The implication of pyroptosis in cancer immunology: Current advances and prospects.
Pyroptosis is a regulated cell death pathway involved in numerous human diseases, especially malignant tumors. Recent studies have identified multiple pyroptosis-associated signaling molecules, like caspases, gasdermin family and inflammasomes. In addition, increasing in vitro and in vivo studies have shown the significant linkage between pyroptosis and immune regulation of cancers. Pyroptosis-associated biomarkers regulate the infiltration of tumor immune cells, such as CD4+ and CD8+ T cells, thus strengthening the sensitivity to therapeutic strategies. In this review, we explained the relationship between pyroptosis and cancer immunology and focused on the significance of pyroptosis in immune regulation. We also proposed the future application of pyroptosis-associated biomarkers in basic research and clinical practices to address malignant behaviors. Exploration of the underlying mechanisms and biological functions of pyroptosis is critical for immune response and cancer immunotherapy.


Bioinspired construction of light-harvesting antenna via hierarchically co-assembling approach.
Biomimetic construction of artificial photosystem capable of converting light energy to chemical energy is a promising strategy in solving the increasing serious energy and environmental problems. Herein, we present a new strategy to construct light-harvesting antenna via hierarchical co-assembly of short-peptide and porphyrin and subsequent self-metallization process. The hierarchically organized antenna exhibits both excellent photocatalytic performance and remarkable sustainability under strong light irradiation (35000 lx) and extraordinary sensitivity to weak light (700 lx). In such cases, light energy can be converted into chemical energy and stored in the energy-storage molecules (nicotinamide adenine dinucleotide, NADH) even under weak light irradiation. This provides a promising step towards an artificial photosystem that can utilize weak light. Moreover, the structures and properties of the antenna are dependent on the competition of short-peptide self-assembling and co-assembling with porphyrin molecules and can be regulated by their molar ratio. This provides new insights into the design and construction of light-harvesting antennas with integrated functionality via precise control of pigments aggregation and coupling of different functional units.


Impact of Reducing Pre-Hospital Delay in Response to Heart Attack Symptoms in Australia.
This research estimates the broader socioeconomic impacts of reducing pre-hospital delay times across Australia in patients with heart attack symptoms. A cost benefit analysis (CBA) was undertaken to demonstrate the costs and benefits of a public awareness/education campaign to reduce pre-hospital delay time from 5.2hours (Base Case) to 4.1hours (Scenario 1) and 2.0hours (Scenario 2). All assumptions underlying the CBA are supported by academic literature. Financial impacts considered include campaign/public education costs, direct inpatient costs and long-term health care costs. Socioeconomic impacts considered include burden of disease, productivity losses, informal care costs and net deadweight loss. The campaign is expected to generate an additional net benefit of $41.2-139.1 million in comparison to the Base Case, resulting in a benefit cost ratio (BCR) of 3.23-5.06. Disability Adjusted Life Years (DALYs) reduced by 6,046-7,575 years. This research illustrates that an investment in public awareness/education campaign can generate considerable benefits, more than offsetting the costs associated with the campaign and keeping people living longer such as ongoing health care costs. However, significant effort, supplementary strategies and sustained investment will be required to ensure the impact and benefit is sustained over the long term.


A comprehensive analysis of transcript signatures of the phosphatidylinositol-3 kinase/protein kinase B signal-transduction pathway in prostate cancer.
To assess the gene activities of various important members of the phosphatidylinositol 3 kinase (PIK3)/protein kinase B (PKB/Akt) pathway (involved in the promotion and regulation of cellular metabolism, proliferation and apoptosis) for alterations in prostate carcinoma. Using quantitative real-time reverse-transcription polymerase chain reaction, we analysed the transcript levels of 12 genes involved in the PIK3/PKB pathway in microdissected tumour tissues from 20 patients with varying stages of prostate cancer, assessing differences from adjacent normal tissues and from a pool of prostate tissues from healthy controls. In cancer samples with a high Gleason grade, the PIK3/PKB pathway was principally affected by marked decreases in expression over almost all the investigated stages of the pathway. These changes were in effectors of the pathway, especially PIK3 p85 alpha (PIK3R1) and integrin-linked kinase, and the pathway target fork-head box protein (FOXO)-1A, while the transcript quantities of regulators, e.g. phosphatase/tensin homologue (PTEN), were decreased in a smaller proportion of the patients. Transcript amounts of FOXO-1A and FOXO-3A were significantly higher in normal tumour-adjacent tissues than in the healthy controls. Down-regulation of the PIK3/PKB pathway by repression of involved effector and regulator genes at all stages of the molecular pathway could represent a marker for the formation of highly de-differentiated prostate cancers from low-grade tumour foci. Also, parts of the pathway are deviant in normal tumour-adjacent tissue; this might represent a reaction to neighbouring tumours or be a sign of pre-cancerous biological alterations.


Blotting and band-shifting: techniques for studying protein-protein interactions.
The type II cAMP-dependent protein kinase (PKA) is localized in certain cellular compartments through association with specific A-kinase anchoring proteins (AKAPs). A variety of blotting and electrophoresis techniques have been developed to study the protein-protein interactions that occur between the regulatory (R) subunit of PKA and AKAPs. These methods have also been used for a variety of purposes such as detecting calmodulin-binding proteins, comparing wild-type- and mutant-form binding affinities and estimating the molecular weight of multiprotein complexes.


Ovarian cancer immuno-reactive antigen domain containing 1 (OCIAD1), a key player in ovarian cancer cell adhesion.
To identify proteins unique to metastatic ovarian cancer and test their potential involvement in cell adhesion. We purified plasma membrane from paired metastatic and primary tumor tissues from patients with stage IIIC ovarian cancer. Membrane proteins unique to metastases were identified by liquid chromatographic mass spectrometry (LC-MS). The role of one of the identified proteins, ovarian cancer immuno-reactive antigen domain containing 1 (OCIAD1) in cell adhesion was determined in the presence of LPA using both over-expression and down regulation approaches. We identified a differentially expressed 29 kDa protein as OCIAD1 over-expressed in metastatic tissues, when compared to primary tumor tissues. OCIAD1 over-expression in HEY ovarian cancer cells increased LPA-induced, but not basal level cell adhesion to extracellular matrix proteins collagen I and laminin 10/11. This enhancement was not blocked by LY294002 and GF109203X, suggesting that OCIAD1 does not use PKC and PI3K signaling pathways to exert its effect on adhesion. In addition, LPA induced cell adhesion to collagen I was unaffected by paclitaxel (5 microM) in OCIAD1 overexpressing cells. This is the first report that OCIAD1 is over-expressed in metastatic ovarian cancer tissues. The effect of OCIAD1 on cell adhesion may be related to its function in ovarian cancer. Failure of paclitaxel to affect ovarian cancer cell adhesion in presence of OCIAD1 raises the possibility of OCIAD1's role in tumor metastasis. Ongoing studies using a mouse orthotopic LPA-dependent ovarian cancer metastasis model are focused on strategies to inhibit the potential role of OCIAD1 in tumor metastasis.


Prevalence and factors associated with traumatic dental injuries among schoolchildren in war-torn Libya.
No previous epidemiological study has investigated the prevalence and associated factors of traumatic dental injuries (TDIs) among Libyan children. Such information is required for the planning and evaluation of health services. The aim of this study was to assess the prevalence of TDIs and associated factors among 12-year-old schoolchildren in Benghazi, Libya. Data for this study were collected as part of a comprehensive, cross-sectional survey investigating oral health status and treatment needs of 12-year-old schoolchildren in Benghazi, Libya, between December 2016 and May 2017. Sociodemographic information was collected through a dental health questionnaire. The children were assessed for oral health status, including TDIs according to modified World Health Organization (WHO) classification criteria, in their classroom by trained and calibrated examiners. Anthropometric measures, lip competence and overjet were all assessed and reported. History of TDIs was sought among those affected. Logistic regression models were applied for TDIs as an outcome variable. The statistical significance for all tests was ≤0.05. Data from 1134 participants were included in this study. TDIs were observed in 10.3% of the sample. Most of these TDIs were enamel fractures only (55.6%) and enamel and dentine fractures (35.9%). "Falling" was the most common cause of TDIs, accounting for 51% of cases. While increased overjet appeared to be associated with higher risk of TDIs (OR: 1.92; 95% CI: 1.29-2.86), being female (OR: 0.34; 95% CI: 0.22-0.53) and overweight (OR: 0.33; 95% CI: 0.13-0.83) were also associated with lower risk of having TDIs. This survey showed that a considerable proportion (10.3%) of 12-year-old Libyan children had TDIs, with relatively high unmet treatment needs. More efforts are required to develop effective prevention programmes and to enhance the provision of dental treatment of TDIs for Libyan children.


Self-administered and noncontingent nicotine enhance reinforced operant responding in rats: impact of nicotine dose and reinforcement schedule.
Nicotine infusions that are self-administered (contingent) or response-independent (noncontingent) increase lever pressing for a reinforcing nonpharmacological stimulus in rats, suggesting that in addition to primary reinforcement, nicotine self-administration may result from nicotine enhancing the reinforcement derived from nonnicotine stimuli. Based on our previous research, in this study, we tested the hypothesis that contingent and noncontingent nicotine would equally elevate responding for a moderately reinforcing visual stimulus, across a range of nicotine doses on both fixed ratio and progressive ratio reinforcement schedules. The rats lever pressed for a visual stimulus with contingent nicotine, noncontingent nicotine, or contingent saline. Separate groups responded for saline or nicotine without the visual stimulus. Three doses of nicotine (0.01, 0.03, and 0.09 mg/kg per infusion, free base) were tested in a between-groups design. After responding on an escalating fixed ratio reinforcement schedule, the rats were tested on a progressive ratio schedule. Compared to responding for the visual stimulus with saline, both contingent and noncontingent nicotine equally elevated lever pressing for the stimulus at each dose on fixed and progressive ratio schedules. In the absence of the stimulus, only the highest nicotine dose sustained self-administration. The ability of noncontingent nicotine to elevate responding for a moderately reinforcing visual stimulus occurs across a range of doses, and both self-administered and noncontingent nicotine equally increase motivation to obtain the stimulus, as reflected by performance on a progressive ratio schedule. In the absence of a contingent stimulus, primary reinforcement from nicotine only supports self-administration at high nicotine doses in rats.


