immediately after the corpse's recovery, was exclusively found in drowning victims. All other drowning signs were either also observed in non-drowning deaths in water or no information could be provided with reasonable assurance. In addition, many of the examined drowning signs were negatively affected by prolonged postmortem intervals, putrefaction, or resuscitation attempts. It can be concluded from our analysis that morbidity is an important factor in deaths in water. Morbidity can support a death by drowning in case of incidents in water. For the examined drowning signs, no high diagnostic certainty could be observed. Nevertheless, these findings can increase their diagnostic value-if forensic physicians take influencing factors into consideration.


Nonverbal communication as a compensative strategy for severely nonfluent aphasics? A quantitative approach.
Seven severely nonfluent aphasics and one relative or close friend were investigated in an interview situation. The conversation was videotaped and analyzed for the use of nonverbal communication between aphasic and partner. The results indicate that the group of aphasics used significantly more frequently and for a significantly longer period of time nonverbal channels of communication than their healthy partners. The aphasic patients also used significantly fewer speech-focused movements and significantly more codified gestures. Nonverbal elements were more frequently used as speech substitutes by the group of aphasics.


Surgery and radiotherapy in the treatment of primary carcinoma of the Fallopian tube--report of 18 cases.
Eighteen cases of primary Fallopian tube carcinoma referred to Christie Hospital, Manchester over the years 1966 to 1980 are reviewed. The overall 5-year survival rate was 14.4%. Treatment by total hysterectomy and bilateral salpingo-oophorectomy resulted in a longer survival compared to bilateral salpingo-oophorectomy or removal of the tumour alone. Postoperative radiotherapy did not seem to improve survival.


Effects of dietary cholesterol and fat, sex and sire on lecithin-cholesterol acyltransferase activity in baboons.
We analyzed the effects of dietary cholesterol, type of dietary fat, sex and sire progeny family on lecithin-cholesterol acyltransferase activity in 80 adult baboons. The animals were the progeny of 80 dams and 6 sires and were randomly assigned at birth to breast feeding or to one of three formulas containing 0.02, 0.30 or 0.60 mg cholesterol/ml. After weaning at 4 months of age the animals were fed one of four diets that were either high or low in cholesterol with 40% of the calories from either saturated or unsaturated fat. The fractional and molar rates of lecithin-cholesterol acyltransferase activity were measured at 7-8 years of age by an HPLC method. Infant diet (breast vs. formula feeding or level of cholesterol in formula had no effect on enzyme activity later in life. The adult diets that were high in cholesterol decreased the fractional lecithin-cholesterol acyltransferase rate by 20% / compared to diets low in cholesterol (7.89 vs. 9.84%/h, P less than 0.002), but dietary cholesterol did not affect the molar activity. Animals fed the high cholesterol diets had higher unesterified cholesterol concentrations compared to those fed the low cholesterol diets (38.1 mg/dl vs. 31.6 mg/dl, P less than 0.0001). The molar lecithin-cholesterol acyltransferase rate was increased 13% by saturated compared to unsaturated fat (83.3 vs. 73.6 nmol/h per ml plasma, P less than 0.07), but no effect of dietary fat was observed on the fractional enzyme activity. Females compared to males had significantly higher fractional (10.9 vs. 7.14%/h, P less than 0.0001) and molar lecithin-cholesterol acyltransferase activities (99.3 vs. 61.7 nmol/h per ml plasma, P less than 0.0001). After adjustment for the effects of diet and sex we observed differences in the fractional activity (range, 7.2-10.8%/h, P less than 0.04) and in the molar rate (range, 63.6-99.8 nmol/h per ml plasma, P less than 0.07) among the six sire progeny groups. The differences among sire progeny groups are evidence for genetic differences in lecithin-cholesterol acyltransferase activities among the baboon families.


Erratum: Neuraxial dysraphism in EPAS1-associated syndrome due to improper mesenchymal transition.
[This corrects the article on p. e414 in vol. 6, PMID: 32337341.].


Systematic review of determinants and interventions of areca nut cessation: curbing a public health menace.
This letter presents a critical appraisal of a recent systematic review article published in Journal of Public Health. Systematic reviews are particularly important research articles that can meaningfully influence policy and research in the field due to their scientific value. We aimed to bring attention to certain methodological issues in this review that affect the validity of the findings on the very important topic of areca nut use and cessation.


Biological and cellular responses of humans to high-level natural radiation: A clarion call for a fresh perspective on the linear no-threshold paradigm.
There remains considerable uncertainty in obtaining risk estimates of adverse health outcomes of chronic low-dose radiation. In the absence of reliable direct data, extrapolation through the linear no-threshold (LNT) hypothesis forms the cardinal tenet of all risk assessments for low doses (≤ 100 mGy) and for the radiation protection principle of As Low As Reasonably Achievable (ALARA). However, as recent evidences demonstrate, LNT assumptions do not appropriately reflect the biology of the cell at the low-dose end of the dose-response curve. In this regard, human populations living in high-level natural radiation areas (HLNRA) of the world can provide valuable insights into the biological and cellular effects of chronic radiation to facilitate improved precision of the dose-response relationship at low doses. Here, data obtained over decades of epidemiological and radiobiological studies on HLNRA populations is summarized. These studies do not show any evidence of unfavourable health effects or adverse cellular effects that can be correlated with high-level natural radiation. Contrary to the assumptions of LNT, no excess cancer risks or untoward pregnancy outcomes have been found to be associated with cumulative radiation dose or in-utero exposures. Molecular biology-driven studies demonstrate that chronic low-dose activates several cellular defence mechanisms that help cells to sense, recover, survive, and adapt to radiation stress. These mechanisms include stress-response signaling, DNA repair, immune alterations and most importantly, the radiation-induced adaptive response. The HLNRA data is consistent with the new evolving paradigms of low-dose radiobiology and can help develop the theoretical framework of an alternate dose-response model. A rational integration of radiobiology with epidemiology data is imperative to reduce uncertainties in predicting the potential health risks of chronic low doses of radiation.


Pregnancy outcome at maternal age 40 and older.
This case-control study was performed to compare the pregnancy outcomes of women aged 40 years and older with those of 20- to 30-year-old women. Among 28,507 women who delivered in the Zeinabieh and Hafez hospitals affiliated to Shiraz University of Medical Sciences between September 2001 and October 2004, 574 women (2.01%) were 40 years old or older at the time of delivery. Eight cases were excluded because of multifetal pregnancies. From the 566 remaining cases, 200 women (case group) were selected by simple random sampling and their hospital admission charts were retrospectively reviewed. They were compared with 200 20- to 30-year-old mothers (control group). The mean age for the case group was 41.56 +/- 2.06 years and that for the control group was 24.63 +/- 2.89 years. The mean birth weight was 2,869 +/- 848 g for the case group and 2,895 +/- 834 g for the control group (p = 0.75). The incidences of preeclampsia, gestational hypertension, cesarean delivery, abruptio placenta, preterm delivery, and 5-minute Apgar scores < 7 were significantly higher in the older group (p < 0.05). Some complications such as diabetes, chronic hypertension and perinatal mortality were more common in the older mothers, but the differences were not statistically significant. A comparison of complications with respect to parity showed that preterm birth (p = 0.002) and low birth weight (p = 0.04) occurred more frequently in primiparous older women. However, preeclampsia (p = 0.002) and abruptio placenta (p = 0.012) were more common in multiparous older women. Maternal and neonatal complications increased in women aged 40 years and above, but neonatal outcomes were similar to those in the younger age group.


Walking ability of individuals fitted with transfemoral bone-anchored prostheses: A comparative study of gait parameters.
This study presents the walking abilities of participants fitted with transfemoral bone-anchored prostheses using a total of 14 gait parameters. Two-centre retrospective cross-sectional comparative study. Research facilities equipped with tridimensional motion capture systems. Two control arms included eight able-bodied participants arm (54 ± 9 years, 1.75 ± 0.07 m, 76 ± 7 kg) and nine participants fitted with transfemoral socket-suspended prostheses arm (59 ± 9 years, 1.73 ± 0.07 m, 80 ± 16 kg). The intervention arm included nine participants fitted with transfemoral bone-anchored prostheses arm (51 ± 13 years, 1.78 ± 0.09 m, 87.3 ± 16.1 kg). Fitting of transfemoral bone-anchored prostheses. Comparisons were performed for two spatio-temporal, three spatial and nine temporal gait parameters. The cadence and speed of walking were 107 ± 6 steps/min and 1.23 ± 0.19 m/s for the able-bodied participants arm, 88 ± 7 steps/min and 0.87 ± 0.17 m/s for the socket-suspended prosthesis arm, and 96 ± 6 steps/min and 1.03 ± 0.17 m/s for bone-anchored prosthesis arm, respectively. Able-bodied participants and bone-anchored prosthesis arms were comparable in age, height, and body mass index as well as cadence and speed of walking, but the able-bodied participant arm showed a swing phase 31% shorter. Bone-anchored and socket-suspended prostheses arms were comparable for age, height, mass, and body mass index as well as cadence and speed of walking, but the bone-anchored prosthesis arm showed a step width and duration of double support in seconds 65% and 41% shorter, respectively. Bone-anchored and socket-suspended prostheses restored equally well the gait parameters at a self-selected speed. This benchmark data provides new insights into the walking ability of individuals using transfemoral bionics bone-anchored prostheses.


