Neural expression and post-transcriptional dosage compensation of the steroid metabolic enzyme 17beta-HSD type 4.
Steroids affect many tissues, including the brain. In the zebra finch, the estrogenic steroid estradiol (E2) is especially effective at promoting growth of the neural circuit specialized for song. In this species, only the males sing and they have a much larger and more interconnected song circuit than females. Thus, it was surprising that the gene for 17beta-hydroxysteroid dehydrogenase type 4 (HSD17B4), an enzyme that converts E2 to a less potent estrogen, had been mapped to the Z sex chromosome. As a consequence, it was likely that HSD17B4 was differentially expressed in males (ZZ) and females (ZW) because dosage compensation of Z chromosome genes is incomplete in birds. If a higher abundance of HSD17B4 mRNA in males than females was translated into functional enzyme in the brain, then contrary to expectation, males could produce less E2 in their brains than females. Here, we used molecular and biochemical techniques to confirm the HSD17B4 Z chromosome location in the zebra finch and to determine that HSD17B4 mRNA and activity were detectable in the early developing and adult brain. As expected, HSD17B4 mRNA expression levels were higher in males compared to females. This provides further evidence of the incomplete Z chromosome inactivation mechanisms in birds. We detected HSD17B4 mRNA in regions that suggested a role for this enzyme in the early organization and adult function of song nuclei. We did not, however, detect significant sex differences in HSD17B4 activity levels in the adult brain. Our results demonstrate that the HSD17B4 gene is expressed and active in the zebra finch brain as an E2 metabolizing enzyme, but that dosage compensation of this Z-linked gene may occur via post-transcriptional mechanisms.


Further studies on the inviability of Escherichia coli K12 rho mutant strains carrying IncFII plasmids.
Previous results (Baumberg and Lovett 1977) showed that many conjugative plasmids, most notably those of the IncFII group, were only transferable to Escherichia coli K12 rho mutants at very low frequencies, and that this appeared to be due to a lethal interaction between plasmid and rho- allele. Experiments reported here were designed to examine this phenomenon further, and in particular to test the possibility that uncontrolled plasmid replication in the presence of the rho mutant allele occurs. The rifampicin resistance allele rpo203 antagonizes the effect of rho201 on conjugal plasmid transfer; since the former is known to counteract the latter's effect on transcription termination, this result indicates that the plasmid-rho interaction stems directly from the lack of transcription termination caused by a rho mutant allele. Direct estimation of Rldrd19 replication after conjugal transfer to rho+ and rho201 recipients showed no difference according to rho status. Also, cotransduction of rho101 and 201 with ilv::Tn5 into recipients carrying miniplasmid derivatives of R1, which retain a restriction fragment containing all the DNA known to be involved in plasmid replication, was normal and the rho- transductants retained the miniplasmids. It therefore appears that the lethal interaction between the Inc FII plasmids and rho mutant alleles does not involve plasmid replication functions.


Increase of regional total cancer incidence in north Sweden due to the Chernobyl accident?
Is there any epidemiologically visible influence on the cancer incidence after the Chernobyl fallout in Sweden? A cohort study was focused on the fallout of caesium-137 in relation to cancer incidence 1988-1996. In northern Sweden, affected by the Chernobyl accident in 1986, 450 parishes were categorised by caesium-137 deposition: < 3 (reference), 3-29, 30-39, 40-59, 60-79, and 80-120 kiloBecquerel/m(2). All people 0-60 years living in these parishes in 1986 to 1987 were identified and enrolled in a cohort of 1 143 182 persons. In the follow up 22 409 incident cancer cases were retrieved in 1988-1996. A further analysis focused on the secular trend. Taking age and population density as confounding factors, and lung cancer incidence in 1988-1996 and total cancer incidence in 1986-1987 by municipality as proxy confounders for smoking and time trends, respectively, the adjusted relative risks for the deposition categories were 1.00 (reference < 3 kiloBecquerel/m(2)), 1.05, 1.03, 1.08, 1.10, and 1.21. The excess relative risk was 0.11 per 100 kiloBecquerel/m(2) (95% CI 0.03 to 0.20). Considering the secular trend, directly age standardised cancer incidence rate differences per 100 000 person years between 1988 to 1996 and the reference period 1986-1987, were 30.3 (indicating a time trend in the reference category), 36.8, 42.0, 45.8, 50.1, and 56.4. No clear excess occurred for leukaemia or thyroid cancer. Unless attributable to chance or remaining uncontrolled confounding, a slight exposure related increase in total cancer incidence has occurred in northern Sweden after the Chernobyl accident.


A case report of allergic fungal rhinosinusitis managed with Dupilumab.
Allergic fungal rhinosinusitis (AFRS) is a subtype of chronic rhinosinusitis with nasal polyps. It is characterized by eosinophilic mucin, which results from an inflammatory reaction to non-invasive fungal hyphae in the rhino-sinuses. It is clinically recognizable due to the criteria set by Bent and Kuhn. The treatment approach is multimodal, and the main treatment approach is surgical debridement, followed by a course of oral and/or topical corticosteroids to decrease recurrence post-surgery. This case report aims to illustrate the effect of Dupilumab, on the number of relapse episodes in a patient and the associated parameters. Herein we report a case of a 40-year-old woman referred to our institution as a case of refractory AFRS for which she underwent four functional endoscopic sinus surgeries (FESS) and was on maximum medical treatment. She presented with complaints of facial fullness and pain, headache, and purulent discharge. After another trial of surgery which did not control her symptoms, she was assessed for criteria to start biological treatment. The symptoms were successfully controlled after initiation of the agent, and she was followed up using multiple subjective and objective measures. AFRS is a non-invasive immune-mediated sub-clinical entity of chronic rhinosinusitis. A multimodal approach to its treatment based on surgical debridement with medical therapy has shown positive outcomes. In this case we present significant improvement after administering Dupilumab; therefore, suggesting its addition to the treatment regimen of refractory AFRS.


Lipopolysaccharides isolated from Aeromonas salmonicida and Vibrio anguillarum show quantitative but not qualitative differences in inflammatory outcome in Sparus aurata (Gilthead seabream).
In fish, the defence system recognises pathogenic microorganisms via pathogen recognition receptors (PRRs) that sense particular structures of the pathogens; the so-called pathogen associated molecular patterns (PAMPs) such as bacterial lipopolysaccharides (LPSs). The result of the PAMP-PRR interactions leads to complex and orchestrated immune responses. In this study, Sparus aurata (Gilthead seabream) were intraperitoneally injected with purified lipopolysaccharide (LPS) from Aeromonas salmonicida (As)- and Vibrio anguillarum (Va) (1 mg*Kgfish(-1)), both Gram negative bacteria responsible for vibriosis and furunculosis respectively, therefore causing an impact upon marine fish cultures. Head-kidney, intestine, spleen, liver and blood samples were collected at 3, 6, 12 and 24 h post-injection. Plasma levels of cortisol, prostaglandins and lactate were measured and were significantly increased after As-LPS and Va-LPS treatment. Furthermore, tissue-specific differences of the gene regulatory patterns were evident for each LPS. When monocyte/macrophage cell cultures were challenged with As-LPS and Va-LPS, the pro-inflammatory cytokine mRNA abundances present a similar pattern of response. However, As-LPS always triggered a stronger response concerning TNFα, IL1β and cyclooxygenase-2 (COX2) mRNA abundance as well as PGE2 levels in the supernatant. Overall, the results indicate that specific LPSs do not activate different pro-inflammatory responses and that the observed gene expression pattern is tissue and concentration dependent.