Guanyl nucleotide regulation of hormonally-responsive adenylyl cyclases.
A large number of hormones and neurotransmitters activate adenylyl cyclase [ATP, pyrophosphate lyase (cyclizing; EC 126.96.36.199.)] catalyzing the formation of cAMP and PPi from ATP in the presence of Mg2+. The cAMP formed is in turn responsible for eliciting the physiological responses of these hormones and neurotransmitters. In addition to hormones and neurotransmitters, fluoride ion, cholera toxin and guanyl nucleotides (GTP and GTP analogs such as GTP gamma S and GMP-P(NH)P) also stimulate adenylyl cyclase activity (Perkins, 1974; Birnbaumer, 1977; Gill, 1977). It has become evident that hormonally-responsive adenylyl cyclase is a multi-component system consisting of at least 3 physically distinct units. The first is the hormone receptor containing a specific site for a given hormone. The second is the catalytic moiety (C component) of adenylyl cyclase bearing the site responsible for catalysis of the cyclizing reaction. The third is the guanyl nucleotide regulatory subunit (G component) which binds guanyl nucleotide. Recently, a GTPase activity has been found to be associated with the G component of adenylyl cyclase (Cassel and Selinger, 1976; Cassel et al., 1977a, b; Lambert et al., 1979). In this review we will present information on the regulation of hormonally-responsive adenylyl cyclases. This is not intended to be a comprehensive review of the literature. Rather, it represents our views on the current status of the regulation of cAMP formation.


Synthesis of benzanilide derivatives as dual acting agents with alpha 1-adrenoceptor antagonistic action and steroid 5-alpha reductase inhibitory activity.
Synthesis of benzanilide derivatives which have dual alpha 1-adrenoceptor antagonistic action and steroid 5 alpha-reductase inhibitory activity and their structure-activity relationships is described.


Age-associated alterations in human natural killer cells. 1. Increased activity as per conventional and kinetic analysis.
We report a positive association between the human peripheral blood natural killer (NK) cell activity and the age (20-94 years) of 137 healthy volunteers. Irrespective of the methods of data representation, the elderly (greater than 80 years) express a statistically significant (at 0.001 level) higher (35-80.7%) mean NK activity when compared to younger adults (less than 40 years). Results of repeat assays and paired assays support a similar conclusion. This difference can be demonstrated at a wide range of effector or target cell concentrations or times of assay and is not influenced by in vivo lymphocyte count. Single-cell assay results suggest that an increase in the frequency of NK cells may be responsible for the higher NK activity in the elderly. These findings were confirmed by an enzyme-like kinetic analysis. Vmax, the maximum cytotoxic potential of the lymphocytes from the elderly, is nearly four times higher than that of younger adults. It is concluded that unlike the age-related general decline in T- and B-cell reactivity (as demonstrated here with concanavalin A and pokeweed mitogen), the NK cell system is highly active in a majority of the healthy elderly.


Relating spidroin motif prevalence and periodicity to the mechanical properties of major ampullate spider silks.
Spider dragline fibers exhibit incredible mechanical properties, outperforming many synthetic polymers in toughness assays, and possess desirable properties for medical and other human applications. These qualities make dragline fibers popular subjects for biomimetics research. The enormous diversity of spiders presents both an opportunity for the development of new bioinspired materials and a challenge for the identification of fundamental design principles, as the mechanical properties of dragline fibers show both intraspecific and interspecific variations. In this regard, the stress-strain curves of draglines from different species have been shown to be effectively compared by the α* parameter, a value derived from maximum-supercontracted silk fibers. To identify potential molecular mechanisms impacting α* values, here we analyze spider fibroin (spidroin) sequences of the Western black widow (Latrodectus hesperus) and the black and yellow garden spider (Argiope aurantia). This study serves as a primer for investigating the molecular properties of spidroins that underlie species-specific α* values. Initial findings are that while overall motif composition was similar between species, certain motifs and higher level periodicities of glycine-rich region lengths showed variation, notably greater distances between poly-A motifs in A. aurantia sequences. In addition to increased period lengths, A. aurantia spidroins tended to have an increased prevalence of charged and hydrophobic residues. These increases may impact the number and strength of hydrogen bond networks within fibers, which have been implicated in conformational changes and formation of nanocrystals, contributing to the greater extensibility of A. aurantia draglines compared to those of L. hesperus.


Lower extremity muscular strength, sedentary behavior, and mortality.
To examine whether lower extremity strength (LES) is predictive of all-cause mortality, independent of physical activity and among those with vary levels of sedentary behavior. Data from the 1999-2002 National Health and Nutrition Examination Survey was used (N = 2768; 50-85 years). Peak isokinetic knee extensor strength was objectively measured, sedentary behavior and physical activity were self-reported, and mortality was assessed via the National Death Index, with follow-up through 2011. Participants were followed for up to 12.6 years with the weighted average follow-up period lasting 9.9 years (standard error, 1.13). In the sample, 321,996 person-months occurred with a mortality rate of 2.1 deaths per 1000 person-months. After adjustments (including physical activity), for every 15 N increase in LES, participants had a 7 % reduced risk of all-cause mortality (HR = 0.93; 95 % CI 0.91-0.95; P < 0.001). When adding a three-level sedentary behavior variable (< 2, 2-4, 5+ h/day) as a covariate in this model, results were unchanged (HR = 0.93; 95 % CI 0.92-0.96; P < 0.001). Similarly, when sedentary behavior was included as a continuous covariate in the model, results regarding the relationship between LES and mortality were unchanged (HR = 0.94; 95 % CI 0.91-0.96; P < 0.001). There was no evidence of statistical interaction between LES and sedentary behavior on all-cause mortality (HRinteraction = 1.01; 95 % CI 0.92-1.10; P = 0.88). LES was inversely associated with all-cause mortality, and this association was unchanged when considering the participant's sedentary behavior.


An Electronic Adherence Measurement Intervention to Reduce Clinical Inertia in the Treatment of Uncontrolled Hypertension: The MATCH Cluster Randomized Clinical Trial.
To appropriately manage uncontrolled hypertension, clinicians must decide whether blood pressure (BP) is above goal due to a need for additional medication or to medication nonadherence. Yet, clinicians are poor judges of adherence, and uncertainty about adherence may promote inertia with respect to medication modification. We aimed to determine the effect of sharing electronically-measured adherence data with clinicians on the management of uncontrolled hypertension. This was a cluster randomized trial. Twenty-four primary care providers (12 intervention, 12 usual care; cluster units) and 100 patients with uncontrolled hypertension (65 intervention, 35 usual care) were included in the study. At one visit per patient, clinicians in the intervention group received a report summarizing electronically measured adherence to the BP regimen and recommended clinical actions. Clinicians in the control group did not receive a report. The primary outcome was the proportion of visits with appropriate clinical management (i.e., treatment intensification among adherent patients and adherence counseling among nonadherent patients). Secondary outcomes included patient-rated quality of care and communication during the visit. The proportion of visits with appropriate clinical management was higher in the intervention group than the control group (45 out of 65; 69 %) versus (12 out of 35; 34 %; p = 0.001). A higher proportion of adherent patients in the intervention group had their regimen intensified (p = 0.01), and a higher proportion of nonadherent patients in the intervention group received adherence counseling (p = 0.005). Patients in the intervention group were more likely to give their clinician high ratings on quality of care (p = 0.05), and on measures of patient-centered (p = 0.001) and collaborative communication (p = 0.02). Providing clinicians with electronically-measured antihypertensive adherence reports reduces inertia in the management of uncontrolled hypertension. NCT01257347 ; http://clinicaltrials.gov/show/ NCT01257347.


Evaluation of Liver Disease in Pregnancy.
Liver disease in pregnancy often requires diagnostic and therapeutic considerations that are unique to pregnancy. Liver disease in pregnancy is commonly thought of as either liver disease unique to pregnancy, chronic liver disease, or liver disease coincidental to pregnancy. This review summarizes the approach to evaluation of liver disease in pregnancy.


Pulmonary cancers across different histotypes share hybrid tuft cell/ionocyte-like molecular features and potentially druggable vulnerabilities.
Tuft cells are chemosensory epithelial cells in the respiratory tract and several other organs. Recent studies revealed tuft cell-like gene expression signatures in some pulmonary adenocarcinomas, squamous cell carcinomas (SQCC), small cell carcinomas (SCLC), and large cell neuroendocrine carcinomas (LCNEC). Identification of their similarities could inform shared druggable vulnerabilities. Clinicopathological features of tuft cell-like (tcl) subsets in various lung cancer histotypes were studied in two independent tumor cohorts using immunohistochemistry (n = 674 and 70). Findings were confirmed, and additional characteristics were explored using public datasets (RNA seq and immunohistochemical data) (n = 555). Drug susceptibilities of tuft cell-like SCLC cell lines were also investigated. By immunohistochemistry, 10-20% of SCLC and LCNEC, and approximately 2% of SQCC expressed POU2F3, the master regulator of tuft cells. These tuft cell-like tumors exhibited "lineage ambiguity" as they co-expressed NCAM1, a marker for neuroendocrine differentiation, and KRT5, a marker for squamous differentiation. In addition, tuft cell-like tumors co-expressed BCL2 and KIT, and tuft cell-like SCLC and LCNEC, but not SQCC, also highly expressed MYC. Data from public datasets confirmed these features and revealed that tuft cell-like SCLC and LCNEC co-clustered on hierarchical clustering. Furthermore, only tuft cell-like subsets among pulmonary cancers significantly expressed FOXI1, the master regulator of ionocytes, suggesting their bidirectional but immature differentiation status. Clinically, tuft cell-like SCLC and LCNEC had a similar prognosis. Experimentally, tuft cell-like SCLC cell lines were susceptible to PARP and BCL2 co-inhibition, indicating synergistic effects. Taken together, pulmonary tuft cell-like cancers maintain histotype-related clinicopathologic characteristics despite overlapping unique molecular features. From a therapeutic perspective, identification of tuft cell-like LCNECs might be crucial given their close kinship with tuft cell-like SCLC.


Genetics and pathogenesis of idiopathic scoliosis.
Idiopathic scoliosis (IS), the most common spinal deformity, affects otherwise healthy children and adolescents during growth. The aetiology is still unknown, although genetic factors are believed to be important. The present review corroborates the understanding of IS as a complex disease with a polygenic background. Presumably IS can be due to a spectrum of genetic risk variants, ranging from very rare or even private to very common. The most promising candidate genes are highlighted.


Time perception deficits and its dose-dependent effect in methamphetamine dependents with short-term abstinence.
Intake of addictive substances acutely modifies dopaminergic transmission in the striatum and prefrontal cortex, which is the neural substrate underlying time processing. However, the persistent effects of methamphetamine (meth) abuse (e.g., during abstinence) on temporal processing have not been fully elucidated. Here, we recruited different samples in two experiments. We first compared the potential differences in motor timing between healthy controls and meth dependents with varied length of abstinence and then examined the ability of perceptual timing between the healthy subjects and the meth group at short abstinence. We found that motor timing, but not perceptual timing, was altered in meth dependents, which persisted for at least 3 months of abstinence. Dose-dependent effects on time perception were only observed when short-term abstinent meth abusers processed long time intervals. We conclude that time perception alteration in meth dependents is task specific and dose dependent.