Significance of the changes in plasma amino-acid levels in meningococcal infection.
A series of patients with meningococcal infections have been studied and divided in two groups: Group I patients with meningococcal sepsis and group II, those with meningococcal meningitis. Patients in group I presented with more severe encephalopathy, shock, DIC and acute systemic complications. Both groups showed a marked hypoaminoacidemia compared with normal controls (other than for the sulfur containing amino acids and phenylalanine). The concentration of aromatic and basic amino acids, the phenylalanine/tyrosine ratio, the transaminase levels and the negative nitrogen balance were higher in group I patients. The ratio of branched chain to aromatic amino acids was lower in group I. All these differences were statistically significant. The close association between the metabolic derangements and clinical manifestations may help in the understanding of several physiopathological aspects of meningococcal infections.


Agenesis of sphenoid sinus: three cases.
Paranasal sinus agenesis is an unusual clinical condition. The frontal sinus agenesis is more frequently seen, whereas agenesis of the sphenoid sinus is extremely rare. This report presents three new cases of sphenoid sinus agenesis. The absence of the sphenoid sinus was demonstrated by computed tomography (CT) in all cases.


Envelopment filter and K-means for the detection of QRS waveforms in electrocardiogram.
The electrocardiogram (ECG) is a well-established technique for determining the electrical activity of the heart and studying its diseases. One of the most common pieces of information that can be read from the ECG is the heart rate (HR) through the detection of its most prominent feature: the QRS complex. This paper describes an offline version and a real-time implementation of a new algorithm to determine QRS localization in the ECG signal based on its envelopment and K-means clustering algorithm. The envelopment is used to obtain a signal with only QRS complexes, deleting P, T, and U waves and baseline wander. Two moving average filters are applied to smooth data. The K-means algorithm classifies data into QRS and non-QRS. The technique is validated using 22 h of ECG data from five Physionet databases. These databases were arbitrarily selected to analyze different morphologies of QRS complexes: three stored data with cardiac pathologies, and two had data with normal heartbeats. The algorithm has a low computational load, with no decision thresholds. Furthermore, it does not require any additional parameter. Sensitivity, positive prediction and accuracy from results are over 99.7%.


Applicability analysis of extended state observer-based control for systems subject to parametric disturbances.
This paper discusses the applicability of Extended State Observer (ESO)-based control when systems are subjected to different types of parametric disturbances. The applicability is analyzed by establishing the characteristic polynomial of the closed-loop system. It is found that High-Bandwidth ESO-based control is beneficial to the elimination of state-parameter disturbances, but it has a negative impact on the elimination of input-parameter disturbances. In spite of this, the ESO-based control with suitable bandwidth can still be applied to systems which are subject to input-parameter disturbances. A Full-Order ESO-based control scheme is proposed so that disturbance rejection-based control is realized for a class of non-minimum phase systems. Numerical simulations are carried out to verify the correctness of the conclusions and the effectiveness of the proposed controller.


Postoperative cognitive dysfunction in geriatric patients.
Postoperative cognitive dysfunction (POCD) is a severe long-term complication after surgical procedures. POCD is mainly seen among geriatric patients. Hospitalization, extent of surgery, and systemic inflammatory response might contribute to POCD. The possible influence of the type of anesthesia is discussed. POCD is often not recognized; thus, incidence rates are likely to be underestimated (19-40%). POCD is associated with major consequences for the individual patient, e.g., delayed long-term recovery, reduced quality of life, and an increased mortality rate. Multiple risk factors have been identified over the last decade. However, the exact etiology is still unknown. This mini-review summarizes the recent developments concerning POCD prevention, diagnosis, and treatment.


Escaping and Falling into Poverty in India Today.
The study examines the dynamic nature of movements into and out of poverty over a period when poverty has fallen substantially in India. The analysis identifies people who escaped poverty and those who fell into it over the period 2005 to 2012. The analysis identifies people who escaped poverty and those who fell into it over the period 2005 to 2012. Using panel data from the India Human Development Survey for 2005 and 2012, we find that the risks of marginalized communities such as Dalits and Adivasis of falling into or remaining in poverty were higher than those for more privileged groups. Some, but not all of these higher risks are explained by educational, financial, and social disadvantages of these groups in 2005. Results from a logistic regression show that some factors that help people escape poverty differ from those that push people into it and that the strength of their effects varies.


Instantaneous and causal connectivity in resting state brain networks derived from functional MRI data.
Most neuroimaging studies of resting state networks have concentrated on functional connectivity (FC) based on instantaneous correlation in a single network. In this study we investigated both FC and effective connectivity (EC) based on Granger causality of four important networks at resting state derived from functional magnetic resonance imaging data - default mode network (DMN), hippocampal cortical memory network (HCMN), dorsal attention network (DAN) and fronto-parietal control network (FPCN). A method called correlation-purged Granger causality analysis was used, not only enabling the simultaneous evaluation of FC and EC of all networks using a single multivariate model, but also accounting for the interaction between them resulting from the smoothing of neuronal activity by hemodynamics. FC was visualized using a force-directed layout upon which causal interactions were overlaid. FC results revealed that DAN is very tightly coupled compared to the other networks while the DMN forms the backbone around which the other networks amalgamate. The pattern of bidirectional causal interactions indicates that posterior cingulate and posterior inferior parietal lobule of DMN act as major hubs. The pattern of unidirectional causal paths revealed that hippocampus and anterior prefrontal cortex (aPFC) receive major inputs, likely reflecting memory encoding/retrieval and cognitive integration, respectively. Major outputs emanating from anterior insula and middle temporal area, which are directed at aPFC, may carry information about interoceptive awareness and external environment, respectively, into aPFC for integration, supporting the hypothesis that aPFC-seeded FPCN acts as a control network. Our findings indicate the following. First, regions whose activities are not synchronized interact via time-delayed causal influences. Second, the causal interactions are organized such that cingulo-parietal regions act as hubs. Finally, segregation of different resting state networks is not clear cut but only by soft boundaries.


Gold nanoparticle-enhanced target for MS analysis and imaging of harmful compounds in plant, animal tissue and on fingerprint.
Gold nanoparticle-enhanced target (AuNPET) was used for detailed investigation of various materials of biological origin - human fingerprint, onion bulb and chicken liver. Analysis of these objects was focused on toxic and harmful compounds - designer drug containing pentedrone, diphenylamine in onion and potentially cancerogenic metronidazole antibiotic in liver. Detection of large quantity of endogenous compounds from mentioned objects is also shown. Most of analyzed compounds were also localized with MS imaging and relationship between their function and location was discussed. Detected compounds belong to a very wide range of chemical compounds such as saccharides, ionic and non-ionic glycerides, amino acids, fatty acids, sulfides, sulfoxides, phenols etc. Fingerprint experiments demonstrate application of AuNPET for detection, structure confirmation and also co-localization of drug with ridge patterns proving person-drug contact.


Influence of glutathione S-transferase T1 donor/recipient mismatch and anti-GSTT1 antibodies in hepatic graft-versus-host-disease.
B cell responses to minor histocompatibility antigens (mHags) have not been extensively studied after allogeneic hematopoietic stem cell transplantation (HSCT). Glutathione S-transferase T1 (GSTT1) is a drug metabolizing enzyme encoded by a single gene that is highly expressed in liver and kidney. Anti-GSTT1 antibodies have been described in the context of antibody-mediated rejection in kidney and liver transplantation, due to a mismatch between donor and recipient. The aim of the present study was to investigate the specific immune response against GSTT1 in HSCT with production of antibodies and their influence in the development of hepatic graft-versus-host-disease (GVHD). Forty patients and their respective donors were included in the study. The median follow-up time was 35.6 months (range 0.6-76 months) and a total of 349 serum samples were tested for the presence of anti-GSTT1 antibodies by ELISA test. Statistical analysis was performed by defining the GSTT1 null donor/positive recipient as mismatch compared with the other three genetic combinations regarded as GSTT1-matched. Antibodies were found in three patients within the group of null donor/positive recipient and one within the null/null group. Development of liver GVHD, particularly its acute form, was highly associated with the GSTT1-mismatch (P=0.0178) and with the presence of post-transplant anti-GSTT1 antibodies (P=0.0076). We conclude that GSTT1 could be considered as a new mHag in hepatic GVHD. The fact that three donors were parous females and the rapid production of antibodies after HSCT suggests the existence in the graft of memory B-cells specific for the GSTT1 antigen.


GABA-related enzymes in the hypothalamus of rats treated with estradiol.
The possibility that the activity of GABA-related enzymes in the hypothalamus, glutamic acid decarboxylase (GAD) and GABA-transaminase (GABA-T), may be modified by circulating prolactin levels was investigated in castrated female and male rats. Estradiol benzoate was chosen to induce an increase, while bromergocriptine was used to obtain a decrease of serum prolactin levels. Acute treatment with estradiol benzoate brought about 3 h later, a significant increase of serum prolactin, and a slight, non-significant increase of GAD activity in the hypothalamus. Chronic treatment with estradiol benzoate for 12 days induced significant increases in serum prolactin and GAD activity in the hypothalamus. Bromergocriptine significantly blocked this increase of GAD activity. Bromergocriptine-treated rats had significant increases of GABA-T activity in the hypothalamus. The results of this investigation support the possibility of the existence of a relationship between GABA-related enzymes in the hypothalamus and circulating prolactin levels.


A serine and a lysine residue implicated in the catalytic mechanism of the Escherichia coli leader peptidase.
We report that a thiol leader peptidase, produced by replacing the critical serine at position 90 with a cysteine residue, is enzymatically active. In contrast to the wild-type leader peptidase, the thiol enzyme can be inactivated with N-ethylmaleimide, a cysteine-specific reagent. This strongly suggests that the serine 90 is involved in catalysis and is located at the active site. Of the three conserved basic residues in the signal peptidase family, only lysine 145 appears to be critical for catalysis; when lysine 145 was mutated to an alanine residue, leader peptidase K145A protein was inactive both in vitro and in vivo. A control experiment showed that the K145A mutant competes with the wild-type leader peptidase for substrate binding, confirming that the K145A mutation did not cause a global conformational change. The data provides evidence that catalysis of leader peptidase is carried out by a serine-lysine dyad.