[Use of rituximab in the treatment of lupus patients. The LESIMAB database].
Systemic lupus erythematosus is an autoimmune disease that may involve the function of organs and reduce the survival of patients. Advances in the diagnosis and treatment have improved the short-term prognosis.However, most therapeutic improvements come from progress in other areas of medicine and only in recent years is this trend changing. Unfortunately, the development of new drugs for lupus is facing specific difficulties and the development of rituximab in lupus has been stopped despite good results in the observational studies. This review examines some of the aspects that influence these difficulties from the perspective of the LESIMAB database.


Factors predicting major complications, mortality, and recovery in percutaneous endoscopic gastrostomy.
Percutaneous endoscopic gastrostomy (PEG) has been used in patients with dysphagia and inadequate food intake via an oral route. Despite being a procedure with a high success rate, complications and death have been reported. The aim was to identify the factors related to major complications and mortality, as well as PEG removal prognostic factors due to improvement of their general condition. Patient characteristics, comorbidities, laboratory data, concomitant medication, sedation, and indication for PEG placement were collected. Major complications, mortality, and PEG removal factors were assessed. A total of 388 patients were enrolled. There were 15 (3.9%) cases of major complications, with major bleeding being the most frequent in 6 (1.5%) patients. Corticosteroids were the independent variable associated with major complications (odds ratio [OR] 5.85; 95% confidence interval [CI] 1.71-20; P = <0.01). Advanced cancer (hazard ratio [HR] 0.5; 95% CI 0.3-1; P = 0.05), albumin (HR 0.6; 95% CI 0.4-0.9; P = <0.01), and C-reactive protein (CRP) (HR 1.1; CI 1-1.2; P = 0.01) were considered risk factors for mortality. Previous pneumonia (HR 0.4; CI 0.2-0.9; P = 0.02) was a factor for permanent use of a PEG; however, oncological indication (HR 8.2; CI 3.2-21; P = <0.01) was factors for PEG withdrawal. Chronic corticosteroid users potentially present with major complications. Low albumin levels and elevated CRP were associated with death. Previous aspiration pneumonia was a factor associated with permanent use of PEG; however, patients with oncological indication were the most benefited.


Peat as a natural solid-phase for copper preconcentration and determination in a multicommuted flow system coupled to flame atomic absorption spectrometry.
The physical and chemical characteristics of peat were assessed through measurement of pH, percentage of organic matter, cationic exchange capacity (CEC), elemental analysis, infrared spectroscopy and quantitative analysis of metals by ICP OES. Despite the material showed to be very acid in view of the percentage of organic matter, its CEC was significant, showing potential for retention of metal ions. This characteristic was exploited by coupling a peat mini-column to a flow system based on the multicommutation approach for the in-line copper concentration prior to flame atomic absorption spectrometric determination. Cu(II) ions were adsorbed at pH 4.5 and eluted with 0.50 molL(-1) HNO(3). The influence of chemical and hydrodynamic parameters, such as sample pH, buffer concentration, eluent type and concentration, sample flow-rate and preconcentration time were investigated. Under the optimized conditions, a linear response was observed between 16 and 100 microgL(-1), with a detection limit estimated as 3 microgL(-1) at the 99.7% confidence level and an enrichment factor of 16. The relative standard deviation was estimated as 3.3% (n=20). The mini-column was used for at least 100 sampling cycles without significant variation in the analytical response. Recoveries from copper spiked to lake water or groundwater as well as concentrates used in hemodialysis were in the 97.3-111% range. The results obtained for copper determination in these samples agreed with those achieved by graphite furnace atomic absorption spectrometry (GFAAS) at the 95% confidence level.


Effect of warming method on embryo quality in a simplified equine embryo vitrification system.
Equine embryo vitrification is still not a well-established technique in equine practice. Notably, little work has been done on the effect of the warming system on viability of vitrified embryos. Our goal was to evaluate the effect of warming without cryoprotectants on in vitro - produced (IVP) embryo viability in culture, quality assessment parameters, and pregnancy after transfer. Equine IVP blastocysts were vitrified using commercial embryo vitrification media and a semi-closed vitrification device. In Exp. 1, we evaluated two warming temperatures (room temperature, RT, ∼22 °C; and 38 °C) for each of three warming systems: commercial warming solution (Kit); commercial embryo holding medium (EHM) with decreasing concentrations of sucrose (EHM + SS); or EHM alone without added sucrose. Embryos (n = 9 to 14 per treatment) were cultured in vitro for 24 h, stained with DAPI, TUNEL, and fluorophore-labelled phalloidin, and evaluated for nucleus number, mitotic rate, apoptotic rate, and actin filament distribution. In Exp. 2, to survey embryo viability in vivo, vitrified IVP blastocysts were shipped to an embryo transfer facility, then warmed immediately before transfer to recipient mares, using the warming treatments associated with the nominally best (Kit-RT, Kit-38, EHM-RT) and poorest (EHM + SS-38) assessed embryo quality in Exp. 1 (n = 7 to 8 per treatment). Subsequently, IVP blastocysts produced as part of our clinical program were vitrified and shipped, then warmed in embryo holding medium at an embryo transfer facility before transfer to recipient mares; fresh IVP embryos were shipped and transferred as controls. In Exp. 1, embryos increased significantly in diameter after culture (P < 0.01), with no difference among treatments. There was no difference (P > 0.05) in the number of viable nuclei, apoptotic rate, or microfilament distribution among treatments, or between vitrified-warmed and Control embryos. The mitotic rate was higher (P = 0.021) for Kit-RT (3.6%) when compared with the other treatment groups (1.5-2.0%). In Exp. 2, there was no difference (P > 0.05) in initial pregnancy (71.4-87.5%) or heartbeat (57.1%-85.7%) rates among warming treatments. In the clinical trial, there was no difference (P > 0.05) between vitrified-warmed and Control embryos in initial pregnancy (90.9% and 66.6%, respectively) or heartbeat (81.8% and 66.6%, respectively) rates. These results indicate that a semi-closed vitrification system using commercially-available media, and incorporating warming in the field in a single step using commercial embryo holding medium without cryoprotectants, can provide high pregnancy rates with IVP equine embryos.