Purification and characterisation of glutathione S-transferases from the freshwater clam Corbicula fluminea (Müller).
Glutathione S-transferases (GSTs) are involved in the phase II detoxification metabolism. To provide a molecular basis for their use as biomarkers of pollution, cytosolic GSTs from the freshwater clam Corbicula fluminea have been purified by glutathione-Sepharose affinity chromatography, anion-exchange chromatography (AEC) and reversed-phase (RP) HPLC. SDS-PAGE of visceral mass (VM) affinity-purified extracts revealed four subunits with apparent molecular masses (MW) of 30.2, 29.2, 28.5 and 27.2 kDa. Analysis by non-denaturing PAGE revealed three acidic dimeric proteins with apparent MW of 64, 55 and 45 kDa, named GSTc1, GSTc2 and GSTc3, respectively, based on their elution order by AEC. Only GSTc2 and GSTc3 exhibited GST activity towards 1-chloro-2,4-dinitrobenzene. A tissue-specific subunit pattern was obtained by RP-HPLC of affinity-purified extracts from VM and gills (GI): three major peaks were resolved, one of which was common to both tissues. MW of each VM subunit was determined by electrospray ionisation-mass spectrometry: 23602+/-1 Da for the major subunit and 23289+/-1 Da for the minor ones. Immunoblot analysis revealed all subunits from both tissues were related to the Pi-class GSTs. In addition, minor VM subunits were slightly related to the Mu-class ones. The interest of such molecular studies in biomonitoring programs is discussed.


Regulatory effects of anesthetics on nitric oxide.
Nitric oxide (NO) is a free radical gas in the biological system, which is produced by nitric oxide synthase (NOS) family. NO acts as a biological mediator and plays important roles in different systems in humans. The NO/NOS system exerts a broad spectrum of signaling functions involved in vasodilation, inflammation, oxidative stress, cardioprotection and neuroprotection. It has been demonstrated that intravenous and volatile anesthetics (such as propofol, ketamine, midazolam, isoflurane, sevoflurane, and desflurane, etc.) modulate NO production through multiple mechanisms that may influence physiological and pathophysiological processes. This review focuses on the effects of different anesthetics on NO/NOS regulation in different disease conditions. Possible cellular mechanisms and intermediate role of NO/NOS in anesthetic-mediated organ protection are also discussed. It would be interesting to clarify the impact of anesthetics on NO/NOS regulation. This review gives an overview of the effects of different anesthetics on NO/NOS regulation and function in different physiologic and pathophysiologic states.


Evaluating the Safety, Tolerability, and Disposition of Trazpiroben, a D2 /D3 Receptor Antagonist: Phase I Single- and Multiple-Ascending Dose Studies in Healthy Japanese Participants.
Trazpiroben (TAK-906) is a peripherally selective dopamine D2 /D3 receptor antagonist being developed to treat chronic gastroparesis. This phase I, randomized, double-blind, placebo-controlled, single- and multiple-ascending dose, parallel-group study evaluated the safety, tolerability, pharmacokinetics, and pharmacodynamics of trazpiroben in healthy Japanese men. Findings were compared with those from a prior US trial in healthy individuals. Overall, 24 participants were enrolled into 3 cohorts (each n = 8). Per cohort, 6 participants received trazpiroben (cohort 1, 50 mg; 2, 100 mg; 3, 10 mg) once on day 1 and twice daily on days 3 through 7, and two received placebo. Trazpiroben was well tolerated, with no clinically meaningful adverse events observed. Following single- and multiple-dose administration, trazpiroben was rapidly absorbed and eliminated (mean elimination half-life, 1.89-6.45 hours; median time to maximum serum concentration [steady state], 1.00-1.25 hours). Serum prolactin increased with trazpiroben treatment (mean maximum serum concentration 93.32 ng/mL [10 mg] vs. 10.83 ng/mL [placebo]), illustrating receptor target engagement. Results reflected those from healthy US participants, indicating a lack of differences between these ethnic populations in trazpiroben disposition and safety profile. Trazpiroben may represent a promising therapy for chronic gastroparesis across different populations, with further evaluation ongoing in a phase IIb study (NCT03544229).


Processing of the intermediate form of the iron-sulfur protein of the BC1 complex to the mature form after import into yeast mitochondria.
The Rieske iron-sulfur protein of the cytochrome bc1 complex is synthesized in the cytosol as a precursor with an additional 30 amino acids at the amino terminus. After import into the mitochondrial matrix, the precursor is processed to the mature form by two distinct proteolytic cleavages. Addition of 2.5 mM EDTA and 0.5 mM o-phenanthroline to the incubation mixture during import of the iron-sulfur protein precursor in vitro resulted in the selective inhibition of the second processing step with the concomitant accumulation of the intermediate form. The intermediate form was chased to the mature form in the presence of antimycin and oligomycin (to block the formation of a membrane potential) provided that 0.5 nM ATP and a metal ion such as Ca2+, Mn2+, or Mg2+ were added. Ca2+ ion was the most effective and at a concentration of 2.5 mM resulted in the complete cleavage of the intermediate to the mature form. Addition of Zn2+, Co2+, Mo2+, and Fe2+ was not effective in restoring the second cleavage. The pH optimum for the processing of the intermediate form of the iron-sulfur protein to the mature form was between 6.8-8.0. Processing of the intermediate form of the iron-sulfur protein to the mature form was observed at temperatures ranging from 12 to 27 degrees C in a temperature-dependent manner. The time course during the chase indicated that the second processing step was completed within 2 min after addition of Ca2+ ions. Attempts to isolate the second processing enzyme by sonication of mitochondria or by solubilization with detergents such as digitonin, Triton X-100, dodecyl-maltoside, or octyl-glucoside were unsuccessful as only the first cleavage was observed. Hence, the second processing enzyme may be present in the inner membrane or matrix in a conformation disrupted by detergents or alternatively the enzyme may be very labile.


Extension of the cleft lip phenotype: the subepithelial cleft.
We present a previously undescribed occult malformation of the upper lip manifest by discontinuity of the orbicularis oris muscle. The relationship of this defect to our current concept of abnormal maxillary process development is discussed along with a proposal to extend the cleft lip phenotype.


Simulated moving bed chromatography for the separation of ethyl esters of eicosapentaenoic acid and docosahexaenoic acid under nonlinear conditions.
In this study, ethyl esters of eicosapentaenoic acid and docosahexaenoic acid were separated with simulated moving bed (SMB) chromatography, where the stationary phase was C18 silica gel with particle size of 10μm packed in eight columns, and the mobile phase was pure methanol. The Henry constants, transport parameters and total porosity were measured from pulse response chromatographic experiments using a single column. The Henry constants were obtained from the first moment analysis. The transport parameters including axial dispersion coefficients and effective mass transfer coefficients were obtained from the second moment analysis. Nonlinear adsorption equilibrium isotherms for the pure components and their mixture were determined from adsorption-desorption method. The Langmuir model was used to fit the experimental data, and the corresponding parameters were further used to predict the competitive adsorption equilibria of the mixture. The validity of mathematical model parameters was checked by a frontal chromatography experiment. The simulated results of the SMB process using these parameters agreed well with the experimental results. At the feed concentration of 100g/L, the SMB separation was able to produce both solutes with relative purity above 99%, productivity of 13.11g/L adsorbent/h, and solvent consumption of 0.46L/g.


Bidirectional allosteric modulation of strychnine-sensitive glycine receptors by tropeines and 5-HT3 serotonin receptor ligands.
Specific binding of [3H]strychnine was studied on membranes prepared from rat spinal cord. Several antagonists and agonists of 5-HT3 receptors and tropane derivatives displaced [3H]strychnine binding with micromolar potencies. In the presence of 10 microM glycine a high affinity (nanomolar) component of displacement was also observed for the tropeines zatosetron, bemesetron and tropisetron. The displacing potency of glycine was also enhanced by these agents which are therefore termed glycine-positive. In contrast, atropine, SR 57227A, m-chlorophenylbiguanide, metoclopramide and granisetron are termed glycine-negative, because they decreased the displacing potency of glycine while glycine decreased the displacing potencies of atropine and metoclopramide. The dissociation of [3H]strychnine binding was accelerated in the presence of m-chlorophenylbiguanide, SR 57227A, atropine and zatosetron with a concentration dependence (EC50 values and Hill slopes) similar to their displacing effects. This demonstrates that the displacement of strychnine binding is associated with allosteric interactions between different binding sites. Structure-activity analysis revealed that the tropeine structure is essential for high affinity binding, and its substitutions (in scopolamine and cocaine) or its replacement (in ondansetron and metoclopramide) strongly decrease the potency and/or efficacy of allosteric modulation. High affinity modulatory sites for tropeines appear to be associated with the potentiation of ionophore function, but distinct from the low affinity channel blocking sites as well as from the binding sites of strychnine and glycine.


A novel nanomicelle composed from PEGylated TB di-peptide could be successfully used as a BCG booster.
Tuberculosis affects one-third of the world's population and leads to a high rate of morbidity and mortality. Bacillus Chalmette-Guerin (BCG) as the only approved vaccine for the Mycobacterium tuberculosis (Mtb) does not show enough protection in the vaccinated population. The main aim of this study was to prepare a self-assembled nanomicelle composed from a di-block polymer in which, a di-fusion peptide was the hydrophobic block and polyethylene glycol (PEG) was the hydrophilic block. The micelles were characterized in vitro and in vivo as an antigen delivery system/adjuvant both with and without a prime BCG. The micellar nanovaccine was able to elicit good dendritic cell maturation. Nanomicelles could efficiently induce systemic cytokines as well as nasal secretory predominant antibody titers (sIgA). The expression pattern of cytokines indicated the superiority of cellular immunity. Nasal administration of two doses of nanomicelles after a prime subcutaneous administration of BCG induced the highest mucosal and systemic immune responses. Based on our results PEG-HspX/EsxS self-assembled nanomicelle is highly immunogenic and can be considered a potential vaccine candidate against Mtb to boost BCG efficiency.