Oropharyngeal Squamous Cell Carcinoma in 390 Patients: Analysis of Clinical and Histological Criteria Which Significantly Impact Outcome.
This study evaluates the prognostic impact of several factors in oropharyngeal squamous cell carcinoma (OPSCC), controlling for human papillomavirus (HPV)-associated tumors and stage (American Joint Committee on Cancer 8th edition). All patients in Southern California Permanente Medical Group diagnosed with OPSCC between 2006 and 2012 tested for p16 immunohistochemistry were included. Review of all pathology materials was combined with central p16 testing. Multivariable analyses were performed. The cohort of 390 patients included 342 p16-positive and 48 p16-negative tumors. For all-comers, on univariate analysis, the following factors, when present, were associated with improved patient survival: p16-positive tumor (n = 324, p < 0.001); crypt versus surface tumor location (n = 312, p = 0.004); nonkeratinizing type (n = 309, p < 0.0001); nonkeratinizing with maturation type (n = 37, p < 0.0001); basaloid pattern (n = 284, p = 0.005); and a broad, pushing border of infiltration (n = 282, p = 0.004). Inferior survival outcomes were observed with: age ≥ 55 years (p < 0.0001); ≥ 10 pack-year smoking history (n = 183, p = 0.003); increasing tumor stage (p < 0.0001); overt radiographic extranodal extension (ORENE) (n = 58, p < 0.0001); low level IV/Vb lymph node involvement (n = 45, p = 0.0002); a jagged pattern of infiltration (n = 76, p = 0.0004); tumor ulceration (n = 76, p = 0.0004); absent lymphocytic infiltrate (p < 0.0001); and concurrent dysplasia (n = 125, p = 0.009). On multivariable analysis, accounting for patient age, smoking history ≥ 10 pack-years, and TNM stage, for patients with p16-positive disease, advanced TNM stage (p = 0.007), the presence of ORENE (p = 0.0002), and low-neck lymphadenopathy (p = 0.0001) were independent negative prognostic factors for disease free survival (DFS). Older age (p < 0.0001), smoking history ≥ 10 pack-years (p = 0.02), advanced TNM stage (p = 0.0002), ORENE (p = 0.004), and low-neck lymphadenopathy (p = 0.002) were independent negative prognostic factors for OS. Among patients with p16-positive OPSCC, older age, smoking history, advanced stage, ORENE, and low-neck lymphadenopathy were significant negative prognostic factors for DFS and/or OS. Further refinement of staging to incorporate additional lymph node findings may be warranted.


An Upper Bound on Topological Entropy of the Bunimovich Stadium Billiard Map.
We show that the topological entropy of the billiard map in a Bunimovich stadium is at most log(3.49066).


Serum malanodialdehyde (TBA reactive substance) levels in cigarette smokers.
Serum malanodialdehyde (MDA) levels in 40 smokers and 23 non-smokers belonging to different age groups were estimated. The MDA levels were high in smokers of all age groups having a history of smoking for less than 10 years. MDA levels, however, were not elevated in smokers with a history of smoking for more than 10 years. These results are discussed and are interpreted as suggestive that MDA might alter the LDL and lead to deposition of cholesterol in arterial wall macrophages explaining thereby the risk of ischaemic heart disease in cigarette smokers.


B7-H3 protein expression in acute myeloid leukemia.
Costimulatory molecules are essential regulators of the immunological synapse and enable the fine-tuning of the immune response. These mechanisms are subverted by cancer cells to evade immunosurveillance. The B7 family of costimulatory molecules comprises several ligands that may contribute to immunoescape. B7-H3 [B7-homolog 3 or CD276] remains poorly investigated in hematological malignancies. To determine the role B7-H3, we analyzed the expression of this molecule in blast cells from a cohort of 111 acute myeloid leukemia (AML) patients. B7-H3 was expressed in blast cells with a mean fluorescence intensity ratio >3 in 30 (27%) of the 111 patients. B7-H3 expression was higher in the M3 and M5 FAB subtypes and in cases with mutated NPM1 and wild type CEBPA. There were no significant differences found for the FLT3-ITD or cytogenetic risk groups. The complete remission (CR) rate between the 17 B7-H3-positive and 58 negative patients who were treated intensively was not different. The event free survival was longer in B7-H3-positive patients (P = 0.014), and there was a trend toward better overall survival. However, this difference was not statistically significant (P = 0.053). In conclusion, B7-H3 is one of the most strongly expressed B7-family molecules in AML and merits further investigation.


Targeting the CD146/Galectin-9 axis protects the integrity of the blood-brain barrier in experimental cerebral malaria.
Cerebral malaria (CM) is a life-threatening diffuse encephalopathy caused by Plasmodium falciparum, in which the destruction of the blood-brain barrier (BBB) is the main cause of death. However, increasing evidence has shown that antimalarial drugs, the current treatment for CM, do little to protect against CM-induced BBB damage. Therefore, a means to alleviate BBB dysfunction would be a promising adjuvant therapy for CM. The adhesion molecule CD146 has been reported to be expressed in both endothelial cells and proinflammatory immune cells and mediates neuroinflammation. Here, we demonstrate that CD146 expressed on BBB endothelial cells but not immune cells is a novel therapeutic target in a mouse model of experimental cerebral malaria (eCM). Endothelial CD146 is upregulated during eCM development and facilitates the sequestration of infected red blood cells (RBCs) and/or proinflammatory lymphocytes in CNS blood vessels, thereby promoting the disruption of BBB integrity. Mechanistic studies showed that the interaction of CD146 and Galectin-9 contributes to the aggregation of infected RBCs and lymphocytes. Deletion of endothelial CD146 or treatment with the anti-CD146 antibody AA98 prevents severe signs of eCM, such as limb paralysis, brain vascular leakage, and death. In addition, AA98 combined with the antiparasitic drug artemether improved the cognition and memory of mice with eCM. Taken together, our findings suggest that endothelial CD146 is a novel and promising target in combination with antiparasitic drugs for future CM therapies.


Platelet 5-hydroxytryptamine accumulation in depressive illness.
The uptake of 5-hydroxytryptamine (5-HT) by blood platelets from controls, depressed patients and recovered depressed patients has been determined using short incubation times and low substrate concentrations. The affinity of serotonin for the platelet membrane appears to be normal in acutely depressed and recovered depressed patients. The capacity of transport of 5-HT through the platelet membrane is impaired in these depressive patients and this impairment is independent of the psychiatric status of the patients and is discussed in the light of the electrolyte and enzyme disturbances that are associated with depressive illness.


Engaging Adults With Chronic Disease in Online Depressive Symptom Self-Management.
The main purpose of this study was to evaluate participant engagement and effects of an Internet-based, self-directed program for depressive symptoms piloted among adults with a chronic disease. Eligible participants ( N = 47) were randomly assigned to either the "Think Clearly About Depression" online depression self-management program or the control group. The Patient Health Questionnaire-8 and Chronic Disease Self-Efficacy Scales were administered at baseline and at Weeks 4 and 8 after initiating the intervention. Number Needed to Treat analysis indicated that one in every three treatment group participants found clinically significant reductions in depressive symptoms by Week 8. Paired-sample t tests showed that depressive symptoms and self-efficacy in management of depressive symptoms improved over time for those in the treatment group and not for those in the control group. Participants' engagement and satisfaction with the online program were favorable.


Artesunate alleviates myocardial ischemia/reperfusion-induced myocardial necrosis in rats and hypoxia/reoxygenation-induced apoptosis in H9C2 cells via regulating the FAK/PI3K/Akt pathway.
The various anti-inflammatory, anti-apoptotic, and antioxidant effects of Artesunate (Art) have been explored in numerous studies. This study aimed to evaluate the function of Art on myocardial necrosis in apoptotic cardiomyocytes in vivo and in vitro. Sprague Dawley (SD) rats were randomly divided into groups: a control group, a myocardial ischemia reperfusion (MI/R) group, and MI/R+ Art groups. To establish a MI/R model, rats were subjected to left anterior descending artery ischemia for 45 minutes, and then reperfusion for 2 hours. Hypoxia was induced in H9C2 cells by subjecting them to hypoxic conditions at 37 °C for 4 hours, before placing them in a normoxic chamber for 2 hours. The test methods were used in this test, such as echocardiography, enzyme-linked immunosorbent assay (ELISA), HE staining, TUNEL staining, immunohistochemistry, flow cytometry, western blot, and CCK-8 assay. Art improved myocardial systolic function caused by MI/R injury in vivo. Simultaneously, Art reduced the levels of cardiac troponin I (cTnl), creatine kinase-MB (CK-MB) and myohemoglobin (Mb) in vivo and in vitro. Moreover, Art inhibited cardiomyocyte apoptosis in vivo and in vitro. The focal adhesion kinase (FAK)/phosphatidylinositide-3 kinases (PI3K)/AKT signaling pathway was also activated by Art in vivo and in vitro. Furthermore, after inhibitor PF573228 was added, Art inhibited apoptosis in H9C2 cells via activation of the FAK/PI3K/AKT signaling pathway in vitro. This study confirms that Art alleviated MI/R injury and inhibited cardiomyocyte apoptosis in vivo and in vitro. Art exerted an inhibitory effect on cardiomyocyte apoptosis by activating the FAK/PI3K/AKT signaling pathway. Therefore, Art may serve as an alternative treatment for MI/R injury.