Safety and immunogenicity studies in animal models support clinical development of a bivalent norovirus-like particle vaccine produced in plants.
Noroviruses (NoV) are the leading cause of epidemic acute gastroenteritis in humans worldwide. A safe and effective vaccine that prevents NoV infection or minimizes NoV disease burden is needed, especially for children and the elderly who are particularly susceptible to NoV disease. A plant-based expression system (magnICON®) was used to manufacture two different virus-like particle (VLP) immunogens derived from human NoV genogroups I and II, genotype 4 (GI.4 and GII.4), which were subsequently blended 1:1 (w/w) into a bivalent vaccine composition (rNV-2v). Here, we report on the safety and immunogenicity of rNV-2v from one pilot and two GLP-compliant toxicity studies in New Zealand White rabbits administered the vaccine subcutaneously (SC) or intramuscularly (IM). Strong genogroup-specific immune responses were induced by vaccination without adjuvant at various doses (200 to 400 μg VLP/administration) and administration schedules (Days 1 and 7; or Days 1, 15 and 29). The results showed sporadic local irritation at the injection site, which resolved over time, and was non-adverse and consistent with expected reactogenicity. There were no signs of systemic toxicity related to vaccine administration relative to vehicle-treated controls with respect to clinical chemistry, haematology, organ weights, macroscopic examinations, or histopathology. In a 3-administration regimen (n + 1 the clinical regimen), the NOAEL for rNV-2v via the SC or IM route was initially determined to be 200 μg. An improved GI.4 VLP variant mixed 1:1 (w/w) with the wild-type GII.4 VLP was subsequently evaluated via the IM route at a higher dose in the same 3-administration model, and the NOAEL was raised to 300 µg. Serology performed in samples of both toxicity studies showed significant and substantial anti-VLP-specific antibody titers for rNV-2v vaccines administered via the IM or SC route, as well as relevant NoV blocking antibody responses. These results support initiation of clinical development of the plant-made NoV vaccine.


Comparison of S-ketamine and midazolam for intravenous preoperative sedative and anxiolytic effects in preschool children: study protocol for a randomized controlled clinical trial.
Preoperative anxiety management is gaining particular attention in paediatric anaesthesia. Pharmacological and non-pharmacological resorts can be implemented to address this special issue. Despite the various approaches currently used for preoperative sedation in children, the different sedative and anti-anxiety effects between the newly marketed anaesthetic, S-ketamine, and the traditional sedative, midazolam, are still unclear. This is a patient- and assessor-blinded randomized controlled clinical trial. Participants (n = 110) will receive S-ketamine (0.5 mg/kg) or midazolam (0.08 mg/kg) intravenously administrated at a ratio of 1:1 in the anaesthesia holding area. The primary outcome of this study is the sedative effect evaluated via the change in the modified Yale preoperative anxiety scale. It will be performed at two timepoints: in the pre-anaesthetic holding area before premedication (baseline, marked as T0) and about 5 min after premedication in the operating room without the existence of their guardians (marked as T1). Our secondary objectives include the parent separation anxiety score, postoperative agitation, caregivers' and anaesthesia care providers' satisfaction, and mask compliance. This randomized controlled trial is the first study to compare the anti-anxiety effect of intravenous S-ketamine and midazolam. We will provide a new approach for the clinical management of preoperative anxiety in preschool children posted for elective surgery. ChiCTR2300069998. Registered on 30 March 2023.


The throwing shoulder in youth elite handball: adaptions of inferior but not anterior capsule thickness differ between the two sexes.
The aim was to investigate side-to-side and sex differences of anterior and inferior capsule thickness (ACT, ICT) between the throwing and non-throwing shoulder (TS, NTS) in youth elite handball players. 125 youth female and male elite handball players (14.1±0.7yo) were assessed for ACT and ICT by ultrasound . ACT measurement was performed from anterior (3 o'clock) in upright position and for ICT from inferior (6 o'clock) in supine position. Measurements of ICT in the TS of all athletes (1.4±0.2 mm) differed significantly but marginally to those in the NTS (1.3±0.2 mm) (p = 0.001). Female (1.2±0.2 mm vs. 1.3±0.2 mm; p = 0.007) but not male youth players (1.4±0.2 mm vs. 1.4±0.2 mm, p = n.s.) demonstrated slight differences in ICT in the TS compared with the NTS. Although significant, the thickness in the TS compared to the NTS was within the measurement accuracy of the ultrasonic assessment. No difference in ACT was observed in the TS (1.4±0.3 mm) compared to the NTS (1.4±0.3 mm) for both sexes (n.s.).In conclusion, the anterior and inferior capsule thickness in youth elite handball athletes is not or only marginally different between throwing and non-throwing shoulders.


Follow-Up of Bone Mineral Density Changes in de novo Kidney Transplant Recipients Treated with Two Doses of the Receptor Activator of Nuclear Factor κB Ligand Inhibitor Denosumab.
Studies in women with post-menopausal osteoporosis have shown that discontinuation of treatment with denosumab leads to an increased risk of vertebral fractures because of rebound bone turnover and rapid loss of bone mineral density (BMD). In a post hoc analysis of the Prolia for Osteoporosis of Transplant Operated Patient study, we analyzed the effect of denosumab withdrawal on BMD changes. Twenty-five de novo kidney transplant recipients (KTR) who were treated for 1 year with 2 six-monthly doses of denosumab on top of standard treatment (daily calcium and vitamin D) were compared to a control group of 29 KTR who received standard treatment alone. BMD changes were analyzed by repeated dual-energy X-ray absorptiometry shortly after transplantation (baseline), after 6 and 12 months (active treatment phase) and after 2-6.5 years (follow-up phase). The average BMD at the lumbar spine declined markedly after discontinuation of treatment with denosumab but increased again thereafter. Thus, the average monthly change in lumbar spine BMD from month 12 onward was only 0.1 ± 2.8‰ in the denosumab group but 1.5 ± 1.9‰ in the control group (p = 0.021). The average monthly change in lumbar spine BMD from baseline to follow-up was similar in the control and denosumab group (1.1 ± 1.2‰ vs. 1.5 ± 2.4‰, p = 0.788). Similar results were seen at the total hip. In de novo KTR treated with 2 doses of denosumab, we detect a marked decrease in lumbar spine and hip BMD when denosumab is discontinued. Denosumab treatment should therefore not be discontinued without considering an alternative antiresorptive treatment.


Golgi apparatus-synthesized sulfated glycosaminoglycans mediate polymerization and activation of the cGAMP sensor STING.
Activation of the cyclic guanosine monophosphate (GMP)-AMP (cGAMP) sensor STING requires its translocation from the endoplasmic reticulum to the Golgi apparatus and subsequent polymerization. Using a genome-wide CRISPR-Cas9 screen to define factors critical for STING activation in cells, we identified proteins critical for biosynthesis of sulfated glycosaminoglycans (sGAGs) in the Golgi apparatus. Binding of sGAGs promoted STING polymerization through luminal, positively charged, polar residues. These residues are evolutionarily conserved, and selective mutation of specific residues inhibited STING activation. Purified or chemically synthesized sGAGs induced STING polymerization and activation of the kinase TBK1. The chain length and O-linked sulfation of sGAGs directly affected the level of STING polymerization and, therefore, its activation. Reducing the expression of Slc35b2 to inhibit GAG sulfation in mice impaired responses to vaccinia virus infection. Thus, sGAGs in the Golgi apparatus are necessary and sufficient to drive STING polymerization, providing a mechanistic understanding of the requirement for endoplasmic reticulum (ER)-to-Golgi apparatus translocation for STING activation.