Low-dose antihypertensive therapy with 1.5 mg sustained-release indapamide: results of randomised double-blind controlled studies. European study group.
In accordance with international recommendations on the need to decrease doses of antihypertensive drugs, a low-dose (1.5 mg) sustained-release (SR) formulation of indapamide was developed to optimize the drug's efficacy : safety ratio. The aim of this work was to evaluate the benefit of a low-dose diuretic by consolidating the efficacy and safety results of two clinical trials with a similar design. Clinical data were obtained in two European randomized double-blind studies with 690 mild to moderate hypertensive patients (95 mmHg < or = supine diastolic blood pressure < or = 114 mmHg using a mercury sphygmomanometer) treated respectively for 2 and 3 months, with a mean age of 53 and 57 years, 44 and 57% males, mean supine diastolic blood pressure of 100.6 and 102.5 mmHg and mean supine systolic blood pressure of 161.0 and 164.5 mmHg. The first study, a dose-finding study with indapamide SR at 1.5, 2 and 2.5 mg versus placebo and the immediate-release (IR) formulation of indapamide, showed that the 1.5 mg dosage of the new indapamide formulation had an improved antihypertensive efficacy : safety ratio. The second study confirmed the equivalence of blood pressure reductions with 1.5 mg indapamide SR and 2.5 mg indapamide IR, and better acceptability with 1.5 mg indapamide SR, particularly in the number of patients with serum potassium levels < 3.4 mmol/l, which was reduced by more than 50%. The long-term efficacy of 1.5 mg indapamide SR was observed through a 9-month open-treatment follow-up to the second study. The 1.5 mg SR formulation of indapamide has an improved antihypertensive efficacy : safety ratio, which is in accordance with international recommendations for the use of low-dose antihypertensive drugs and diuretics in first-line therapy of hypertension.


Conductive Metal-Organic Framework Thin Film Hybrids by Electropolymerization of Monosubstituted Acetylenes.
1-Hexyne monomers were potentiostatically electropolymerized upon confinement in 1D channels of a surface-mounted metal-organic framework Cu(BDC) (SURMOF-2). A layer-by-layer deposition method allowed for SURMOF depostition on substrates with prepatterned electrodes, making it possible to characterize electrical conductivity in situ, i.e., without having to delaminate the conductive polymer thin film. Successful polymerization was evidenced by mass spectroscopy, and the electrical measurements demonstrated an increase of the electrical conductivity of the MOF material by 8 orders of magnitude. Extensive DFT calculations revealed that the final conductivity is limited by electron hopping between the conductive oligomers.


Wave VII recognizability in brainstem auditory-evoked potentials.
Brainstem auditory-evoked potentials (BAEP) recorded with a far-field from the scalp technique are generally described as 7 positive waves in the initial post-stimulatory 10 ms period. Also at high stimulus intensities, the Jewett wave VII appears to be undetectable in the majority of normal subjects. We present an original recording method to reproducibly detect this late BAEP wave. 48 normal ears were examined and wave VII was detectable in all the recordings with clicks delivered at an intensity of 75 dBHL.


Derangement of mucosal barrier function by bacteria colonizing the rat colonic mucosa.
Interaction between gut flora and the intestinal barrier may involve changes in permeability. Rats with a colonic segment excluded from faecal transit were surgically prepared. Matched groups were either kept on luminal antibiotics to prevent colonization of the segment or recolonized with mixed rat flora. Permeability to low-dose trinitrobenzenesulphonic acid (TNBS) or trinitrophenol (TNP), and mucosal injury by the compounds at a high dose were tested in antibiotic and recolonized rats (the compounds differ in water solubility but share a common antigenic domain). Lumen to blood clearance of the hydrophilic probe (TNBS) was faster in recolonized than in antibiotic rats. The hydrophobic compound TNP was absorbed at faster rates than TNBS, but there was no difference between antibiotic and recolonized rats. Instillation of TNBS at a high dose induced mucosal release of inflammatory mediators and tissue myeloperoxidase accumulation in recolonized rats but not in antibiotic rats. Large necrotic lesions with submucosal involvement after TNBS were only observed in recolonized rats. In contrast, TNP induced mucosal inflammation and large lesions with submucosal necrosis both in recolonized and in antibiotic rats. Colonizing bacteria may increase intestinal permeability to hydrophilic compounds and render the mucosa susceptible to injury.


Effects of posture on metabolic and hemodynamic predischarge exercise response after acute myocardial infarction.
Predischarge exercise testing after acute myocardial infarction (AMI) is an important noninvasive modality for risk stratification. To study the impact of position on cardiopulmonary exercise response, 30 patients performed symptom-limited upright treadmill and supine bicycle ergometry exercise an average of 8 days after an AMI. The exercise sequence was randomly assigned with a minimum 4-hour interval between tests. Exercise time and peak oxygen consumption were significantly greater in the upright position (7.0 +/- 2.0 vs 5.6 +/- 2.0 minutes; p less than 0.001 and 14.9 vs 12.0 ml/min/kg; p less than 0.001, respectively). Compared to the supine position, exercise in the upright position was associated with a significant increased incidence of ischemic exercise-induced ST-segment depression (33 vs 20%; p less than 0.03), and chest pain (20 vs 10%; p less than 0.04). Thus, position is an important determinant of myocardial ischemic response and exercise tolerance in patients who perform symptom-limited exercise tests early after AMI.


Individual differences and moderating participant characteristics in the effect of reducing portion size on meal energy intake: Pooled analysis of three randomized controlled trials.
Portion size impacts on the amount of energy consumed during a meal. However, research findings on participant characteristics that moderate the effect of portion size on energy intake are mixed. Using data pooled across three randomized control trials, we examined the impact of reducing meal portion size on meal energy intake in 111 adult participants varying in sex (55 M, 56 F), body weight (BMI range = 19-42) and a broad range of participant characteristics, including usual portion size, restrained, emotional and external eating, satiety responsiveness, plate clearing tendencies, concerns about wasting food and self-control. In each trial, a repeated-measures design was used and participants consumed three ad-libitum lunchtime meals differing in portion size; large-normal portion size condition (100%) vs. small-normal portion size condition (~ 75%) vs. smaller than normal portion size condition (~ 50%). In mixed ANOVAs, we did not find convincing evidence that any participant characteristic reliably moderated the impact that reducing portion size had on energy intake. For the majority of participants energy intake decreased when portion size was reduced and it was more common for participants to consistently reduce their energy intake than consume a similar amount when portion size was reduced. We also found little evidence that a sub-group of participants existed whose energy intake was consistently resistant to portion size reductions. Portion size may be a universal driver of energy intake, as reducing meal portion size appears to decrease meal energy intake among most people. Food portion downsizing may therefore be an equitable intervention approach to reducing population level energy intake.


Targeting RNA-splicing for SMA treatment.
The central dogma of DNA-RNA-protein was established more than 40 years ago. However, important biological processes have been identified since the central dogma was developed. For example, methylation is important in the regulation of transcription. In contrast, proteins, are more complex due to modifications such as phosphorylation, glycosylation, ubiquitination, or cleavage. RNA is the mediator between DNA and protein, but it can also be modulated at several levels. Among the most profound discoveries of RNA regulation is RNA splicing. It has been estimated that 80% of pre-mRNA undergo alternative splicing, which exponentially increases biological information flow in cellular processes. However, an increased number of regulated steps inevitably accompanies an increased number of errors. Abnormal splicing is often found in cells, resulting in protein dysfunction that causes disease. Splicing of the survival motor neuron (SMN) gene has been extensively studied during the last two decades. Accumulating knowledge on SMN splicing has led to speculation and search for spinal muscular atrophy (SMA) treatment by stimulating the inclusion of exon 7 into SMN mRNA. This mini-review summaries the latest progress on SMN splicing research as a potential treatment for SMA disease.


Cloning, soluble expression, rapid purification and characterization of human Cofilin1.
Cofilin1 is an actin-binding protein that plays a critical role in the regulation of actin cytoskeleton and consequently affects various physiological processes. In this study, the human Cofilin1 cDNA was cloned into the expression vector pET-28a(+) with a 6 × His tag and expressed as soluble protein in Escherichia coli BL21(DE3). Approximately 78 mg of Cofilin1, which showed high activity as determined by native PAGE, could be purified from each liter of LB medium by His-tag affinity chromatography and gel filtration. Further, high-titer IgG against Cofilin1 was positively detected after immunization in rabbits and the polyclonal antibodies were purified and identified. Together, this report provides the first protocol to efficiently obtain human Cofilin1 with high biological activity and immunogenicity using E. coli BL21 (DE3) expression system.


Dermoid cyst of the parotid gland.
A dermoid cyst occurring within the parotid gland of a 37-year-old Chinese man is reported. The diagnostic difficulties, histopathological features and pathogenesis are considered.


Procyanidins and its metabolites by gut microbiome improves insulin resistance in gestational diabetes mellitus mice model via regulating NF-κB and NLRP3 inflammasome pathway.
Gestational Diabetes Mellitus (GDM) has an effect on the health of pregnant women and fetuses. Procyanidins (PA) is a flavonoid with anti-diabetic activity, but its effects and mechanisms on GDM have not been defined. Herein, we studied further the functions and mechanisms of PA on insulin resistance (IR) in GDM mice, as well as on postpartum and offspring mice. GDM mice model was built by feeding a high-fat-high-sucrose diet, and PA intervention (27.8 mg/kg/d) was performed from 4 weeks before pregnancy to delivery. Intestinal flora deficient (IFD) mice model was established by broad spectrum antibiotics. PA decreased the gestational weight gain, and the levels of fasting blood glucose, insulin, homeostasis model of assessment for IR index, yet increased the levels of HOMA for insulin sensitivity index. Interestingly, in IFD mice the effect of PA on improving IR was significantly weakened. PA inhibited inflammation by decreasing the levels of IL-6, TNF-α, IL-17 and CRP, which also been blocked in the IFD mice. Moreover, PA improved glycometabolism and reduced the secretion of inflammatory factors and hepatic inflammation infiltration of mice at 4 weeks postpartum, but had no significant effect on offspring mice. Mechanistically, PA treatment suppressed the nuclear factor-κB (NF-κB) p65 nuclear translocation and nucleotide-binding domain like receptor protein 3 (NLRP3) inflammasome activation. In vitro studies, 4-hydroxyphenylacetic acid and 3-(4-hydroxyphenyl) propionic acid, main intestinal flora metabolites of PA restrained NF-κB/NLRP3 activation. In conclusions, PA improved IR via NF-κB/NLRP3 pathway in GDM and postpartum mice, which partly through its metabolites by gut microbiome.