Detecting Pulmonary Nodules in Lung Cancer Patients Using Whole Body FDG PET/CT, High-resolution Lung Reformat of FDG PET/CT, or Diagnostic Breath Hold Chest CT.
Pulmonary nodules can be missed on the non-breath hold computed tomography (CT) portion of 18F-fluorodeoxyglucose positron emission tomography/computed tomography (FDG PET/CT), and for this reason prior studies have advocated for routinely performing dedicated breath hold CT of the chest in addition to PET/CT for routine staging of malignancy. We evaluated the rate of pulmonary nodule detection on standard CT images from whole body PET/CT studies (WB-PET/CT), high-resolution lung reconstruction CT images from PET/CT studies (HR-PET/CT), and diagnostic breath hold chest CT (BH-CT). A cohort of 25 patients was identified who had a history of lung cancer as well as a PET/CT staging or restaging scan and BH-CT within 30 days of each other. All PET/CTs included a set of CT images using a soft tissue algorithm filter and 3.75- to 5-mm slice thickness, as well as high-resolution reformats with a sharp reconstruction filter and 2-mm slice thickness. The CT images from WB-PET/CT, HR-PET/CT, and BH-CT were reviewed by three radiologists. Significance was analyzed by two-way repeated measures analysis of variance. There were 2.84 nodules found per patient with WB-PET/CT, 3.85 nodules with HR-PET/CT, and 3.91 nodules with BH-CT. When only nodules less than or equal to 8 mm in size were considered, WB-PET/CT also demonstrated significantly fewer nodules (1.98) compared to the HR-PET/CT (2.94) or a BH-CT (2.86) (P < 0.001). No difference in detection rate was noted between the two higher resolution modalities. More pulmonary nodules are detected on the CT portion of PET/CT studies when high-resolution reformatted images are created and reviewed. The ability to detect nodules with the reformatted images was indistinguishable from dedicated BH-CT. Overall, high-resolution reformats of PET/CT images of the lungs can increase the sensitivity for pulmonary nodule detection, approaching that of dedicated BH-CT. These data suggest that if HR-PET/CT reformats are used, additional dedicated BH-CT is unnecessary for routine staging of lung cancer.


Effect of ZnO morphology on affecting bactericidal property of ultra high molecular weight polyethylene biocomposite.
Bacterial infection of implants can be controlled by selective trapping of bacteria, followed with consequent killing by targeted antibacterial agents. Herein, the role of various ZnO morphologies, viz. micro-rods (R), nanoparticles (NP), and micro-disks (D) on antibacterial efficacy of ZnO via release of Zn(2+) and H2O2 is assessed, both as isolated powders and via incorporating them in cytocompatible ultra high molecular weight polyethylene (UHMWPE). Though ZnO is antibacterial, interestingly, all ZnO morphologies elicited a supportive growth of gram-negative bacteria (Escherichia coli) in culture medium (until 28-35 μg/ml). But, all ZnO morphologies did elicit bactericidal effect on gram positive bacteria (Staphylococcus aureus or Staphylococcus epidermidis) both in culture medium (for 0-2.5 μg/ml) or when incorporated (5-20 wt.%) into UHMWPE. The bactericidal mechanisms were quantified for various ZnO morphologies via: (i) H2O2 production, (ii) Zn(2+) release, and (iii) the presence of surface oxygen vacancies. On one hand, where only ZnO(NP) elicited release of H2O2 in the absence of light, maximum Zn(2+) release was elicited by ZnO(D). Interestingly, when ZnO is incorporated as reinforcement (5-20 wt.%), its antibacterial action against E. coli was vividly observed due to selective proliferation of bacteria only on friendly UHMWPE matrix. Hence, luring bacteria on affable UHMWPE surface can be complemented with their targeted killing by ZnO present in composite.


Exploring the Interior of Europa with the Europa Clipper.
The Galileo mission to Jupiter revealed that Europa is an ocean world. The Galileo magnetometer experiment in particular provided strong evidence for a salty subsurface ocean beneath the ice shell, likely in contact with the rocky core. Within the ice shell and ocean, a number of tectonic and geodynamic processes may operate today or have operated at some point in the past, including solid ice convection, diapirism, subsumption, and interstitial lake formation. The science objectives of the Europa Clipper mission include the characterization of Europa's interior; confirmation of the presence of a subsurface ocean; identification of constraints on the depth to this ocean, and on its salinity and thickness; and determination of processes of material exchange between the surface, ice shell, and ocean. Three broad categories of investigation are planned to interrogate different aspects of the subsurface structure and properties of the ice shell and ocean: magnetic induction, subsurface radar sounding, and tidal deformation. These investigations are supplemented by several auxiliary measurements. Alone, each of these investigations will reveal unique information. Together, the synergy between these investigations will expose the secrets of the Europan interior in unprecedented detail, an essential step in evaluating the habitability of this ocean world.


The role of ultrasonography in the diagnosis of certain neurologic disorders. A preliminary report.
Ultrasonography is the most innocuous and noninvasive procedure, ideally suited for screening patients suspected of having cerebrovascular insufficiency. The Doppler ultrasound and real-time techniques complement each other. The latter can actually display a two-dimensional dynamic image of the carotid artery. B-scan can also be used in fetuses, infants, and young children for precise assessment of the size of the ventricular system. It can be used for serial follow-up evaluation of hydrocephalus. Ultrasound can be utilized in determination of the depth and width of the lumbar spinal canal. Differentiation of cystic from solid masses in the spinal canal may also be made by this modality.


Dendritic spread of dorsal horn neurons in cats.
Observations of neurons in dorsal horn laminae IV-VI of the lumbosacral segments of Golgi-stained spinal cords in kittens and adult cats revealed laminar differences in dendritic architecture. Many neurons in lamina IV had dense, bushy dendritic fields. Lamina V contained, in addition to bushy cells similar in appearance to those of lamina IV, increasing numbers of neurons with radiating dendritic fields. Lamina VI was composed almost exclusively of neurons with radiating dendritic fields. These qualitative differences among laminae were accompanied by systematic variations in mean dendritic spread, which increased more than two-fold in adult cats between laminae IV and VI. A second gradient of dendritic spread was found within individual laminae: dendritic spread, particularly medial to lateral spread, increased for successively more lateral cells within a lamina. These differences in the spread of dendrites for neurons in different regions of the dorsal horn may be related to variations in the areas of peripheral receptive fields of dorsal horn neurons.


Physical Activity and Quality of Sleep in Patients with End-Stage Renal Disease on Hemodialysis: A Preliminary Report.
Chronic kidney disease significantly impairs patients' daily lives and worsens their quality of life. The aim of this study was to investigate the physical activity and quality of sleep, during three days (previous day of dialysis, on the day of dialysis and after day of dialysis), in patients with end-stage renal on hemodialysis. 12 hemodialysis patients were included in our study, answered the Pittsburgh Sleep Quality Index (PSQI) questionnaire, and for each patient were used a smart bracelet for three days (day-pre- and posthemodialysis and day at hemodialysis) to record daily physical activity (steps, distance) and estimate the quality of sleep. Results showed differences between three days average of steps and distance and PSQI parameters "…engaging in social activity?" (steps, p = 0.006, distance, p = 0.006) and "…enthusiasm to get things done?" (steps, p = 0.029, distance, p = 0.030). Our study suggests interrelationship between sleep quality and physical activity.


Neuroendocrine differentiation in stage D2 prostate cancers.
Chromogranin A (CgA) and neuro-specific enolase (NSE) are gaining acceptance as markers of several types of neuroendocrine tumors and the concentration of CgA and NSE have been reported to be elevated in relation to neuroendocrine differentiation of prostate cancer. The aim of the present study was to examine the correlation between the immunohistochemical (IHC) findings and serum value for CgA and NSE in untreated stage D(2) prostate cancer patients. Immunohistochemistry was carried out using antibodies against CgA and NSE in 58 patients and, pretreatment serum CgA and NSE levels were measured by monoclonal immunoradiometric assay in 18 patients with stage D(2) prostate cancer treated by androgen ablation. We examined the relationship of the pretreatment serum level to IHC findings for CgA and NSE in prostate cancer patients to clinicopathological parameters, and prognosis. Also, we evaluated the correlation of IHC findings to serum levels for CgA and NSE. There was a statistically significant correlation between CgA positivity and serum CgA level (P = 0.0421). However, there was no statistically significant correlation between NSE positivity and serum NSE level (P > 0.05). We divided stage D(2) patients into three groups according to IHC positivity of CgA and NSE. The cause-specific survival was significantly poorer in patients with strongly positive (++) patients for independent CgA and combined CgA with NSE (P = 0.0379). Multivariate analysis of cause-specific survivals in patients with stage D(2) prostate cancer demonstrated that strong IHC stain was considered as independent variable associated with greater risk of death (P = 0.0142). Neuroendocrine differentiation in stage D(2) prostate cancer has attracted considerable attention as a potentially findings prognosis. Thus, CgA had a stronger relationship between serum levels and IHC positivity in contrast to NSE, suggesting clinical usefulness as a tumor marker in predicting the extent of neuroendocrine differentiation in prostate cancer.


Compensation Claims for Sub-substandard Care of Patients with Gastroentero-pancreatic Neuroendocrine Tumors: A Nationwide Descriptive Study of Cases Between 2005-2016 in Norway.
Management of patients with neuroendocrine tumors of the gastrointestinal tract or pancreas (GEP-NENs) poses diagnostic and therapeutic challenges. This study described the medico-legal claims reported to a national governmental system that oversees compensation to patients with GEP-NENs Materials and Methods: An electronic search of the Norwegian System of Compensation to Patients database was performed to identify claims evaluated between 2005-2016. The clinical information and the medico-legal evaluation were reviewed. We identified seven patients, five women and two men, with a median age of 57 (range=47-73) years. Delayed diagnosis (median diagnostic delay of 18 (range=6-48) months) was the main cause for claims in six out of the seven patients). Four patients received financial compensation based on the claim judgement. This review of claims that were evaluated by the Norwegian System of Compensation to Patients showed that a timely diagnosis of GEP-NENs remains a clinical challenge.