Reducing the ionizing radiation background does not significantly affect the evolution of Escherichia coli populations over 500 generations.
Over millennia, life has been exposed to ionizing radiation from cosmic rays and natural radioisotopes. Biological experiments in underground laboratories have recently demonstrated that the contemporary terrestrial radiation background impacts the physiology of living organisms, yet the evolutionary consequences of this biological stress have not been investigated. Explaining the mechanisms that give rise to the results of underground biological experiments remains difficult, and it has been speculated that hereditary mechanisms may be involved. Here, we have used evolution experiments in standard and very low-radiation backgrounds to demonstrate that environmental ionizing radiation does not significantly impact the evolutionary trajectories of E. coli bacterial populations in a 500 generations evolution experiment.


Use of the polymerase chain reaction to detect genomes of human immunodeficiency virus and cytomegalovirus in post-mortem tissues.
The polymerase chain reaction (PCR) was used to amplify a 149 base-pair region of the cytomegalovirus (CMV) genome and a 551 base-pair region of the HIV-1 proviral long terminal repeat (LTR) present in DNA extracted from post-mortem tissue. Multiple tissues (n = 116) obtained from 16 patients which were subjected to PCR were also subjected to cell culture and histopathological analyses. One hundred and seven samples (92%) contained CMV DNA and 66/116 (57%) contained HIV proviral DNA at a level of > or = 10 genomes. Both viruses were detected in 60/116 (51.7%) of samples, with co-infection most frequent in the lung (69%). Cell culture for CMV detected 9.3% of the PCR-positive samples, whilst histology identified CMV inclusions in 15.9% of samples, all of which were CMV PCR-positive. CMV was most frequently detected in adrenal and lung tissues by histology. These results show that co-infection with CMV and HIV is a common occurrence in organs from AIDS patients and provide further evidence for a role of cytomegalovirus in the pathogenesis of AIDS.


Increased killer cell activity in insulin dependent (type 1) diabetes mellitus.
Antibody dependent cell mediated cytotoxicity in relation to the levels of circulating killer cells was investigated in 16 newly diagnosed classical insulin dependent (Type 1) diabetics, 11 islet cell antibody positive non diabetic children with at least one HLA haplotype in common with their diabetic sibling, and in 15 normal controls. Antibody dependent cell mediated cytotoxicity was evaluated using, as target, 51Cr labelled human 0+ erythrocytes sensitised with an anti-CD antiserum. Killer cells were measured by the low affinity E-rosetting cell technique. Increased killer cell levels (greater than normal mean + 2SD) were accompanied by a significant enhancement in antibody dependent cell mediated cytotoxicity both in newly diagnosed diabetics (p less than 0.05) and in unaffected siblings (p less than 0.01). These preliminary results indicate that raised antibody dependent cell mediated cytotoxicity is a feature of insulin dependent diabetes at diagnosis and suggest that active B cell damage might be occurring some time before the onset of clinical symptoms.


Structural alterations in the ciliary process and the blood-aqueous barrier of the monkey after systemic urea injections.
The structural alterations induced in the monkey ciliary epithelium by intravascular injection of urea solutions were studied with the light and electron microscopes. Arterial injection of urea resulted in destruction of the nonpigmented epithelium and the consequent breakdown of the blood-aqueous barrier. The intravenous injection did not significantly affect the structural integrity of the ciliary epithelium. The intercellular zonulae occludens were not altered and the intercellular pathway from blood to posterior chamber remained closed to horseradish peroxidase. Intercellular uptake in large cytoplasmic vacuoles appeared to account for some late transport to the basal end of the nonpigmented epithelium. There was no comparable transport of peroxidase in vesicles or vacuoles through the nonpigmented epithelium in animals not subjected to intravenous urea treatment. Compared to the arterial route, intravenous administration of urea does not appear to pose a serious threat to the integrity of the ciliary epithelium.


Long-acting tunable release of amlodipine loaded PEG-PCL micelles for tailored treatment of chronic hypertension.
Hypertension is a chronic condition that requires lifelong therapeutic management. Strict adherence to drug administration timing improves efficacy, while poor adherence leads to safety concerns. In light of these challenges, we present a nanofluidic technology that enables long-acting drug delivery with tunable timing of drug administration using buried gate electrodes in nanochannels. We developed a poly(ethylene glycol) methyl ether-block-poly(ε-caprolactone) (PEG-PCL)-based micellar formulation of amlodipine besylate, a calcium channel blocker for hypertension treatment. The electrostatically charged PEG-PCL micellar formulation enhanced drug solubility and rendered amlodipine responsive to electrostatic release gating in nanochannels for sustained release at clinically relevant therapeutic dose. Using a low-power (<3 VDC) gating potential, we demonstrated tunable release of amlodipine-loaded micelles. Additionally, we showed that the released drug maintained biological activity via calcium ion blockade in vitro. This study represents a proof of concept for the potential applicability of our strategy for chronotherapeutic management of hypertension.


A Bayesian perspective on severity: risky predictions and specific hypotheses.
A tradition that goes back to Sir Karl R. Popper assesses the value of a statistical test primarily by its severity: was there an honest and stringent attempt to prove the tested hypothesis wrong? For "error statisticians" such as Mayo (1996, 2018), and frequentists more generally, severity is a key virtue in hypothesis tests. Conversely, failure to incorporate severity into statistical inference, as allegedly happens in Bayesian inference, counts as a major methodological shortcoming. Our paper pursues a double goal: First, we argue that the error-statistical explication of severity has substantive drawbacks; specifically, the neglect of research context and the specificity of the predictions of the hypothesis. Second, we argue that severity matters for Bayesian inference via the value of specific, risky predictions: severity boosts the expected evidential value of a Bayesian hypothesis test. We illustrate severity-based reasoning in Bayesian statistics by means of a practical example and discuss its advantages and potential drawbacks.


Thermal denaturation of mesophilic and thermophilic 5S ribonucleic acids.
The Tm of Bacillus stearothermophilus 5S ribonucleic acid (RNA) is 1.5 +/- 0.5 C higher than that of 5S RNAs from B. subtilis and Escherichia coli. Melting in 50% methanol and in formaldehyde indicate that both base stacking and helical regions are involved in the slightly increased thermal stability of B. stearothermophilus 5S RNA. It is probable that the 5S RNA makes only a minor contribution to the thermostability of B. stearothermophilus 50S ribosomal subunits.