Beta-adrenergic receptor polymorphisms associated with length of ICU stay in pediatric status asthmaticus.
During severe exacerbations, asthmatic children vary significantly in their response to high-dose continuous β(2) -adrenergic receptor (ADRβ(2) ) agonist therapy. Genetic polymorphisms have been identified within the ADRβ(2) that may be functionally relevant, but few studies have been performed in this population. Our hypothesis was that genotypic differences are associated with magnitude of response to ADRβ(2) agonist treatment during severe asthma exacerbations in children. Children aged 2-18 years admitted to the ICU (intensive care unit) with a severe asthma exacerbation between 2006 and 2008 were eligible. Genotyping of the ADRβ(2) was performed. Eighty-nine children consented and were enrolled. Despite similar clinical asthma scores on admission, children with the Gly(16) Gly genotype at amino acid position 16 had significantly shorter ICU length of stay (LOS) and hospital LOS, compared to children with Arg(16) Arg and Arg(16) Gly genotypes. Children with either the Gln(27) Glu or Glu(27) Glu genotype at amino acid position 27 also had significantly shorter ICU LOS and hospital LOS compared to children with the Gln(27) Gln genotype. The Arg(16) Gly-Gln(27) Gln haplotype was associated with the longest ICU LOS, but this was not statistically different from other haplotypes. In this cohort of children with severe asthma exacerbations, ADRβ(2) polymorphisms were associated with responses to therapy. Knowledge of the genetic profile of children with asthma may allow for targeted therapy during acute exacerbations.


Performance assessment of the fecal leukocyte test for inpatients.
Traditionally, fecal leukocyte testing detects large bowel inflammation or disruption, conditions that allow leukocytes into the stool. However, test usefulness with inpatients is unclear. Two hundred five inpatients who had undergone one to three tests were identified, and their FLT results were compared to their gastrointestinal disease diagnoses at time of discharge. A specificity of 92% for detecting intact colonic mucosae in inpatients was found.


Analysis of FET-PET imaging for target volume definition in patients with gliomas treated with conformal radiotherapy.
Modern radiotherapy (RT) techniques such as stereotactic RT, intensity-modulated RT, or particle irradiation allow local dose escalation with simultaneous sparing of critical organs. Several trials are currently investigating their benefit in glioma reirradiation and boost irradiation. Target volume definition is of critical importance especially when steep dose gradient techniques are employed. In this manuscript we investigate the impact of O-(2-(F-18)fluoroethyl)-l-tyrosine-positron emission tomography/computer tomography (FET-PET/CT) on target volume definition in low and high grade glioma patients undergoing either first or re-irradiation with particles. We investigated volumetric size and uniformity of magnetic resonance imaging (MRI)- vs. FET-PET/CT-derived gross tumor volumes (GTVs) and planning target volumes (PTVs) of 41 glioma patients. Clinical cases are presented to demonstrate potential benefits of integrating FET-PET/CT-planning into daily routine. Integrating FET-uptake into the delineation of GTVs yields larger volumes. Combined modality-derived PTVs are significantly enlarged in high grade glioma patients and in case of primary RT. The congruence of MRI and FET signals for the identification of glioma GTVs is poor with mean uniformity indices of 0.39. MRI-based PTVs miss 17% of FET-PET/CT-based GTVs. Non significant alterations were detected in low grade glioma patients and in those undergoing reirradiation. Target volume definition for malignant gliomas during initial RT may yield significantly differing results depending upon the imaging modality, which the contouring process is based upon. The integration of both MRI and FET-PET/CT may help to improve GTV coverage by avoiding larger incongruences between physical and biological imaging techniques. In low grade gliomas and in cases of reirradiation, more studies are needed in order to investigate a potential benefit of FET-PET/CT for planning of RT.


Arterial stiffness, lipoprotein particle size, and lipoprotein particle concentration in children with type 1 diabetes.
To determine if lipoprotein particle abnormalities correlate with arterial stiffness in children with type 1 diabetes (T1D). In this case-control study, we evaluated 70 children, 35 with T1D and 35 controls, ages 10-18 years, matched for age, sex, race, and BMI. Arterial stiffness was assessed by radial tonometry (AI75) and blood was collected for lipoprotein subclass analysis. T1D subjects had increased AI75, decreased small LDL particle concentration (P = 0.0067), increased large LDL particle concentration (P = 0.007), increased large HDL particle concentration (P = 0.0012), increased mean LDL particle size (P = 0.0028), and increased mean HDL particle size (P < 0.0001) compared to controls. No significant correlations were found between lipoprotein subclasses and arterial stiffness in T1D subjects. T1D subjects have increased arterial stiffness when compared to controls, despite a less pro-atherogenic lipoprotein profile, indicating the need to identify other risk factors that correlate with arterial stiffness in T1D youth.


Desipramine and restraint stress induce odor conditioned aversion in rats: suppression by repeated conditioning.
Rats exposed to one, three, or seven conditioning sessions defined by an olfactory conditioned stimulus and stress or antidepressant administration as unconditioned stimulus were later tested for their preference for the conditioned olfactory stimulus. A significant reduction of the time spent in the conditioned stimulus was observed in animals exposed to one and three pairings with stress or three pairings with desipramine. A lack of conditioned aversion was observed in animals exposed to seven pairings with either reinforcer. These data could indicate that the adaptative mechanisms elicited by repeated stress or desipramine may be involved in the decrease of conditioned aversion.


Differentiating cells of murine stratified squamous epithelia constitutively express plasminogen activator inhibitor type 2 (PAI-2).
In stratified squamous epithelia a critical balance among cell proliferation, differentiation, and death must be maintained in order for these tissues to fulfill their barrier function. Previous studies have demonstrated that plasminogen activator inhibitor 2 (PAI-2) is a product of differentiating epidermal keratinocytes, suggesting a role for this inhibitor during squamous differentiation. Furthermore, in certain tumor cell lines, overexpression of PAI-2 confers resistance to the induction of programmed cell death, suggesting cytoprotective function(s). In the present study we demonstrate that PAI-2 mRNA and protein are constitutively and uniquely expressed in differentiating cells of murine stratified squamous epithelia, including epidermis, esophagus, vagina, oral mucosa, and tongue. PAI-2 immunohistochemical localization patterns suggest a predominantly cytosolic distribution, consistent with biochemical identification of the major PAI-2 species as a 43-kDa, presumably non-glycosylated protein. Functional analysis shows that the majority of epithelial PAI-2 is active. In contrast to the high levels of PAI-2 expression in stratified squamous epithelia, little or no PAI-2 is detectable in simple epithelia. These findings suggest that epithelial PAI-2 may mediate inhibition of intracellular proteinases associated with events during terminal differentiation and death that are unique to stratified squamous epithelia.


Response to comment on 'A conserved strategy for inducing appendage regeneration in moon jellyfish, Drosophila, and mice'.
Previously we reported evidence that a regenerative response in the appendages of moon jellyfish, fruit flies, and mice can be promoted by nutrient modulation (Abrams et al., 2021). Sustar and Tuthill subsequently reported that they had not been able to reproduce the induced regenerative response in flies (Sustar and Tuthill, 2023). Here we discuss that differences in the amputation method, treatment concentrations, age of the animals, and stress management explain why they did not observe a regenerative response in flies. Typically, 30-50% of treated flies showed response in our assay.


Audiological Findings in Children Suspected to Have Been Exposed to the Zika Virus in the Intrauterine Period.
To evaluate auditory manifestations in children born to mothers who had exanthema during pregnancy, suspected to have been exposed to the Zika virus (ZIKV). Prospective observational. Tertiary referral center. Children born in Rio de Janeiro, Brazil, between April 2016 and September 2017, who were referred for newborn hearing screening (NHS). The NHS was performed by the automated brainstem auditory-evoked potential test at an intensity of 30 dBHL (decibels Hearing Level) with the result presented as "PASS/FAIL." A follow-up test was performed 6 months after the first examination. Hearing outcomes by audiological assessment. Ninety-eight children were recruited and 78 underwent the NHS test. In the first evaluation, the FAIL NHS result was observed in 4 of the 78 children. Three were diagnosed with sensorineural hearing loss and one had conductive loss. Including the first and second evaluation, the frequency of audiological alterations was 5.1%. Of the four children diagnosed with hearing loss, two were carriers of ZIKV, one had suspected ZIKV infection, and one was asymptomatic with confirmed exposure to the virus. There was no progression of hearing loss or other hearing abnormality in the children by the time of the second evaluation. The group of nonexposed children (negative quantitative reverse transcription polymerase chain reaction for ZIKV) showed no hearing loss. Uni or bilateral sensorineural hearing loss was diagnosed in asymptomatic children at birth. These observations highlight the importance of periodic follow-up of patients with congenital Zika syndrome to better understand their long-term auditory clinical outcome.


Discovery of an imidazopyridine-containing 1,4-benzodiazepine nonpeptide vitronectin receptor (alpha v beta 3) antagonist with efficacy in a restenosis model.
In the 3-oxo-1,4-benzodiazepine-2-acetic acid series of vitronectin receptor (alpha v beta 3) antagonists, a compound containing an imidazopyridine arginine mimetic was discovered which had sufficient potency and i.v. pharmacokinetics for demonstration of efficacy in a rat restenosis model.


The promise of low-tech intervention in a high-tech era: Remodeling pathological brain circuits using behavioral reverse engineering.
As an academic pursuit, neuroscience is enjoying a golden age. From a clinical perspective, our field is failing. Conventional 20th century drugs and devices are not well-matched to the heterogeneity, scale, and connectivity of neural circuits that produce aberrant mental states and behavior. Laboratory-based methods for editing neural genomes and sculpting activity patterns are exciting, but their applications for hundreds of millions of people with mental health disorders is uncertain. We argue that mechanisms for regulating adult brain plasticity and remodeling pathological activity are substantially pre-wired, and we suggest new minimally invasive strategies to harness and direct these endogenous systems. Drawing from studies across the neuroscience literature, we describe approaches that identify neural biomarkers more closely linked to upstream causes-rather than downstream consequences-of disordered behavioral states. We highlight the potential for innovation and discovery in reverse engineering approaches that refine bespoke behavioral "agonists" to drive upstream neural biomarkers in normative directions and reduce clinical symptoms for select classes of neuropsychiatric disorders.


Design of oncology clinical trials: a review.
Cancer is a disease that occurs due to the uncontrolled multiplication of cells that invade nearby tissues and can spread to other parts of the body. An increased incidence of cancer in the world has led to an increase in oncology research and in the number of oncology trials. Well designed oncology clinical trials are a key part of developing effective anti-cancer drugs. This review focuses on statistical considerations in the design and analysis of oncology clinical trials.