High-resolution computed tomographic features of the stapedius muscle and facial nerve in chronic otitis media.
To improve preoperative recognition of the morphologic features of stapedius muscle and facial nerve in cases of chronic otitis media by providing a systemized description using temporal bone high-resolution computed tomography (HRCT). Retrospective review of HRCT scans from 212 patients. Tertiary hospital affiliated to Fudan University. Men and women undergoing surgery for chronic otitis media. No preference for demographics or side presenting otitis media. Therapeutic surgery. Location and morphology of stapedius muscle and facial nerve. The stapedius muscle was encountered in 90.5% of axial (n = 181) and 87% of coronal sections (n = 174), and differences between sides and genders were not significant (p > 0.05). Five categories of anomalies or pathologic features were identified in axial layers, and 3 categories were identified in coronal layers. Two axial and 2 coronal CT planes were found to be especially significant in imaging the facial nerve and its morphology (p < 0.001), whereas axial planes were more apt to show stapedius muscle features. Other pathologic features were also observed significantly more from specific CT imaging planes. The presence the stapedius muscle and the morphology between the stapedius muscle and the facial nerve vary between different observation areas, and some CT planes provide more useful information than others. The imaging planes outlined in this study can be used to systematically and correctly identify certain facial nerve and stapedius muscle features and clarify unfamiliar pathologic anatomy in preoperative planning.


Cigarette smoking and HDL cholesterol: the Framingham offspring study.
High density lipoproteins were measured on fasting blood samples from 4107 men and women. Control for reported alcohol consumption and subscapular skinfold thickness using multiple regression analysis allowed an examination of the relationship between cigarette smoking and HDL cholesterol. Cigarette smoking was found to be associated with an average difference in HDL cholesterol of about 4 mg/dl in men and 6 mg/dl in women. Furthermore, when heavy alcohol drinkers were eliminated a significant negative association between number of cigarettes smoked and HDL cholesterol was demonstrable in both men and women. There was no evidence that former cigarette smokers, with the exception of those who switched to cigars or pipes or had quit less than one year, had lower HDL levels. Cigar or pipe smokers who had never smoked cigarettes had alcohol- and skinfold-adjusted HDL cholesterol comparable to the non-smoker. These observations indicate another possible link between inhaled tobacco smoke and the atherosclerotic process and suggest the need for further studies and experiments that might clarify the mutual relationship of HDL cholesterol, cigarette smoking and the atherosclerotic process.


Human hyperthermic therapy: relation between tumor type and capacity to induce hyperthermia by radiofrequency.
There is mounting evidence that hyperthermia of 42 degrees C or greater is tumoricidal to cell cultures and to animal and human tumors. However, temperatures of 45 degrees C or greater may have greater potential therapeutic benefit. The ability to selectively achieve such highintratratumor temperatures without injury to normal tissue may be due to the relatively poor blood flow in tumors compared with that in normal tissues. While vascularity and blood flow are known to vary significantly among tumors, we found that of 52 tumors evaluated, temperatures of 42 degrees C or greater in 42 tumors (81 per cent) and of 45 degrees C or greater in 23 tumors (44 per cent) appeared to be independent of the histologic type of tumor. Therefore, therapeutic hyperthermia may be possible for most varieties of human solid cancer.


Relationship between acne and the use of cosmetics: Results of a questionnaire study in 539 Korean individuals.
Acne vulgaris is one of the most common dermatological diseases, and it is known that various factors are related to triggering this condition in a patient. In particular, although the use of cosmetics is thought to be associated with the onset of a patient developing acne, there are few studies that have been conducted to date on this disease and its related factors. To begin with, a total of 539 patients with acne vulgaris, who visited three dermatologic clinics in Korea, were asked to complete a questionnaire regarding their condition in relation to clinical features and exacerbating factors, including the use of cosmetics. The patients all provided an accurate acne treatment history as well. Among the respondents, 38.1% of patients who failed treatment answered that the condition of their acne was worsened by the continued use of cosmetics, which was significantly higher than 26.3% of the surveyed treatment-naive patients (P < .05). In this relation, double cleansing (cleansing twice using oil and water-based cleanser) and the number of cosmetics in use were also noted in higher numbers than in the treatment-failure patients. As noted, the liquid-type foundation and concealer were frequently used in this group. This study showed the influence of cosmetics, especially in acne patients with a history of treatment failures. These results also show differences according to specific cosmetic types and formulations. Therefore, overall dermatologists should consider advising about cosmetic use to acne patients along with medical treatment options for the patients with acne.


An efficient synthesis of a dual PPAR alpha/gamma agonist and the formation of a sterically congested alpha-aryloxyisobutyric acid via a Bargellini reaction.
A practical synthesis of benzisoxazole 1 and its conversion to alpha-aryloxyisobutyric acid 2 using 1,1,1-trichloro-2-methyl-2-propanol (chloretone) was developed. Benzisoxazole 1 was formed in high yields by the action of either methanesulfonyl chloride/base upon intermediate oxime 8 or with thionyl chloride/base, which initially forms cyclic sulfite 10. A highly reactive, short-lived intermediate derived from chloretone was detected by ReacIR and its half-life determined to be approximately 5 min. Reaction conditions for the Bargellini reaction were developed that resulted in a 95% yield of 2 from the reaction of highly hindered phenol 1 with chloretone hemihydrate and powdered NaOH in acetone. Thus highly hindered alpha-aryloxyisobutyric acids can be made in a single step in high yield.


Synthesis of a redox-responsive quadruple hydrogen-bonding unit for applications in supramolecular chemistry.
A redox-responsive quadruple hydrogen-bonding module (eDAN) has been developed. The strong binding between the reduced form and its partner (DeUG) can be significantly decreased upon oxidation but restored upon subsequent reduction. This on-off switch was successfully applied to provide reversible control of macroscopic supramolecular polymer networks.


Evolution of plasma acetate concentration during ethanol metabolism in man.
Following oral administration of ethanol to ethylic as well as non-ethylic volunteers, the entire time course of plasma acetate concentration has been observed. The curve shows a typical evolution in three phases: (1) a quick ascending phase (2) a steady state characterized by a mean concentration (-C) (3) a first-order decrease, characterized by its half-life (t1/2) These parameters show significant variations (increase of -C, decrease of t1/2) in the ethylic subjects, in comparison with the non-ethylic ones. The variation of the area under the acetate curve according to the dose of ethanol given, is linear. The comparison of such a development with the one, typically non-linear, of the area under ethanol curve previously analyzed for the same subjects, may guess the origin of the non-linearity of ethanol kinetics.


The pelage of bats (Chiroptera) and the presence of aerodynamic riblets: the effect on aerodynamic cleanliness.
We measured qualitative and quantitative aspects of the head and body pelage of 23 species of Western Australian bats. A functionally appropriate relationship was found with the normal flight speeds and foraging strategy of the bats at three levels of geometric consideration: overall fur texture, individual hair length and cuticular scale attributes (scale type, scale length and diameter, as well as sub-scale detail design). This relationship is best explained by describing the pelage surface as characterised by aerodynamic riblets. For species that utilise high-speed and aerodynamically efficient flight during commuting and foraging, riblets should reduce the skin friction drag of the head and body by up to 10%. The molossids, emballonurids and one pteropid studied have fur that falls within the non-dimensional height range that gives best aerodynamic efficiency, 8<h+ <15. The carnivore studied falls marginally below this range.


Inadvertent epidural anesthesia associated with catheterization following continuous psoas compartment block in a patient with scoliosis: A Case report.
Psoas compartment block (PCB) is typically performed using surface anatomical landmarks and neurostimulation for guidance. However, anatomical anomalies, such as scoliosis, make this technique unreliable, posing a challenge for the anesthesiologist when inducing regional anesthesia. A 69-year-old woman with lumbar scoliosis scheduled for total hip arthroplasty underwent PCB with catheterization. Inadvertent epidural anesthesia with catheterization following PCB was diagnosed using a lumbar radiograph. Due to hypotension induced by local anesthetic (LA) epidural diffusion, the patient received intravenous hydration and vasopressor. Since bilateral sensory block was noted at the T3 level, with an incomplete motor blockade in both legs, the surgery was performed under epidural anesthesia. The patient remained hemodynamically stable throughout the duration of the surgical procedure. The surgery was uneventful and without further complications. Patients with lumbar scoliosis are highly at risk of LA epidural diffusion, following PCB using traditional landmark-based approach. Other nerve-localizing technique can minimize the risk of this complication.


One nuclear calcium transient induced by a single burst of action potentials represents the minimum signal strength in activity-dependent transcription in hippocampal neurons.
Neurons undergo dramatic changes in their gene expression profiles in response to synaptic stimulation. The coupling of neuronal excitation to gene transcription is well studied and is mediated by signaling pathways activated by cytoplasmic and nuclear calcium transients. Despite this, the minimum synaptic activity required to induce gene expression remains unknown. To address this, we used cultured hippocampal neurons and cellular compartment analysis of temporal activity by fluorescence in situ hybridization (catFISH) that allows detection of nascent transcripts in the cell nucleus. We found that a single burst of action potentials, consisting of 24.4±5.1 action potentials during a 6.7±1.9s depolarization of 19.5±2.0mV causing a 9.3±0.9s somatic calcium transient, is sufficient to activate transcription of the immediate early gene arc (also known as Arg3.1). The total arc mRNA yield produced after a single burst-induced nuclear calcium transient was very small and, compared to unstimulated control neurons, did not lead to a significant increase in arc mRNA levels measured using quantitative reverse transcriptase PCR (qRT-PCR) of cell lysates. Significantly increased arc mRNA levels became detectable in hippocampal neurons that had undergone 5-8 consecutive burst-induced nuclear calcium transients at 0.05-0.15Hz. These results indicate that a single burst-induced nuclear calcium transient can activate gene expression and that transcription is rapidly shut off after synaptic stimulation has ceased.