Characteristics and correlates of fentanyl preferences among people with opioid use disorder.
Fentanyl has come to dominate the U.S. illicit opioid supply. We aimed to characterize and examine correlates of preferences for fentanyl vs. other opioids among individuals starting OUD treatment. We interviewed 250 adults initiating buprenorphine treatment with positive fentanyl toxicology at intake. We characterized opioid preferences and examined bivariate associations between opioid preference (preference for heroin, fentanyl, heroin-fentanyl mix, or other opioid) and sociodemographic characteristics, psychosocial factors, and substance use behaviors. We then used multinomial logistic regression to examine factors independently associated with fentanyl preferences. Over half (52.0 %) of participants preferred fentanyl (21.2 % fentanyl alone, 30.8 % heroin-fentanyl mix). In bivariate comparisons, participants who preferred fentanyl were a higher acuity group with respect to risks and problems in general. In the multinomial logistic regression, people who preferred fentanyl, either alone or mixed with heroin, used non-prescribed buprenorphine less in the 30 days preceding treatment entry compared to people who preferred heroin or other opioids (RRRalone= 0.88 [0.78, 0.99]; P = 0.037 and RRRmixed= 0.91 [0.84, 0.99]; P = 0.046). People who preferred fentanyl alone were also younger (RRR= 0.93 [0.90, 0.97]; P < 0.001) and more likely to have severe mental illness (RRR= 2.5 [1.1, 5.6]; P = 0.027) than people who prefer heroin or other opioids. Many people with OUD report preferring fentanyl. People who express preference for fentanyl differ substantively from those with other opioid preferences, and may be at elevated risk for poor health outcomes. Understanding preferences surrounding fentanyl could inform treatment and harm reduction interventions.


Is aryl hydrocarbon hydroxylase activity a new prognostic indicator for breast cancer?
Aryl hydrocarbon hydroxylase (AHH) activity was measured in the breast tumours of 153 primary and 17 recurrent cancer patients, and in 18 patients with benign breast tumour. All operations were carried out in 1983-84. The cytosolic fraction was collected for steroid receptor determination, and microsomes were separated for AHH assay from the same tissue samples. The AHH distribution was wide and highly skewed in all groups. About 10% of the samples showed activities below detection limit. The medians and ranges for primary cancers were 34 (less than 5-2683), for recurrent cancers 40 (20-239) and for benign tumours 11 (less than 5-37) fmol min-1 mg-1 protein. After logarithmic transformation, the mean AHH activities of cancer samples differed significantly from those of benign tumours. The logarithm of AHH activity (log AHH) correlates positively with axillary lymph node status, and negatively with steroid receptor levels. The development of the disease and the survival of the patients were followed for 4 years. The survival and the disease-free interval of the cancer patients who had low AHH activity was significantly higher than that of the high AHH group. The multivariate analysis with Cox's proportional hazad model showed primary tumour size, progesterone receptor concentration, nodal status and log AHH to be the most important independent prognostic factors for survival, while the occurrence of metastases, log AHH and tumour size were the equivalent factors for the disease-free interval in primary breast cancers. We conclude that AHH activity may reflect the overall malignant potential of breast cancer tissue.


Isolation and inhibitory activity against ERK phosphorylation of hydroxyanthraquinones from rhubarb.
Five hydroxyanthraquinone compounds were purified from Chinese medicinal herb rhubarb by microwave-assisted extraction and silica gel column isolation. Their structures were identified by spectroscopic analysis. One of them, emodin, was found to block the ERK phosphorylation of PC3 cells at 20 microM. And two other compounds had potent proliferation inhibitory activity on A431 and PC3 cells at 20 microM. Furthermore, crude extracts revealed an antifungal activity stronger than that of purified compounds against several plant pathogens tested. Together, our study suggests that these compounds are biologically active and may lead to development of anticancer medicine.


Effects of brief early exposure to partially hydrolyzed and whole cow milk proteins.
Clinical experience ("the dangerous bottle") and experimental evidence indicate that the early life of an infant is particularly important for the development of the immune responses to food antigens. However, the clinical and immunologic consequences of a brief exposure to, or avoidance of, food antigens during the neonatal period in human infants are poorly understood and documented. We present the preliminary results of a prospective controlled study of 256 normal breast-fed infants randomly assigned to receive (blind) either an adapted formula (Nidina) or a partially hydrolyzed formula (Nidal HA) as a supplement to breast-feeding for a few days when necessary, and to be examined at days 5, 90, 150, and 365. The results indicated that (1) the prevalence of clinical symptoms and of total and specific IgE responses was not statistically different in the two groups of infants and (2) infants fed a hydrolyzed formula had median titers of specific IgG lower than those fed an adapted formula; the difference was significant for alpha-lactalbumin at day 90 (p < 0.005) and for alpha-lactalbumin (p < 0.05), casein (p < 0.05), and hydrolyzed formula (p < 0.01) at day 150. Humoral immune responses of breast-fed infants to food antigens thus appear to be modulated by early, short-term exposure to them.


The use of questions to determine the presence of photophobia and phonophobia during migraine.
To investigate whether the use of more detailed close-ended questions as part of the routine headache history is helpful when patients initially deny that they are sensitive to light and noise during migraine headaches. According to the International Headache Society 2004 criteria, the diagnosis of migraine requires the presence of at least one of the following during a headache: (1) nausea and/or vomiting, (2) photophobia and phonophobia. Evans anecdotally noted that many patients answer the question, "does light or noise bother you during a headache," with a "no" when the answer is really "yes" if they are asked more detailed close-ended questions. Consecutive patients fulfilling International Headache Society 2004 criteria for migraine or probable migraine presenting to a headache clinic and a neurology clinic were asked the following questions: "does light bother you during a headache?" If "no," they were then asked, "during a headache, would you prefer to be in bright sunlight or in a dark room?""does noise bother you during a headache?" If "no," they were then asked, "during a headache, would you prefer to be in a room with loud music or in a quiet room?" Eighty-five consecutive patients with migraine or probable migraine were questioned, 71 females (83.5%) and 14 males (16.5%). There was denial of light and sound sensitivity in 24% of patients with routine questioning and then awareness of sensitivity in 93% with the further questioning. A total of 7.1% of the patients were diagnosed with probable migraine. However, if the additional questions were not asked, 8% more of the patients with definite migraine would have been incorrectly diagnosed as probable migraine. When patients initially deny light and noise sensitivity during migraine headaches, additional questions should be asked to ensure that their answer is accurate. Not asking the additional questions may result in the over-diagnosis of probable migraine.


Trends of Underweight Malnutrition Among Chinese Residents Aged 60 Years and Above - China, 1992-2015.
The prevalence of underweight malnutrition largely decreased in Chinese adults in recent thirty years while obesity became increasingly concerning. However, underweight malnutrition still affected elderly populations and increased risk of anemia, infection diseases, some non-communicable chronic diseases and disability. In this study, data from 4 national surveys from 1992 to 2015 were analyzed to study underweight malnutrition. There was an 80.5% reduction for underweight malnutrition nationally, including a 67.5% reduction in rural areas and 67.4% in urban areas, and 76.2% in males and 79.4% in females. Underweight malnutrition seriously affects the health and quality of life for older people and will lead to heavy burdens for families and society overall. Therefore, efforts should be maintained to screen, treat, and safeguard elderly populations with underweight malnutrition using nutritional improvement strategies, especially for the oldest elderly individuals in rural areas.