Molecular simulations of fluoxetine in hydrated lipid bilayers, as well as in aqueous solutions containing β-cyclodextrin.
Fluoxetine, which is a well-known antidepressant drug, is studied in hydrated cholesterol-free and cholesterol-containing lipid bilayers through unbiased and biased atomistic molecular dynamics simulations. The latter are conducted for the calculation of the potential of mean force (PMF) of fluoxetine along an axis perpendicular to the two leaflets of the bilayer. The PMF indicates that the drug prefers to reside inside the lipid phase and allows us to calculate important thermodynamic properties, such as the Gibbs energy difference of partitioning from the water to the lipid phase and the Gibbs energy barrier for hopping events between the two leaflets of the bilayer. The results from the biased simulations are in accord with the mass density profiles calculated from the unbiased simulations. Moreover, we estimate the effect of fluoxetine mole fraction on the order parameters of the lipid alkyl chains and on the area per lipid. It is also found that fluoxetine forms a hydrogen bond network with lipids and water molecules penetrating into the lipid phase. In addition, fluoxoetine is studied in detail in aqueous solutions containing β-cyclodextrin. It is observed from unbiased molecular dynamics simulations that the two aforementioned molecules form a noncovalent complex spontaneously and the calculated binding free energy is in agreement with the literature.


Does flavor impact function? Potential consequences of polyphenol-protein interactions in delivery and bioactivity of flavan-3-ols from foods.
Astringency is a component of the overall flavor experienced when consuming polyphenol rich foods and beverages such as tea, wine, cocoa and select fruits. Following consumption, the astringent sensation results from the well documented ability of polyphenols to bind to salivary proline rich proteins (PRP) and facilitate their precipitation in the oral cavity. In a similar fashion, polyphenols are also known to non-specifically bind food and other biological proteins. While much is known regarding the polyphenol-protein interactions leading to astringency, significantly less information is available regarding the impact of these polyphenol-protein interactions with food or other biological proteins on relevant physiological outcomes. This paper focuses on the interactions between flavan-3-ols, one of the most abundant dietary polyphenol forms, with proteins in food, salivary PRP and other physiological proteins. The physiological implications of these interactions in food and through the gut will be discussed in relation to manipulation of flavan-3-ol bioavailability, metabolism and biological activities including inhibition of digestive enzymes in the gut.


Choroidal neovascularization secondary to tubulointerstitial nephritis and uveitis syndrome (TINU) in an adult patient.
Inflammation is a well-known risk factor for the development of choroidal neovascularization (CNV), yet not all causes of intraocular inflammation have been documented to cause CNV. Tubulointerstitial nephritis and uveitis syndrome (TINU) is a rare cause of intraocular inflammation mostly in pediatric patients and only seldom has been associated with development of CNV. A 34-year-old pregnant female with a past history of bilateral ocular inflammation secondary to TINU presents 1 year after diagnosis with vision loss in the left eye. Clinical examination and investigations show the development of CNV in the left eye. The patient was treated with ranibizumab (Genentech, San Francisco, CA) intravitreal injections with improvement in symptoms and clinical findings. We report the first case of CNV secondary to TINU in an adult patient. The CNV associated with TINU is responsive to intravitreal anti-vascular endothelial growth factor (anti-VEGF) therapy.


Dually innervated dendritic spines develop in the absence of excitatory activity and resist plasticity through tonic inhibitory crosstalk.
Dendritic spines can be directly connected to both inhibitory and excitatory presynaptic terminals, resulting in nanometer-scale proximity of opposing synaptic functions. While dually innervated spines (DiSs) are observed throughout the central nervous system, their developmental timeline and functional properties remain uncharacterized. Here we used a combination of serial section electron microscopy, live imaging, and local synapse activity manipulations to investigate DiS development and function in rodent hippocampus. Dual innervation occurred early in development, even on spines where the excitatory input was locally silenced. Synaptic NMDA receptor currents were selectively reduced at DiSs through tonic GABAB receptor signaling. Accordingly, spine enlargement normally associated with long-term potentiation on singly innervated spines (SiSs) was blocked at DiSs. Silencing somatostatin interneurons or pharmacologically blocking GABABRs restored NMDA receptor function and structural plasticity to levels comparable to neighboring SiSs. Thus, hippocampal DiSs are stable structures where function and plasticity are potently regulated by nanometer-scale GABAergic signaling.


Acoustic and Semantic Processing of Auditory Scenes in Children with Autism Spectrum Disorders.
Processing real-world sounds requires acoustic and higher-order semantic information. We tested the theory that individuals with autism spectrum disorder (ASD) show enhanced processing of acoustic features and impaired processing of semantic information. We used a change deafness task that required detection of speech and non-speech auditory objects being replaced and a speech-in-noise task using spoken sentences that must be comprehended in the presence of background speech to examine the extent to which 7-15 year old children with ASD (n = 27) rely on acoustic and semantic information, compared to age-matched (n = 27) and IQ-matched (n = 27) groups of typically developing (TD) children. Within a larger group of 7-15 year old TD children (n = 105) we correlated IQ, ASD symptoms, and the use of acoustic and semantic information. Children with ASD performed worse overall at the change deafness task relative to the age-matched TD controls, but they did not differ from IQ-matched controls. All groups utilized acoustic and semantic information similarly and displayed an attentional bias towards changes that involved the human voice. Similarly, for the speech-in-noise task, age-matched-but not IQ-matched-TD controls performed better overall than the ASD group. However, all groups used semantic context to a similar degree. Among TD children, neither IQ nor the presence of ASD symptoms predict the use of acoustic or semantic information. Children with and without ASD used acoustic and semantic information similarly during auditory change deafness and speech-in-noise tasks.


Clinical pharmacodynamics of anticancer drugs: a basis for extending the concept of dose-intensity.
The studies reviewed herein support the precept that "systemic dose-intensity" (i.e., systemic exposure) may be more informative than "administered dose-intensity" for certain anticancer drugs. This does not mean that the administered dose-intensity should be ignored; in fact these data indicate the importance of documenting and assessing administered dose-intensity as an initial step toward identifying those situations where systemic dose-intensity may be most important. The studies described in this review were selected as representative examples of successful clinical pharmacodynamic studies; other published examples include vincristine AUC versus severity of neurotoxicity, etoposide systemic exposure versus leukopenia, red cell concentration of mercaptopurine metabolites versus neutropenia in children with ALL, and ARA-CTP retention in leukemic blasts versus clinical response in acute non-lymphocytic leukemia. As is the case with other types of clinical trials in cancer patients, there are also examples of negative pharmacodynamic studies (i.e., no relationship found between concentration and effects). There are several possible reasons for such negative findings, including the lack of such a relationship for some drugs, measuring the inappropriate drug moiety (e.g., failure to measure all active metabolites), measuring drug concentrations in the wrong biological fluid, evaluating systemic exposure over too narrow a range (i.e., all patients have either sub- or supra-therapeutic systemic exposure), selecting inappropriate sampling times or pharmacokinetic parameters, inadequately assessing drug toxicity or response, or simply studying an inadequate number of patients or patients with drug-resistant cancers. Therefore, negative findings in some pharmacodynamic studies should not deter the investigation of other drugs and/or other malignant diseases, just as negative therapeutic trials do not preclude subsequent clinical trials in oncology. Also, finding a relation between systemic exposure and drug toxicity, in the absence of a clear relation to antitumor effects, is potentially of great clinical utility. Such data should allow more objective escalation of drug dosages in individual patients, to ensure maximum dose-intensity while avoiding host toxicity. Obviously, if such dose escalation could be guided by more easily measured patient characteristics (e.g., age, weight, CrCl, shoe size, etc.), then using drug concentrations in individual patients might be obviated.(ABSTRACT TRUNCATED AT 400 WORDS)


Bilateral Foot Skin Eruption in a Hepatitis C Patient.
A 58-year-old female with history of hepatitis C virus presented to the emergency department with a bilateral skin eruption to her feet for one year. Following skin biopsy, the patient was diagnosed with Necrolytic acral erythema (NAE). She was treated with clobetasol ointment, zinc supplementation, and mupirocin, which resulted in improvement in her symptoms. NAE is a rash described as sharply demarcated, lichenified plaques on the dorsal foot and is a rare extra-hepatic manifestation of hepatitis C. This case details a patient with a skin eruption consistent with NAE.


Interleukin-10 and Small Molecule SHIP1 Allosteric Regulators Trigger Anti-inflammatory Effects through SHIP1/STAT3 Complexes.
The anti-inflammatory actions of interleukin-10 (IL10) are thought to be mediated primarily by the STAT3 transcription factor, but pro-inflammatory cytokines such as interleukin-6 (IL6) also act through STAT3. We now report that IL10, but not IL6 signaling, induces formation of a complex between STAT3 and the inositol polyphosphate-5-phosphatase SHIP1 in macrophages. Both SHIP1 and STAT3 translocate to the nucleus in macrophages. Remarkably, sesquiterpenes of the Pelorol family, which we previously described as allosteric activators of SHIP1 phosphatase activity, could induce SHIP1/STAT3 complex formation in cells and mimic the anti-inflammatory action of IL10 in a mouse model of colitis. Using crystallography and docking studies we identified a drug-binding pocket in SHIP1. Our studies reveal new mechanisms of action for both STAT3 and SHIP1 and provide a rationale for use of allosteric SHIP1-activating compounds, which mimic the beneficial anti-inflammatory actions of IL10. VIDEO ABSTRACT.


Codeine alters female reproductive function by targeting ovarian steroidogenesis and folliculogenesis via the induction of oxidative stress, inflammation, and apoptosis.
The rise in the abuse of codeine raises concerns about its impact on the health of users, and little has appeared on its effect on the female reproductive function. Therefore, this study evaluated the impact of codeine on female reproductive function. We administered codeine at low (2 mg/kg) and high (5 mg/kg) doses to female animals prior to mating for 8 weeks. In comparison with a vehicle-treated group, we then assessed the impact of codeine on body weight gain and ovarian weight, female sexual behaviour, ovarian steroidogenesis, and folliculogenesis. The role of oxidative stress, inflammation, and apoptosis were also evaluated. Codeine at either dose elicited a profound deficit in the absolute and relative ovarian weight, indicative of ovarian toxicity. Also, codeine induced female sexual dysfunction, and suppressed ovarian steroidogenesis and folliculogenesis, with degeneration of the ovarian cytoarchitecture and follicles. The effects of codeine were associated with a rise in ovarian hydroxyl radical generation and oxidative stress, evident by an increase in ovarian malondialdehyde, a reduction in reduced glutathione, and a decline in the activities of ovarian enzymatic antioxidants. In addition, codeine triggered an increase in the ovarian concentration of inflammatory cytokines, TNF-α and IL-1β, and myeloperoxidase activity. Furthermore, codeine caused an increase in 8-hydroxydeoxyguanosine (8OHdG), ovarian DNA fragmentation, and caspase-3 activity, suggestive of genotoxicity and apoptosis respectively. The current study provides some of the first evidence for the adverse effects of prolong codeine use on female sexual function, ovarian steroidogenesis, and folliculogenesis. It also emphasizes the reproductive health consequences of drug abuse.