Laparoscopic gastric fundus tamponade: a novel adaptation of the Toupet fundoplication for large paraesophageal hernia repair.
Laparoscopic repair of large paraesophageal hiatal hernia with defects too large to close primarily or greater than 8 cm is technically challenging. The ideal repair remains unclear and is often debated. Utilizing the gastric fundus as an autologous patch to obliterate and tamponade large hiatal defects may offer a new solution. The aim of this study was to evaluate the short-term outcomes following partial posterior fundoplication with gastric fundus tamponade. Retrospective chart review and prospective patient follow up was conducted on patients who underwent laparoscopic hiatal hernia repair between 2015 and 2019 by a single surgeon. Basic demographics, pre-operative diagnoses, operative technique, and clinical outcomes were recorded. Fifteen patients underwent the described technique for repair of large paraesophageal hiatal hernia. All procedures were completed laparoscopically with a short post-operative length of stay (mean of 3 days) and no 30-day readmissions. The majority of patients reported resolution of their pre-operative symptoms. Only one patient required surgery for emergent indications and the same patient was the only mortality in the study, which was secondary to respiratory failure, necrotizing pneumonia, and sepsis as a result of gastric volvulus and obstruction. Utilizing the gastric fundus as an autologous patch to repair large hiatal hernia may be a safe and efficacious solution with good short-term outcomes. However, further studies should be conducted to elucidate long-term results.


Rural-urban differences in prevalence and correlates of suicidal ideation in adolescent patients with depression in a large sample of Chinese.
Suicidal ideation (SI) is severe comorbidity of depression that has been extensively studied in the past. Residence differences between SI have rarely been systematically studied, especially in parental rearing behavior. This large-scale explored the residence differences in the prevalence and correlation of SI adolescent patients with depression. A total of 1417 patients with depression were recruited, and their demographic data and clinical data were collected. The Children's Depression Inventory (CDI) and the Egna Minnen Beträffande Uppfostran (EMBU) scale were used to assess depression, and parental rearing behavior, respectively. The prevalence of suicidal ideation was higher in urban patients than in rural patients (43.7 % vs.37.7 %, P < 0.05). Patients with SI scored higher on total CDI scores, parental punishment, parental rejection, and paternal overprotection compared to their respective patients without SI. In the urban group, patients with SI had lower parental emotional warmth scores and higher parental intervention scores compared to patients without SI. Logistic regression analysis showed that total CDI score, gender, alcohol consumption, father's emotional warmth, father's rejection, and mother's intervention were significantly associated with SI in urban patients (P < 0.05); total CDI score and mother's rejection were significantly associated with SI in rural patients (P < 0.05). No causal relationship could be drawn due to the cross-sectional design. The results of this study showed significant residential differences in risk and associated factors for SI among adolescents with depression. Focusing on the parenting styles of adolescent patients can help with the early identification and intervention of SI.


HIV-1 transmission biology: selection and characteristics of infecting viruses.
Individuals with recent human immunodeficiency virus type 1 (HIV-1) acquisition are likely to be a major source for other new infections because they have a high level of plasma virus, and the circulating virions possess unique properties that are highly suited for transmission. The acute infection period, however, presents a unique "window of opportunity," because there are a limited number of genetic variants. Studies aim to elucidate the nature of the transmitted viruses and understand the mechanisms that inhibit the majority of variants present in the chronically infected partner from establishing a productive infection in the naive host. Greater understanding of these issues may open promising new ways to effectively block HIV-1 transmission.


The chemical composition of pine foliage in relation to the population dynamics of the pine beauty moth, Panolis flammea, in Scotland.
This paper reports part of a study to determine why damaging outbreaks of the pine beauty moth, Panolis flammea (D & S) (Lepidoptera: Noctuidae), in Scotland are frequent on lodgepole pine but do not occur on Scots pine, and why outbreaks on lodgepole pine are mainly confined to trees growing in deep unflushed peat. The elongation of shoots and the growth of needles of Scots pine occurred later in the season than did those of lodgepole pine. The foliage of Scots pine generally had a higher level of nitrogen, and consistently had a higher level of phosporus, but had a consistently lower level of tannins than that of lodgepole pine during the period when the larvae were feeding each year. The nitrogen content of the foliage of lodgepole pine growing in an iron pan soil was generally higher than that of lodgepole pine growing in deep peat during the same period but there were no general differences in the phosphorus or tannin contents of lodgepole pine in the 2 soil types. These findings suggest that Scots pine is a more suitable host plant than lodgepole pine and that the foliage of lodgepole pine growing in deep peat is not more suitable than lodgepole pine growing in an iron pan soil. On the basis of the chemical analyses used in this study, it is concluded that the abundance of pine beauty moth in Scotland is not strongly influenced by the nutritional suitability of its host plants.


Establishment of Rat Model of Female Genital Sexual Arousal Disorder.
Female Genital Sexual Arousal Disorder (FGSAD) seriously affects women's quality of life and Sexual life, but it still lacks ideal FGSAD animal models for further study. To establish a specific model of female genital sexual arousal disorder and explore the mechanisms resulting in FGSAD. After delivery, female rats were guided by expansions of the vagina and ovariectomy (VD+OVX, n = 10); in VD group female rats were just extended by the vagina (VD, n = 10), in OVX group female rats were treated with ovariectomy (OVX, n = 10);the remaining had 1 longitudinal incision as sham group(n = 10). Vaginal dilatation combined with ovariectomy in rats may reflect female genital sexual arousal disorder with high reproducibility and stability. Vaginal tissue of female rats in OVX group and VD+OVX group showed an increase in blood flow, decrease in muscle content compared to the sham group. The proportion of collagen fiber I/III decreased and the elastic fiber showed significant rupture and fragmentation; Structural reticular integrity was also significantly separated and broken from the muscle fibers. However, there was no significant difference in vaginal blood flow, fibers and vascular between VD group and Sham group. The damage of vaginal tissue in VD+OVX group was more significant than that in OVX and VD groups. We have constructed a specific animal model that can provide clinical insights into the mechanism of FGSAD and serves as a good avenue for further research of its treatment. Vaginal dilatation combined with ovariectomy in rats is a specific animal model with high reproducibility and stability, but we do acknowledge the shortcomings and limitation present in our study. Since genital arousal disorder has many different etiologies that impact the vagina, the clitoris and surrounding tissues, there is no "gold standard" model that different models attempt to investigate different etiologies. The female genital sexual arousal disorder model established by vaginal dilatation combined with ovariectomy is a novel rat model with simple induction conditions, which pathogenic mechanism of female genital sexual arousal disorders maybe connected with the change of VEGF and MMP-9 in vaginal fibromuscular system and microvascular. Li G, Yu P, Hu Y, et al. Establishment of Rat Model of Female Genital Sexual Arousal Disorder. Sex Med 2022;10:100530.


Efficacy and safety of Huashi Baidu granule plus Nirmatrelvir-Ritonavir combination therapy in patients with high-risk factors infected with Omicron (B.1.1.529): A multi-arm single-center, open-label, randomized controlled trial.
Huashi Baidu granule (HSBD) and Paxlovid (Nirmatrelvir-Ritonavir) are antiviral Chinese patent medicine and western medicine specially developed for treating coronavirus disease 2019 (COVID-19). Their efficacy and safety in treating COVID-19 are still under investigated. To assess and compare the efficacy and safety of HSBD, Paxlovid, and the combination in treating high-risk patients infected with SARS-CoV-2 Omicron. The study was a prospective single-center, open-label, randomized, controlled clinical trial conducted from April 18 to June 5, 2022. (ClinicalTrial.gov registration number: ChiCTR2200059390) METHODS: 312 severe patients aged 18 years and older infected with SARS-CoV-2 Omicron from Shuguang Hospital in Shanghai were randomly allocated to HSBD monotherapy (orally 137 g twice daily for 7 days, n = 105), Paxlovid monotherapy (orally 300 mg of Nirmatrelvir plus 100 mg of Ritonavir every 12 h for 5 days, n = 103), or combination therapy (n = 104). The primary outcome was SARS-CoV-2 nucleic acid negative conversion within 7-day treatment. The secondary outcome included hospital discharging conditions, severe conversion of symptom, and adverse events. Of 312 participants, 85 (82%) of 104 in combination therapy, 71 (68%) of 105 in HSBD monotherapy, and 73 (71%) of 103 in Paxlovid monotherapy had a primary outcome event. The hazard ratios of primary outcome were 1.37 (95% CI 1.03 - 1.84, p = 0.012) for combination versus HSBD, 1.28 (0.98-1.69, p = 0.043) for combination versus Paxlovid, and 0.88 (0.66-1.18, p = 0.33) for HSBD versus Paxlovid. There was no statistical difference of efficacy between HSBD and Paxlovid, while combination therapy exhibited more effective than either alone. For secondary outcomes, the hospital discharging rates within 7 days exhibited the significant increase in combination therapy than in HSBD or Paxlovid monotherapy (71% (74/104) vs 55% (58/105) vs 52% (54/103), p < 0.05). The risk of severe conversion of symptom showed no statistical significance among three interventions (1% (1/104) vs 3% (3/105) vs 3% (3/103), p > 0.05). No severe adverse events occurred among combination therapy and monotherapies in the trial. For patients with severe COVID-19, HSBD exhibits similar efficacy to Paxlovid, while combination therapy is more likely to increase the curative efficacy of Omicron variant than monotherapies, with few serious adverse events.