Improvement in nutrition-related knowledge and behaviour of urban Asian Indian school children: findings from the 'Medical education for children/Adolescents for Realistic prevention of obesity and diabetes and for healthy aGeing' ( MARG) intervention study.
Increasing prevalence of childhood obesity calls for comprehensive and cost-effective educative measures in developing countries such as India. School-based educative programmes greatly influence children's behaviour towards healthy living. We aimed to evaluate the impact of a school-based health and nutritional education programme on knowledge and behaviour of urban Asian Indian school children. Benchmark assessment of parents and teachers was also done. We educated 40 196 children (aged 8-18 years), 25 000 parents and 1500 teachers about health, nutrition, physical activity, non-communicable diseases and healthy cooking practices in three cities of North India. A pre-tested questionnaire was used to assess randomly selected 3128 children, 2241 parents and 841 teachers before intervention and 2329 children after intervention. Low baseline knowledge and behaviour scores were reported in 75-94 % government and 48-78 % private school children, across all age groups. A small proportion of government school children gave correct answers about protein (14-17 %), carbohydrates (25-27 %) and saturated fats (18-32 %). Private school children, parents and teachers performed significantly better than government school subjects (P < 0.05). Following the intervention, scores improved in all children irrespective of the type of school (P < 0.001). A significantly higher improvement was observed in younger children (aged 8-11 years) as compared with those aged 12-18 years, in females compared with males and in government schools compared with private schools (P < 0.05 for all). Major gaps exist in health and nutrition-related knowledge and behaviour of urban Asian Indian children, parents and teachers. This successful and comprehensive educative intervention could be incorporated in future school-based health and nutritional education programmes.


Techniques of Esophageal Anastomoses for Esophagectomy.
This article discusses and illustrates a variety of accepted techniques of esophagogastric anastomosis during an esophagectomy. The performance of an anastomotic technique can be surgeon specific, although it is of great benefit for the esophageal surgeon to be facile and adept in multiple techniques, as occasionally the clinical situation may be better suited for a particular technique. Regardless of the method of creating the esophagogastric anastomosis, the goal is to create a viable, tension-free and nonobstructive anastomosis with adequate margins.


Implementation of brief dialectical behavior therapy skills training among borderline personality disorder patients in Malaysia: feasibility, acceptability, and preliminary outcomes.
Even though dialectical behavior therapy (DBT) has received substantial empirical support in treating patients with borderline personality disorder (BPD), fewer studies have evaluated whether a brief DBT skills group may be effective in improving clinical outcomes in this population. Further, less is known regarding the feasibility and outcomes of DBT beyond Euro-American contexts. This paper describes outcomes from a pilot study examining the feasibility, acceptability, and clinical outcomes following completion of a shortened, 14-week DBT skills group in a sample of Muslim-majority BPD patients in Malaysia. Twenty patients were recruited from a public hospital and attended DBT skills groups in an outpatient clinic. Participants completed measures assessing psychological symptoms, self-harm behaviors, suicidal ideation, emotion regulation difficulties, self-compassion, and well-being pre- and post-intervention. There were significant reductions in depressive symptoms, stress, and emotion regulation difficulties, as well as increases in self-compassion and well-being from pre- to post-intervention. A trend was found for decreases in frequency and types of non-suicidal self-harm behaviors, suicidal ideation, and anxiety symptoms. Qualitative content analyses of participants' feedback indicated that the vast majority of participants perceived a positive impact from the skills group, with mindfulness and distress tolerance being rated frequently as skills that were beneficial. These preliminary findings suggest that DBT skills training is feasible and acceptable in a Muslim-majority, low resource clinical setting, and holds promise in improving clinical outcomes among BPD patients in Malaysia.


Psychophenomenology of the postpsychotic adjustment process.
A clinical phenomenological study with nine adults with schizophrenia explored the postpsychotic adjustment stage of recovery from a psychotic episode to map a psychological recovery trajectory. Participants (ages 21-37 years) were actively involved in an early psychosis outpatient treatment program. Psychophenomenological analysis of interview data resulted in 458 descriptive expressions reflecting four structural elements. Cognitive dissonance involved achieving pharmacological efficacy and cognitive efforts to "sort out" the experience. Insight was distinguished by mastery of autonomous performance of reality checks. Cognitive constancy was marked by resuming interpersonal relationships and age-appropriate activities. Ordinariness involved consistent engagement in daily activities reflective of prepsychosis functioning.


Biochemical studies on the 30-40 kDa Schistosoma mansoni surface antigens.
Biochemical studies of the previously identified 30-40 kDa surface antigens of Schistosoma mansoni schistosomula confirmed that four molecules could be discriminated in this antigenic group. The antigens presented slightly different molecular mass in sodium dodecyl sulfate polyacrylamide gel electrophoresis (40, 38, 37 and 32 kDa) but were all found in isoelectric focusing at the same pH (6.2-6 and 7.5). The four antigens bound to concanavalin A and only the 32 kDa molecule had affinity for the Lens culinaris agglutinin. These results indicated almost similar biochemical characteristics of the 30-40 kDa antigens and partial hydrolysis of the 38 and 32 kDa antigens suggested that they were affected by a similar cleavage process. The possibility of a structural homology between these two components is discussed.


Therapeutic factors in a group for parents with mental illness.
Parents with mental illness face many parenting related challenges that are exacerbated by the lack of services focusing on these needs. A study was conducted with 35 persons who participated in a group for parents with mental illness in Israel in order to examine the parenting related concerns the participants might bring up in a group modality, and the therapeutic factors in the group process. The findings illuminate the centrality of the parenting role in the participants lives and the value of the group modality as a tool enabling the participants to reveal their vulnerabilities. The therapeutic factors at work in the group, such as, imparting information, interpersonal learning, socialization techniques helped them deal with the difficulties of fulfilling their parenting roles at the same time they cope with their own mental illness.


I Didn't Ask to Come to this Country…I was a Child: The Mental Health Implications of Growing Up Undocumented.
Growing up as an undocumented immigrant and transitioning to "illegal" adulthood can expose the person to adverse social determinants, which can detrimentally affect mental health by acting as chronic stressors. Although there have been several attempts to reform immigration, none have been entirely successful. Recently, the Dream Act and the path toward citizenship may be important steps for reducing mental health disparities among the undocumented, immigrant population. This case report will describe the experiences of one Latino "dreamer", reveal the effects of an undocumented status on mental health, and posit future directions for mental health promotion in this vulnerable population.