Decreased forebrain [35S]TBPS binding and increased [3H]muscimol binding in rats that do not develop stress-induced behavioral depression.
Recent evidence suggests that anxiety and its biological concomitants may be involved in the pathophysiology of depression. In the present study, the in vitro radioligand binding of [3H]flunitrazepam, [3H]muscimol and [35S]t-butylbicyclophosphorothionate (TBPS) sites on the benzodiazepine/GABA chloride ionophore receptor complex (BGRC) was examined using the learned helplessness paradigm. Only rats which did not develop the syndrome showed a significant increase in [3H]muscimol binding in cerebral cortex and a decrease in [35S]TBPS binding in cerebral cortex and hippocampus in comparison to naive controls. For both ligands, this represented a change in Bmax rather than a change in affinity. Adrenalectomy had no impact on these alterations indicating that critical endogenous factors are not manufactured by the adrenal glands. These findings suggest that the BGRC in the forebrain may be a site mediating the 'coping' ability of rats that do not develop the learned helplessness syndrome. The possible involvement of neurosteroids in this effect is discussed.


A Dual HiBiT-GFP-LC3 Lentiviral Reporter for Autophagy Flux Assessment.
Autophagy is an intracellular degradation process that maintains the cellular homeostasis and it is regulated in multiple ways, both in health and disease. Assessment of autophagic flux in cells is an important approach for understanding the function of autophagy in biological contexts. Here, we describe a new tool for the qualitative and quantitative determination of autophagic flux using a dual lentiviral reporter system that generates a fusion HiBiT-GFP-LC3B protein suitable for generating stable cell lines.


Investigation into the differences and relationships between gasSOA and aqSOA in winter haze pollution on Chongming Island, Shanghai, based on VOCs observation.
To investigate the formation of secondary organic aerosol (SOA) under current atmospheric conditions, we conducted a field observation of SOA precursors in the downwind region of the Yangtze River Delta (YRD) in winter 2019 using a variety of offline and online instruments. During the entire observation period, the averaged fine particulate SOA was 7.9 ± 2.3 μg m-3, with precursor concentrations of 31 ± 11 ppbv for the measured volatile organic compounds (VOCs) and 16 ± 12 ppbv for NOx. Compared to those on the clean days, SOA on the haze days increased by a factor of 1.6, while the VOC and NOx increased by a factor of 1.3 and 2.0, respectively. Aerosol liquid water content (ALWC) and oxygenated VOCs (OVOCs, including acetaldehyde, formic acid, acetone, acetic acid, methyl ethyl ketone, and methylglyoxal) relationships suggested that the gasSOA and aqSOA occurred simultaneously on Chongming Island in winter. The gasSOA was primarily formed by the oxidation of aromatics and NOx at low RH (RH < 80%) conditions. In contrast, the aqSOA was formed under higher RH (RH > 80%) conditions via a combination of daytime photochemical aqueous phase processes of water-soluble OVOCs and nocturnal dark aqueous phase processes of primary emissions from biomass. The inversed higher mass ratio of NACs to (benzene + toluene) and nitrogen oxidation ratio (NOR) in the daytime during the gasSOA-dominated haze periods indicated that gasSOA could be transformed to aqSOA at high NOx levels. Our results also suggested the importance of NOx and VOC reduction measures in directly mitigating gasSOA and indirectly mitigating aqSOA during winter haze pollution.


Coupling of two endothelin receptor subtypes to differing signal transduction in transfected Chinese hamster ovary cells.
We examined the intracellular signal transduction of two endothelin receptor subtypes (ETA and ETB) by transfection and stable expression of individual receptor cDNAs in Chinese hamster ovary cells. Both receptors showed a rapid and marked stimulation of phosphatidylinositol hydrolysis and arachidonic acid release in response to agonist interaction. The two receptors, however, exhibited different responses in the cyclic AMP transduction cascades. ETA mediated the accumulation of cyclic AMP formation, whereas ETB displayed an inhibitory action on the forskolin-stimulated cyclic AMP accumulation. In both receptors, the responses of phosphatidylinositol hydrolysis, arachidonic acid release, and cyclic AMP formation were induced in complete agreement with the endothelin-binding selectivity of each receptor subtype. Endothelin, added together with GTP, activated the adenylate cyclase activity in membrane preparations of ETA-expressing cells, indicating the direct linkage of ETA to the adenylate cyclase system. Pertussis toxin treatment of ETA-expressing cells resulted in partial inhibition of the endothelin-induced cyclic AMP accumulation, whereas the same treatment of ETB-expressing cells completely abolished the endothelin-induced inhibition of cyclic AMP formation. Thus, the two endothelin receptor subtypes are coupled to multiple but distinct signal transduction cascades through different G proteins.


A look at corporal punishment and some implications of its use.
The author notes several legal, social, philosophical and educational attitudes common to Canada and the United States which have, for centuries, characterized the uses of corporal punishment with children. Specifically, corporal punishment is viewed as a technique for developing discipline within the school system. Inconsistencies in both Canada and the U.S. are noted regarding court decisions and their application in the classroom. Recent revisions to The Ontario Child Welfare Act are discussed in light of its implications for parents and teachers who physically punish their children or students. Research findings related to corporal punishment and their implications for schools are cited. Negative side-effects of administering punishment are also described. The evidence suggests that corporal punishment besides being an ineffective learning technique, is not the uncomplicated, quick solution many may think it. The author concludes by proposing that because of their important role in the lives of developing children and considering the resources devoted to teacher training, teachers should be held as legally accountable for their use of corporal punishment with children as parents are. As well, he indicates the need for (1) increased teacher training in the areas of child management, classroom management and interactional processes; (2) greater opportunity to devise creative problem-solving strategies; and (3) a re-ordering of priorities at universities, colleges and faculties of education which would benefit not only teachers, but ultimately their students.


[Fatal hemorrhage from ruptured varicose veins of the sigmoid colon in liver cirrhosis].
A 41-year-old woman died within a few hours one morning due to massive rectal hemorrhage. At autopsy, complete liver cirrhosis, signs of portal hypertension, liquid blood in the entire colon, and high-grade anemia were detected. The source of bleeding was a ruptured submucosal varix in the sigmoid colon, which was almost invisible even microscopically and had been caused by portal hypertension. In the vicinity, and somewhat further away from the rupture site, numerous, greatly dilated veins with wall sclerosis and intimal thickening, as well as paravascular iron deposits, were found as indications that severe hemorrhages had already occurred earlier. To detect the source of bleeding, meticulous inspection and dissection with hematoxylin and eosin, elastica van Gieson, and iron staining, were necessary.


Robotic-Assisted Gynecologic Surgery and Perioperative Morbidity in Elderly Women.
To assess perioperative complications, conversions, and operative times in patients age ≥75 years undergoing robotic-assisted gynecologic surgery. Retrospective cohort study (Canadian Task Force classification II-2). High-volume, 2-physician gynecologic oncology practice. A total of 705 women who underwent any robot-assisted gynecologic procedure for benign (n = 380) or malignant (n = 325) conditions between July 2008 and May 2014. Fifty patients age ≥75 years (elderly group) were compared with 655 patients age <75 years (younger group). Operative data were gathered prospectively for all robotic-assisted procedures. Demographic and perioperative outcomes were analyzed retrospectively for this study. The mean age was 81.3 ± 4.2 years (range, 75.0-90.5 years) in the elderly group and 52.8 ± 11.5 years (range, 22.9-74.6 years) in the younger group. The elderly group had higher rates of surgery for malignancy (90.0% vs 43.2%; p < .01) and lymphadenectomy (44.0% vs 23.4%; p < .01), and was more likely to have cardiovascular disease (88.0% vs 37.6%; p < .01). There were no between-group differences in body mass index or history of chronic obstructive pulmonary disease, diabetes mellitus, or more than 1 previous abdominal surgical procedure. The elderly group was more likely to have a length of stay greater than postoperative day one (30.0% vs 14.8%; p = .01) and had a higher incidence of postoperative cardiac arrhythmia (8.0% vs 1.2%; p < .01). The elderly group also had a smaller median uterine size (83.0 ± 49.1 g vs 126.0 ± 189.5 g; p < .01), but total operative time, rate of conversion (6.0% vs 1.8%) and rate of blood transfusion (2.0% vs 1.5%) were not significantly different between the 2 groups. Rates of bowel and genitourinary injury were <1% in both groups, and there was no between-group difference in postoperative infectious morbidity, vaginal cuff complications, or reoperation. The perioperative complication rates of robotic-assisted surgery are comparable in elderly women and younger women, despite a longer hospital length of stay and greater likelihood of postoperative arrhythmia in elderly women.


Protection against translocating Salmonella typhimurium infection in mice by feeding the immuno-enhancing probiotic Lactobacillus rhamnosus strain HN001.
The probiotic lactic acid bacterium Lactobacillus rhamnosus (strain HN001) is known to stimulate enhanced innate and acquired immune responses in mice. following oral delivery. Here, the ability of HN001 to confer immune enhancement and protection against an oral challenge of Salmonella tYphimurium was investigated. HN001-fed and non-probiotic-fed control BALB/c mice were challenged with either a single dose of S. typhimurium (ATCC strain 1772), or with five repeated daily doses of the pathogen; post-challenge clinical, behavioural, bacteriological and immunological parameters were assessed. Mice began to show ostensible signs of infection 3-4 days following the initiation of Salmonella challenge, and the first mortalities were observed after 6 days. Following single-dose Salmonella challenge, HN001-fed mice maintained a higher mean pre-mortality general health score than control mice; retained significantly greater food and water intake and weight gain, produced higher titres of serum and intestinal tract anti-Salmonella antibodies, and showed greater overall survival of infection (27/30 mice surviving at 21 days post-challenge, compared to 2/29 in the control group). Following repeated-dose Salmonella challenge, HN001-fed mice had significantly lower mean pathogen burdens in visceral organs (spleen, liver) compared to controls, and additionally, blood and peritoneal leucocytes obtained from HN001-fed mice exhibited significantly higher ex vivo phagocytic capacity compared to control-mice. This study affirms that Lb. rhamnosus strain HN001 displays immuno-enhancing properties in S. typhimurium-infected mice, and demonstrates that oral delivery of this probiotic can promote increased protection against a highly virulent enteric bacterial pathogen.