Long-Term Outcomes and Disease Burden of Neonatal Onset Short Bowel Syndrome.
The study aims to describe long-term outcomes and disease burden of neonatal onset short bowel syndrome (SBS). Utilizing the WHO criteria for adolescence, patients 10-19 years of age with neonatal onset SBS requiring parenteral nutrition (PN) for >90 days and followed by our multidisciplinary intestinal rehabilitation center between 2009 and 2018 were included for analysis. Seventy adolescents with SBS were studied. Median (IQR) age at last follow up in our center was 15 (11, 17) years. There was 0% mortality in the cohort, and 94% remained transplant free. Fifty-three patients (76%) achieved enteral autonomy. Three patients were weaned from PN without transplantation after six years of follow-up and another four after ten years of care at our multidisciplinary center. Disease burden remained higher in adolescents receiving PN, including inpatient hospitalizations (p < 0.01), procedures (p = 0.01), clinic visits (p < 0.01), and number of prescribed medications (p < 0.01). Survival for adolescents with neonatal onset SBS is excellent. Of the cohort studied, there was no mortality, and more than 75% achieved enteral autonomy. Disease burden remains high for adolescents who remain dependent on PN. However, achievement of enteral autonomy is feasible with long-term multidisciplinary rehabilitation. Prognosis study. Level II.


Alcoholic hepatitis: a clinician's guide.
Alcoholic hepatitis is a frequent reason for admission and a common consultation request for hepatologists and gastroenterologists. Although it seems to occur acutely, it is usually subacute and often superimposed on underlying alcoholic cirrhosis. Typically patients have a background of drinking on a daily basis, but, in response to a life crisis, patients have started drinking massively.


The association between mental health and cognitive screening scores in older veterans.
: To examine overall cognitive screening results and the relationship between cognitive screen score and sociodemographic characteristics, reason for referral, and clinical outcomes of older veterans referred by primary care for a behavioral health assessment. : Cross-sectional, naturalistic study. : Primary care clinics affiliated with two VA Medical Centers. : The sample included 4,325 older veterans referred to the Behavioral Health Laboratory who completed an initial mental health/substance abuse assessment. Veterans were categorized into the following three groups on the basis of cognitive status: within normal limits, possible cognitive impairment, and possible dementia. : Sociodemographic and clinical data on reason for referral, cognitive functioning (i.e., Blessed Orientation-Memory-Concentration test), and behavioral health assessment outcomes were extracted from patients' medical records. Data were analyzed using multiple linear and logistic regressions. : Results of cognitive screenings indicated that the majority of the sample was within normal limits (62.5%), with 25.8%, 8.1%, and 3.6% of patients evidencing possible cognitive impairment, possible dementia, and Blessed Orientation-Memory-Concentration scores of 17 or more, respectively. With regard to reason for referral, patients with greater cognitive impairment were more likely to be identified by the antidepressant case finder than patients with less impairment. Increased age, non-white ethnicity, self-perceived inadequate finances, major depressive disorder, and symptoms of psychosis were associated with greater cognitive impairment. : Findings highlight the importance of evaluating cognitive status in older adults who are referred for a behavioral health assessment and/or receive a new mental health/substance abuse diagnosis. Doing so has the potential to improve recognition and treatment of cognitive impairment and dementia, thereby improving quality of care for many older adults.


Which "neural activity" do you mean? fMRI, MEG, oscillations and neurotransmitters.
Over the last 20 years, BOLD-FMRI has proved itself to be a powerful and versatile tool for the study of the neural substrate underpinning many of our cognitive and perceptual functions. However, exactly how it is coupled to the underlying neurophysiology, and how this coupling varies across the brain, across tasks and across individuals is still unclear. The story is further complicated by the fact that within the same cortical region, multiple evoked and induced oscillatory effects may be modulated during task execution, supporting different cognitive roles, and any or all of these may have metabolic demands that then drive the BOLD response. In this paper I shall concentrate on one experimental approach to shedding light on this problem i.e. the execution of the same experimental tasks using MEG and fMRI in order to reveal which electrophysiological responses best match the BOLD response spatially, temporally and functionally. The results demonstrate a rich and complex story that does not fit with a simplistic view of BOLD reflecting "neural activity" and suggests that we could consider the coupling between BOLD and the various parameters of neural function as an ill-posed inverse problem. Finally, I describe recent work linking individual variability in both cortical oscillations and the BOLD-fMRI response to variability in endogenous GABA concentration.


The genetics of symptom dimensions of schizophrenia: review and meta-analysis.
The use of symptom dimensions of schizophrenia as quantitative phenotypes has been proposed as a mean to reduce the heterogeneity of schizophrenia and facilitate genetic research. However, the genetic background of symptom dimensions is not clear. We aim to investigate whether the symptom dimensions "reality distortion", "psychomotor poverty" and "disorganization" are heritable phenotypes. We performed a Medline search including all papers from 1980 to August 2007. In addition to reviewing the articles, we performed meta-analyses on these studies where possible. We identified 18 relevant papers. Only the studies on affected sibling pairs were suitable for meta-analysis. Data from twin and affected sibling studies are consistent with a genetic contribution to the disorganization dimension. However these studies did not unequivocally support a large genetic contribution to neither the reality distortion symptom dimension nor to the psychomotor poverty symptom dimension. In contrast several molecular genetic studies did report associations of genes with psychomotor poverty. These data suggest that only the disorganization symptom dimension may provide an useful alternative phenotype for genetic research. More research is required to make any definitive conclusions.


5-(2-Cyano-benz-yl)-4,5,6,7-tetra-hydro-thieno[3,2-c]pyridin-2-yl acetate.
In the title mol-ecule, C17H16N2O2S, the tetra-hydro-pyridine ring exhibits a half-chair conformation. The mean planes of the ester chain and benzene ring are twisted by 5.5 (1) and 81.32 (5)°, respectively, from the plane of thio-phene ring. In the crystal, weak C-H⋯O inter-actions link mol-ecules related by translation along [100] into chains.


Non-phthalate plasticizer DEHT preserves adequate blood component quality during storage in PVC blood bags.
Commercial blood bags are predominantly made of polyvinyl chloride (PVC) plasticized with di(2-ethylhexyl) phthalate (DEHP). DEHP is favourable for storage of red blood cells (RBC). Historically, removal of DEHP from blood bags has been linked to unacceptable haemolysis levels. Oncoming regulatory restrictions for DEHP due to toxicity concerns increase the urgency to replace DEHP without compromising RBC quality. Di(2-ethylhexyl) terephthalate (DEHT) is one suggested substitute. The aim of this study was to compare PVC-DEHT to PVC-DEHP blood bags using additive solutions saline-adenine-glucose-mannitol (SAGM) and phosphate-adenine-glucose-guanosine-saline-mannitol (PAGGSM), to determine whether DEHT can maintain acceptable component quality. RBC concentrates (N = 64), platelet concentrates (N = 16) and fresh frozen plasma (N = 32) were produced from whole blood collected into either DEHT or DEHP plasticized systems. Using a pool-and-split study design, pairs of identical RBC content were created within each plasticizer arm and assigned either SAGM or PAGGSM. Storage effects were assessed weekly for 49 days (RBC), 7 days (platelets) and before/after freezing (plasma). Though haemolysis was slightly higher in DEHT, all study arms remained below half of the European limit 0·8%. K+ was lower in DEHT than in DEHP independent of additive solution. The metabolic parameters were not influenced by choice of plasticizer. Platelet activation/metabolism and plasma content were similarly preserved. Our study demonstrates that the plasticizer DEHT provides adequate blood component quality. We propose DEHT as a strong future candidate for replacement of DEHP in blood bags.


A novel approach to direct carotid cavernous fistula repair: HydroCoil-assisted revision after balloon reconstruction.
Direct carotid cavernous fistulae (CCF) are commonly treated by endovascular deployment of a detachable balloon into the cavernous sinus to reconstruct the sidewall of the carotid artery and preserve flow in that vessel. Relatively few reports exist describing revisions using constructive, transarterial approaches when this technique fails. We describe a novel method using expandable hydrogel-coated platinum coils to revise a failed balloon reconstruction in which the balloon had migrated within the cavernous sinus away from the rent in the carotid wall. This new technique to buttress the balloon back into the desired position using expandable coils proved to be effective, safe, and durable. As endovascular treatments for direct CCF continue to evolve, techniques for revision will likely follow. This report adds a novel approach to our therapeutic armamentarium.


Doctors' attitude towards people with mental illness in Western Nigeria.
It had been suggested that those more knowledgeable about mental illness are less likely to endorse negative or stigmatizing attitudes. This study aimed to evaluate the attitude of doctors in Nigeria towards the mentally ill. Medical doctors (n = 312) from eight selected health institutions in Nigeria completed various questionnaires on knowledge and attitude towards people with mental illness. Beliefs in supernatural causes were prevalent. The mentally ill were perceived as dangerous and their prognosis perceived as poor. High social distance was found amongst 64.1% and the associated factors include not having a family member/friend with mental illness (OR 7.12, 95% CI 3.71-13.65), age less than 45 years (OR 2.33, 95% CI 1.23-4.40), less than 10 years of clinical experience (OR 6.75, 95% CI 3.86-11.82) and female sex (OR 4.98, 95% CI 2.70-9.18). Culturally enshrined beliefs about mental illness were prevalent among Nigerian doctors. A review of medical curriculum is needed and the present anti-stigma campaigns should start from the doctors.