Acetaldehyde activation of poly(ADP-ribose)polymerase in hepatocytes of mice treated in vivo.
The activities of poly(ADP-ribose) polymerase and of DNA polymerases alpha and beta and the level of cytochrome P450 were determined in mouse parenchymal liver cells 5 h after treatment with 0.1, 0.3, 1.0, and 3.0 mumole of acetaldehyde. Injection with 1.0 and 3.0 mumole of acetaldehyde induced an increase in poly(ADP-ribose) polymerase activity and in the P450 level, but had no effect on DNA polymerases. The stimulation of poly(ADP-ribose) polymerase activity can be used as an index of induced DNA damage. The possibility of using this experimental approach with other cells derived from mice treated in vivo with different xenobiotics is discussed.


Subclavian Broviac catheters in children--technical considerations in 146 consecutive placements.
During a 42-month span, 146 subclavian Broviac type catheters were placed in 129 children. In an additional 6 patients, a venotomy was necessary for successful cannulation, bringing the total number of attempts to 152. Indications were: parenteral nutrition (78), chemotherapy/bone marrow transplant (54), longterm antibiotic or other medication administration (14). Fifty-two were under 1 year of age. Forty-one weighed less than 5 kg and 7 were under 1 kg. Thirty-five had previous central lines (subclavian Broviacs--15). Additional procedures were common (31). Eight had thrombocytopenia. Insertion related problems were inability to cannulate vein--6 (3.9%). All had successful catheter placement by cut down. Over five punctures--27 (17.7%). Initially misdirected catheters--13 (8.9%) and, Arterial puncture--four (2.6%). Complications were pneumothorax--two. Tube thoracostomy required in one (650 g). Subclavian vein thrombosis after unsuccessful cannulation--one (1500 g). Questionable phrenic nerve injury--one (900 g). Transient venous occlusion of left arm--one (650 g). Accidental catheter damage--two; and air embolization without consequences, perioperative catheter clotting, and hematoma of tract occurred once each. There was no catheter-related mortality. Because the only complications producing untoward sequelae were in very small infants, our present recommendation is that if successful cannulation of the subclavian is not possible with the first few passages of the needle, a cut-down insertion is preferred in this group. Our experience indicates that subclavian indwelling central catheter placement in the pediatric population can be accomplished with a low morbidity.


The Critical Imperative: Prehospital Management of the Patient with ST-Elevation Myocardial Infarction.
Prehospital care is critical to achieve the goal of timely reperfusion in patients with ST-elevation myocardial infarction. Prehospital care is delivered by emergency medical services (EMS) personnel, which include emergency medical dispatchers, first responders, and ambulance response. There is considerable variation in the training and capabilities of the EMS providers in the United States depending on the location (ie, rural vs urban) and local jurisdictions. In this article, the key components of prehospital care of the patient with ST-elevation myocardial infarction and the various levels of training and capabilities of EMS providers are discussed.


Factors influencing livelihood strategy choice and food security among youths in Mashonaland East Province, Zimbabwe.
Several governments and development practitioners view youths as critical to the strategy of enhancing food and nutrition security and sustainable livelihoods in rural Africa. Despite youths being at the centre of food and nutrition security, their contribution to household food security remains understudied. The lack of such evidence has made it difficult to develop and implement effective and sustainable solutions to food insecurity and poverty in rural Africa. Thus, the study examines the factors influencing livelihood strategy choice and food security among youths in three districts of Mashonaland East Province, Zimbabwe. A total sample of 200 randomly selected youths was analysed using both descriptive and inferential statistics. The results show that agriculture was the main livelihood strategy followed by remittance dependant, self-employment, migration, and cross-border trading. In terms of remuneration, cross-border trading was found to be the most remunerative livelihood strategy followed by remittance dependant, self-employment, migration, and agriculture. The youths associated their choice of livelihood strategy with factors such as gender, age, land ownership, access to the internet, social group membership, access to credit and level of education. The study also finds food insecurity, notably severe food insecurity to be a general characteristic among the respondents. The nature of the livelihood strategy of the youths, their socioeconomic characteristics and livelihood capital were found to significantly influence household food security. The study recommends that the government implements strategies to make agriculture a sustainable livelihood option and policies to support youth in the non-farm sector should be a priority.


Prognostic value of serial blood S100B determinations in stage IIB-III melanoma patients: a corollary study to EORTC trial 18952.
S100B is a prognostic factor for melanoma as elevated levels correlate with disease progression and poor outcome. We determined its prognostic value based on updated information using serial determinations in stage IIb/III melanoma patients. 211 Patients who participated in the EORTC 18952 trial, evaluating efficacy of adjuvant intermediate doses of interferon α2b (IFN) versus observation, entered a corollary study. Over a period of 36 months, 918 serum samples were collected. The Cox time-dependent model was used to assess prognostic value of the latest (most recent) S100B determination. At first measurement, 178 patients had S100B values <0.2 μg/l and 33 ≥ 0.2 μg/l. Within the first group, 61 patients had, later on, an increased value of S100B (≥ 0.2 μg/l). An initial increased value of S100B, or during follow-up, was associated with worse distant metastasis-free survival (DMFS); hazard ratio (HR) of S100B ≥ 0.2 versus S100B < 0.2 was 5.57 (95% confidence interval (CI) 3.81-8.16), P < 0.0001, after adjustment for stage, number of lymph nodes and sex. In stage IIb patients, the HR adjusted for sex was 2.14 (95% CI 0.71, 6.42), whereas in stage III, the HR adjusted for stage, number of lymph nodes and sex was 6.76 (95% CI 4.50-10.16). Similar results were observed regarding overall survival (OS). Serial determination of S100B in stage IIb-III melanoma is a strong independent prognostic marker, even stronger compared to stage and number of positive lymph nodes. The prognostic impact of S100B ≥ 0.2 μg/l is more pronounced in stage III disease compared with stage IIb.


Work zone sign design for increased driver compliance and worker safety.
Many studies have investigated the effect of dynamic message signs (DMS) on drivers' speed reduction and compliance in work zones, yet only a few studies have examined the design of sign content of DMS. The purpose of this study was to develop design standards for DMS to improve driver compliance and worker safety. This study investigated the impact of sign content, frame refresh rate, and sign placement on driver speed reduction, compliance, and eye movements. A total of 44 participants were recruited for this study. Each participant completed 12 simulated driving tasks in a high-fidelity driving simulator. A small-scale field study was also conducted to test the effect of DMS on vehicle speed in a highway work zone. Results showed sign content and placement had no impact on speed reduction and compliance. However, sign frame refresh rate was found to have a significant effect on drivers' initial speed and speed reduction. Participants had longer fixation duration on DMS when worker presence was mentioned in the sign content. Results of the field study suggested that the DMS is most effective at night.