Idiopathic bilateral gluteus maximus contracture: a case report and review of literature.
Bilateral gluteus maximus contracture is an infrequently reported clinical entity. There are only two case reports from the Indian subcontinent. We report a case of idiopathic bilateral gluteus maximus contracture in a 14-year-old girl.


Phospholipid asymmetry of goat sperm plasma membrane during epididymal maturation.
The phospholipids and their fatty acids of the inner and outer plasma membrane leaflets of the maturing goat caput-, corpus-and cauda-epididymal spermatozoa were analyzed by treating the intact spermatozoa with phospholipase C and trinitrobenzene sulphonate. The inner and outer membrane showed marked differences in the phospholipid composition at all stages of epididymal sperm maturation. The outer membrane was rich in phosphatidylcholine (PC) and sphingomyelin (SPH) whereas the inner leaflet was dominated by phosphatidylethanolamine (PE). Although the ratio of PE/PC in the inner membrane was similar in both the mature cauda sperm and the immature caput sperm, it decreased significantly in sperm undergoing maturation in the corpus-epididymis. The distribution of the saturated and unsaturated fatty acids in the phospholipid fractions of both the membrane leaflets underwent profound alterations during the epididymal maturation. The data demonstrate asymmetry of phospholipids and their fatty acids in the sperm inner and outer plasma membranes and this lipid asymmetry is greatly altered during epididymal maturity of the male gametes.


Determination of molybdenum in human serum by neutron activation analysis.
Several investigators have reported serum molybdenum determinations in healthy humans. However, their results diverge quite widely. We determined the element by neutron activation analysis in 30 individuals. We found a mean value of 0.58 ng/ml, a standard deviation of 0.21 ng/ml and a range of 0.28--1.17 ng/ml.


Cannabis and adverse cardiovascular events: A systematic review and meta-analysis of observational studies.
Cannabis is the most used illicit drug in the world. Global trends of decriminalization and legalization of cannabis lead to various forms of cannabis use and bring great concerns over adverse events, particularly in the cardiovascular (CV) system. To date, the association between cannabis and adverse CV events is still controversial. We aim to conduct a systematic review and meta-analysis to assess the adverse CV events from cannabis use. A systematic search for publications describing the adverse CV events of cannabis use, including acute myocardial infarction (MI) and stroke, was performed via PubMed, Scopus, and Cochrane Library databases. Data on effect estimates in individual studies were extracted and combined via random-effects meta-analysis using the DerSimonian and Laird method, a generic inverse-variance strategy. Twenty studies with a total of 183,410,651 patients were included. The proportion of males was 23.7%. The median age and follow-up time were 42.4 years old (IQR: 37.4, 50.0) and 6.2 years (IQR: 1.7, 27.7), respectively. The prevalence of cannabis use was 1.9%. Cannabis use was not significantly associated with acute MI (pooled odds ratio (OR): 1.29; 95%CI: 0.80, 2.08), stroke (pooled OR 1.35; 95%CI: 0.74, 2.47), and adverse CV events (pooled OR: 1.47; 95%CI: 0.98, 2.20). The risk of adverse CV events including acute MI and stroke does not exhibit a significant increase with cannabis exposure. However, caution should be exercised when interpreting the findings due to the heterogeneity of the studies.


Environmental surveillance of SARS-CoV-2 RNA in wastewater systems and related environments in Wuhan: April to May of 2020.
Wastewater-based epidemiology (WBE) has emerged as an effective environmental surveillance tool in monitoring fecal-oral pathogen infections within a community. Congruently, SARS-CoV-2, the etiologic agent of COVID-19, has been demonstrated to infect the gastrointestinal tissues, and be shed in feces. In the present study, SARS-CoV-2 RNA was concentrated from wastewater, sludge, surface water, ground water, sediment, and soil samples of municipal and hospital wastewater systems and related environments in Wuhan during the COVID-19 middle and low risk periods, and the viral RNA copies quantified using reverse transcription quantitative polymerase chain reaction (RT-qPCR). From the findings of this study, during the middle risk period, one influent sample and three secondary effluents collected from waste water treatment plant 2, as well as two samples from Jinyintan Hospital wastewater system influent were SARS-CoV-2 RNA positive. One sludge sample collected from Guanggu Branch of Tongji Hospital, which was obtained during the low risk period, was also positive for SARS-CoV-2 RNA. These study findings demonstrate the significance of WBE in continuous surveillance of SARS-CoV-2 at the community level, even when the COVID-19 prevalence is low. Overall, this study can be used as an important reference for contingency management of wastewater treatment plants and COVID-19 prevention and control departments of Wuhan.


Effects of surgical stress and corticotrophin on the peripheral metabolism of thyroid hormones in rabbits.
The effect of surgical stress and ACTH injection on the peripheral monodeiodination of thyroxine (T4) was studied in the rabbit. These stimuli resulted in a switch from the peripheral formation of tri-iodothyronine (T3) to reverse T3 in normal rabbits and in rabbits whose thyroidal secretion was suppressed by administration of T4. This is analogous to the situation in man. These changes were not due to alterations in the serum binding capacity for thyroid hormones.


Community-engaged sustainable health care education.
Climate and ecological changes substantially impact human health. Sustainable health care education (SHE) teaches health professions students about the interdependence of ecosystems and human health, the health sector's impact on the environment, and sustainable solutions for both ecosystems and human health. Yet little is understood about the methods used to facilitate SHE learning within the local context. Community-engaged medical education (CEME), a concept used in medicine and other health professions, underscores the relationship between the community served and education, which is both interdependent and reciprocal. Our objective was to characterise how SHE could be made relevant to the local context and the health of the community. Qualitative content analysis was used to explore the perspectives of faculty members, community experts and health professions students on the relationship between SHE and CEME. Semi-structured interviews were conducted with 51 participants between March 2016 and May 2017. Participants highlighted that it was vital for students to become familiar with real-world, locally relevant issues by collaborating with community members and identifying opportunities for engagement. For optimal learning, CEME experiences should be accompanied by relevant curricular changes. Educational partnerships with local organisations, societies and activists provide continuing opportunities for dialogue about, and integration of, SHE. The integration of SHE through CEME will draw the community voice into the curriculum and will compel students to connect CEME SHE learning to their continuing education. The credible and respected role of the health professionals and health professions institutions provide a foundation for the development of community partnerships and the promotion of SHE. The integration of SHE through CEME will draw the community voice into the curriculum and will compel students to connect CEME SHE learning to their continuing education.


[Outpatient care and disease burden of rheumatoid arthritis : Results of a linkage of claims data and a survey of insured persons].
Healthcare of patients with rheumatoid arthritis (RA) in Germany has mainly been evaluated in the past in RA cohorts from specialized arthritis centers. This study investigated rheumatological care on a population basis, using claims data from a nationwide statutory health insurance fund (BARMER GEK) in combination with patient-reported outcomes from a questionnaire survey of insured persons with RA. Data from insurants aged 18-79 years with M05 (seropositive RA) or M06 (other RA, ICD-10) diagnoses were analyzed concerning diagnostics, medication and prescribing physician. A 31-item questionnaire covering patient reported diagnosis, healthcare utilization and burden of illness was sent to a stratified random sample of 6193 insured persons. Data from the respondents regarding rheumatological care and disease status were evaluated. In 2013 and 2014, a total of 96,921 adults with M05 or M06 diagnosis were insured. The questionnaire was answered by 51% of the sample and of these 81% confirmed the RA diagnosis. RA had been diagnosed by a rheumatologist in 59% of the cases, 70% reported moderate to severe pain and 46% had functional disability. Between at least 40% (claims data) and up to 68% (respondents) were in specialized rheumatological care. Treatment with disease-modifying antirheumatic drugs (DMARDs) was 61% (claims data) and 63% (respondents) in persons in rheumatological care but only 18% outside rheumatological care. The results indicate that specialized rheumatological care is required to provide adequate treatment for patients with RA in Germany. Patients with higher age and patients with M06 diagnosis had less drug prescriptions and were less frequently treated by rheumatologists.


Mobile messaging: emergency image transfer.
This is the first reported integration of picture archiving and communications systems (PACS) with general packet radio services (GPRS)-compliant mobile telephones allowing digital image transmission using multimedia messaging service (MMS) technology for mobile telementoring (advice and teaching).


Changes in bronchial anaphylactic reactivity induced in guinea-pigs by long-term treatment with histamine H2-agents.
Guinea-pigs were sensitized to ovalbumin (OA) by immunization regimens chosen to cause antigen-induced bronchial anaphylactic responses mediated mainly either by IgE-like antibodies or by IgG1-like antibodies. Treatment of the IgE-producing animals for three weeks with the histamine H2-receptor antagonist cimetidine (1 mg kg-1 i.p. once a day) or with the H2-agonist dimaprit (0.1, 1.0, or 10 mg kg-1 i.p. once a day) led to a significantly reduced bronchial response capacity compared with that of the saline-treated controls challenged intravenously with antigen one week after the end of treatment. The changes were biphasic and not strictly dose-dependent. In contrast, acute treatment of immunized animals with a single dose of cimetidine (10 or 30 mg kg-1 i.v.) or dimaprit (1 or 10 mg kg-1 i.v.) 2 min before challenge with OA did not significantly affect the bronchial anaphylactic response. However, long-term treatment with cimetidine (10 mg kg-1) or the dimaprit analogue, S-[4-(N, N-dimethylamino)-butyl] isothiourea (SKF Compound 91488) (1 mg kg-1), which is reported not to activate H2-receptors, had no effect on the response capacity. Treatment with cimetidine (1 mg kg-1) or dimaprit (1 mg kg-1) did not influence the response capacity to antigen challenge in IgG1- type animals. Dimaprit (1 mg kg-1) did not affect the responsiveness to intravenous provocation with histamine in 'IgE-type' animals. Antigen-induced release of histamine from chopped lung tissue in vitro was not significantly affected in 'IgE-type' animals treated with cimetidine (1 mg kg-1) or dimaprit (1 mg kg-1). Treatment of immunized animals with cimetidine or dimaprit one week before and one week after a booster injection of antigen also led to reduced response capacity compared with that of saline-treated controls. However, the serum levels of IgE-like homocytotropic antibodies of these animals were not reduced; on the contrary, those of IgG1-antibody were increased in dimaprit-treated animals. These data show that intermittent treatment with histamine H2-agents reduces reagin-mediated anaphylactic response capacity in vivo in actively sensitized guinea-pigs by an as yet undefined mode of action.