Fibronectin enhances early shear stress resistance of seeded adult human venous endothelial cells.
An in vitro parallel plate perfusion chamber was used to study the shear stress resistance of seeded adult human saphenous vein endothelial cells (AHSVECs) on glass surfaces coated with different substrates. Endothelial cells were seeded onto glass slides precoated with these substrates and then exposed to pulsatile flow with an average shear stress of 8 dyn/cm2 for 1 hr. After AHSVEC attachment periods of 15 min, 1 hr, and 2 hr, flow dislodged all but 1.4, 30.4, and 72.2%, respectively, of cells that had been seeded onto 1% gelatin. Control slides that were not exposed to flow retained 12.9% (P less than 0.03), 49.8% (NS), and 95.2% (NS) of seeded cells. Precoating the slides with 10 micrograms/ml fibronectin resulted in 69.4, 89.5, and 97.7% of cells remaining after flow, compared with 6.4% (P less than 0.03), 53.7% (NS), and 93.3% (NS), respectively, when using matched slides coated with 1% gelatin. Results with 20% fetal bovine serum as the substrate were not statistically different from those obtained with 1% gelatin. We conclude that fibronectin enhances the early attachment of AHSVECs to artificial surfaces and is, therefore, potentially useful for increasing attached cell yields on arterial prostheses prepared with immediate cell seeding techniques.


Molecular dynamics of sugars bound to wheat germ agglutinin, as studied by deuterium nuclear magnetic resonance.
Deuterium nuclear magnetic resonance is used to delineate the molecular dynamics of sugars bound to a lectin. 2H spin-spin relaxation times (from linewidth measurements) and reorientational correlation times are determined for N-acetylglucosamine specifically-labeled with 2H in the N-acetyl group and at carbon-3 of the pyranoside ring, in the presence and absence of wheat germ agglutinin. The correlation time for the 2H-label of N-acetylglucosamine-3-2H in the bound state is the same as that of the protein (3 X 10(-8)S), indicating that the six-membered ring has negligible motional freedom relative to the protein. The correlation time for the C2H3 group of N-acetyl-2H3-glucosamine (1.7 X 10(-9)S) shows that the N-acetyl side chain is also immobilized in the binding site, the only motion available being rotation of the C2H3 group about its threefold axis.


A particle-associated ATP-dependent proteolytic activity in erythroleukemia cells.
An ATP-dependent proteolytic activity has been detected in both mouse erythroleukemia (Friend) cells and human (K562) erythroleukemia cells. Exposure of the Friend cells to dimethyl sulfoxide, which stimulates differentiation, increased ATP-dependent proteolysis approximately 2-fold although inducing differentiation in the K562 line had no significant effect on proteolysis. In contrast to the previously described soluble ATP-dependent proteolytic system of reticulocytes, the activity in the more primative erythroid cells is associated with a particulate fraction and is readily sedimentable by centrifugation at 100,000 X g for 1 h. Like the soluble reticulocyte system, the particulate activity requires divalent cation and is inhibited by hemin as well as vanadate. The activity was isolated on a sucrose cushion (30%) and did not appear to be associated with membranes, cytoskeleton, or polysomes. This enzymatic activity which degrades abnormal globin chains may initially reside in a particulate fraction and then become solubilized during erythroid maturation to the reticulocyte stage. Alternatively, the particulate activity may disappear with cell maturation being replaced by a distinct soluble activity. ATP-dependent proteolytic activity is eventually lost with reticulocyte maturation and further aging of erythrocytes.


Structure of the O-polysaccharide of Edwardsiella tarda PCM 1156.
Mild acid degradation of the lipopolysaccharide of Edwardsiella tarda PCM 1156 afforded an O-polysaccharide, which was isolated by gel-permeation chromatography on Sephadex G-50 and studied by sugar and methylation analyses along with (1)H NMR and (13)C NMR spectroscopy, including 2D (1)H,(1)H COSY, TOCSY, ROESY, (1)H,(13)C HSQC, and HMBC experiments. The following structure of the linear tetrasaccharide repeating unit of the O-polysaccharide was established: [structure: see text].


Synthesis and biological evaluation of thiabendazole derivatives as anti-angiogenesis and vascular disrupting agents.
Thiabendazole, already approved by FDA for oral use as an anti-fungal and anti-helminthic drug since 1967, has recently been repurposed as a vascular disrupting agent. By optimization of the structure of the lead compound, we successfully identified compound TBZ-19 and the new derivative is over 100-fold more potent than the lead compound against the growth of four different cell lines (A549, HCT-116, HepG2 and HUVECs). The most potent two candidates TBZ-07 and TBZ-19, exhibiting moderate inhibitory cell proliferation activity, were also verified as anti-angiogenesis and vascular disrupting agents. Therefore, TBZ-07 and TBZ-19 would be promising candidates with vasculature targeting activity and merit further development.


Inverted terminal repeats in rabbit poxvirus and vaccinia virus DNA.
In both rabbit poxvirus and vaccinia virus DNA have demonstrated an identical distribution of eight HinfI. The length of the terminal repeats was found to be 3.4 to 3.6 megadaltons (Mdaltons) for rabbit poxvirus DNA and 7.4 to 8.0 Mdaltons for vaccinia virus DNA. Maps of the HinfI restriction sites within isolated EcoRI end fragments of rabbit poxvirus and vaccinia virus DNA PHAVE DEMONSTRATED AN IDENTICAL DISTRIBUTION OF EIGHT HinfI sites in an internal part (approximately 2 Mdaltons) of the EcoRI end fragments of the two genomes.


Out-of-hospital cardiac arrest and airborne fine particulate matter: a case-crossover analysis of emergency medical services data in Indianapolis, Indiana.
Previous studies have found particulate matter (PM) < 2.5 microm in aerodynamic diameter (PM2.5) associated with heart disease mortality. Although rapid effects of PM2.5 exposure on the cardiovascular system have been proposed, few studies have investigated the effect of short-term exposures on out-of-hospital cardiac arrest (OHCA). We aimed to determine whether short-term PM2.5 exposures increased the risk of OHCA and whether risk depended on subject characteristics or presenting heart rhythm. A case-crossover analysis determined hazard ratios (HRs) for OHCAs logged by emergency medical systems (EMS) versus hourly and daily PM2.5 exposures at the time of the OHCA and for daily and hourly periods before it. For all OHCAs (n = 1,374), exposures on the day of the arrest or 1-3 days before arrest had no significant effect on the incidence of OHCA. For cardiac arrests witnessed by bystanders (n = 511), OHCA risk significantly increased with PM2.5 exposure during the hour of the arrest (HR for a 10-microg/m3 increase in PM2.5 exposure = 1.12; 95% confidence interval, 1.01-1.25). For the subsets of subjects who were white, 60-75 years of age, or presented with asystole, OHCA risk significantly increased with PM2.5 during the hour of the arrest (HRs for a 10-microg/m3 increase in PM2.5 = 1.18, 1.25, or 1.22, respectively; p < 0.05). HR generally decreased as the time lag between PM2.5 exposure and OHCA increased. The results suggest an acute effect of short-term PM2.5 exposure in precipitating OHCAs, and a need to investigate further the role of subject factors in the effects of PM on the risk of OHCA.


Cost-effectiveness of Ombitasvir/Paritaprevir/Ritonavir, Dasabuvir+Ribavirin for US Post-Liver Transplant Recurrent Genotype 1 HCV.
Orthotopic liver transplant patients with recurrent hepatitis C (HCV) historically have had limited treatment options. Ombitasvir/paritaprevir/ritonavir, dasabuvir and ribavirin (3D+R) was approved by the FDA in December 2014 for liver transplant recipients with recurrent genotype 1 HCV, in whom it is effective and well-tolerated. Using a two-phase Markov model, we analysed the cost-effectiveness of 3D+R in liver transplant recipients, the only HCV treatment with FDA approval in this population. As a sensitivity analysis, we also considered the cost-effectiveness of pegylated interferon plus ribavirin, the only other therapy with data from Phase III trials in this population. Patients were given one of three options: 3D+R for 24 weeks, pegylated interferon and ribavirin for 48 weeks (PR48) or no treatment (NT). Patients were then followed through subsequent disease progression until death. Outcome measures analysed were: lifetime risks of liver morbidity and mortality, treatment costs, non-treatment medical expenditures, and quality-adjusted life years. Treatment with 3D+R was associated with a significantly lower lifetime risk of liver-related morbidity and mortality than treatment with PR48 or NT. 3D+R also was associated with a higher gain in quality-adjusted life years (11.3 compared to 8.25 with NT) and lower discounted overall costs ($423,585 compared to $724,757 with NT). The use of 3D+R for liver transplant recipients with recurrent HCV is an outcome-improving and cost-effective regimen for this population with limited treatment options and large unmet need.


Abnormal glucose modulation of islet A- and B-cell responses to arginine in non-insulin-dependent diabetes mellitus.
To assess the normality of islet A- and B-cell responses to a nonglucose secretogogue as well as the modulating effect of glucose in NIDDM, we examined plasma C-peptide and glucagon responses to arginine in eight patients with NIDDM and in six age- and weight-matched nondiabetic volunteers under conditions of identical hypoglycemia (approximately 70 mg/dl), euglycemia (94 mg/dl), and hyperglycemia (approximately 190 mg/dl). Plasma C-peptide responses to glucose and to arginine in the diabetic subjects were both significantly reduced at all glucose concentrations studied (P less than 0.01-0.005). The modulating effect of glucose on both islet A- and B-cell responses (slope of relation between plasma C-peptide or glucagon response versus plasma glucose concentration) was reduced greater than 80% in the diabetic subjects (P less than 0.01). We conclude that islet A- and B-cell responses to nonglucose secretogogues are abnormal in patients with NIDDM and that this may result from a functional defect in the modulating effect of glucose on insulin and glucagon secretion, which in some patients may be compensated for by hyperglycemia.