Noncalcified plaque: relationship between results of multislice computed tomography, risk factors, and late clinical outcome.
Contrast-enhanced multislice computed tomographic angiography (MSCTA) detects noncalcified plaque (NCP) in coronary arteries and associated coronary stenoses. However, the clinical relevance of NCP is poorly defined. Our goal was to examine the relationship NCP, risk factors (RFs), and clinical follow-up in unselected outpatients undergoing MSCTA. Five hundred six patients undergoing contrast MSCTA were evaluated for NCP (intraluminal density 25 < Hounsfield units < 130). One hundred twenty-four patients (24.5%) had calcium scores (CAC) of zero. Of these, 111 patients were examined for RFs and followed clinically for a mean of 34 months. Of 124 patients with zero CAC, 111 (89.5%) included 52 (46.8%) with no NCP, 40 (36.0%) with NCP, and mild luminal stenosis, 14 (12.6%) and 5 (4.5%) with NCP causing significant and severe stenosis, respectively. Patients in each group were similar in age but differed significantly in number of RFs. Current or former smokers, hypertensive, and obese patients had more NCP and associated stenosis. At a mean of 34 months, there were no events in the no NCP group, 2/54 (3.7%) events in the NCP without severe stenosis group (one sudden cardiac death and one ventricular tachycardia), and 2/5 (40.0%) patients had revascularization in the NCP with severe stenosis group. (1) In patients with zero CAC, presence of NCP on MSCTA was associated with more RFs, especially smoking, obesity, and hypertension. (2) NCP can result in severe coronary stenosis. (3) NCP detected by MSCTA in patients with zero CAC may identify patients with late cardiac events.


Cell therapy in vascularized composite allotransplantation.
Allograft rejection is one of the obstacles in achieving a successful vascularized composite allotransplantation (VCA). Treatments of graft rejection with lifelong immunosuppression (IS) subject the recipients to a lifelong risk of cancer development and opportunistic infections. Cell therapy has recently emerged as a promising strategy to modulate the immune system, minimize immunosuppressant drug dosages, and induce allograft tolerance. In this review, the recent works regarding the use of cell therapy to improve allograft outcomes are discussed. The current data supports the safety of cell therapy. The suitable type of cell therapy in allotransplantation is clinically dependent. Bone marrow cell therapy is more suitable for the induction phase, while other cell therapies are more feasible in either the induction or maintenance phase, or for salvage of allograft rejection. Immune cell therapy focuses on modulating the immune response, whereas stem cells may have an additional role in promoting structural regenerations, such as nerve regeneration. Source, frequency, dosage, and route of cell therapy delivery are also dependent on the specific need in the clinical setting.


Impairment of cytokine production following immunological synapse formation in patients with Wiskott-Aldrich syndrome and leukocyte adhesion deficiency type 1.
T cells following immunological synapse (IS) formation with antigen-presenting cells produce multiple cytokines through T cell receptor, integrin, and costimulatory signaling. Here, we investigated the cytokine profiles following IS formation in response to staphylococcal superantigen exposure in three adolescent patients with classical Wiskott-Aldrich syndrome (WAS) and in one patient with leukocyte adhesion deficiency (LAD) type 1. All WAS patients showed lower Th1 and Th2-skewed cytokine production; similar results were observed in the flow cytometric analysis of IFNγ- and IL-4-producing T cells. The patient with LAD type 1 with somatic mosaicism in 2% of CD8+ T cells showed lower Th1 and Th2 cytokine production than healthy controls. The patients with WAS were susceptible to infections and atopic manifestations, and the patients with LAD type 1 showed cold abscess on their skin, our findings using patient samples provide clinical insights into the mechanisms underlying immunodeficiency related to the symptoms of each disease.


Satisfaction with dental appearance in two cohorts of 75-year-olds examined in 2007 and 2017: A repeated cross-sectional study.
Satisfaction with dental appearance plays an important role in the self-esteem and psychological well-being of the elderly, the significance of which the attending dentist may not always be fully cognisant of. To assess the level of satisfaction with dental appearance, its associated factors and temporal changes in two cohorts of 75-year-old Swedes born 10 years apart. In 2007, a questionnaire was mailed to all those living in Örebro and Östergötland counties, Sweden, who were born in 1932 (n = 5195), and in 2017 to all born in 1942 (n = 7204). The evaluation was carried out with a global question 'Are you satisfied with the appearance of your teeth?', and four attitude-related statements about dental appearance. About 80% in both cohorts were 'very satisfied' or 'to large extent satisfied' with their dental appearance. The 1932 cohort was significantly more concerned about their dental appearance than the 1942 cohort, and women were generally also significantly more concerned than men. In the regression analysis, 'very satisfied' with dental appearance was predicted by good chewing efficiency, having complete dentures, no impact from Oral Impacts on Daily Performance, disagreement that 'minor esthetic imperfections of the teeth have no importance, only they should function well', better perceived general health than same-aged peers and belonging to the 1932 cohort. Satisfaction with dental appearance among 75-year-olds was generally high, with attitudes varying by gender and temporally. Women and the earlier-born generation (1932) were more concerned about dental appearance than men and the later-born generation (1942), respectively.


Secondary Hyperparathyroidism: Clinical Exploration of Endoscopic Total Parathyroidectomy Using the Oral Vestibular Approach with Forearm Autotransplantation.
For secondary hyperparathyroidism (SHPT), physicians prefer conservative treatments, and surgical intervention has proven to be the best solution for some patients. Among the surgical interventions, total parathyroidectomy plus autotransplantation (TPTX+AT), using the forearm, is the major effective treatment. TPTX+AT, in conjunction with transoral endoscopic thyroidectomy vestibular approach (TOETVA), includes many advantages. The study intended to evaluate the clinical value of performing an endoscopic total parathyroidectomy TPTX+AT in conjunction with TOETVA in treating SHPT and to summarize and share the clinical experience. The research team performed a prospective controlled study. The study took place at the Zhongshan Boai Hospital affiliated with Southern Medical University in Zhong Shan, Guangdong, China. Participants were 97 SHPT patients who were admitted to the hospital between March 2020 and March 2022. The intervention group included 47 SHPT patients who received endoscopic TPTX+AT combined with the TOETVA, and the control group included 50 SHPT patients who received routine TPTX+AT. The research team performed comparisons between the groups regarding: (1) operating conditions, including intraoperative blood loss, operating time, and number of parathyroid glands detected intraoperatively; (2) clinical efficacy, (3) postoperative complications, (4) parathyroid hormone (PTH) and calcium (Ca) levels, (5) psychological status using the Hamilton Anxiety (HAMA) and the Hamilton Depression Scale (HAMD), and (9) life quality using the 36-Item Short Form Health Survey (SF-36). The intervention group had significantly longer operation times and significantly greater intraoperative blood loss than the control group did, but the intervention group had fewer complications, lower PTH and Ca levels, and a higher efficacy (P < .05). The intervention group also had a significantly better psychological state and prognostic quality of life than the control group did (P < .05). Endoscopic treatment of SHPT using TPTX+AT in combination with TOETVA can significantly relieve clinical symptoms and lower serum PTH and Ca levels. The results suggest that the operation is safe and effective.


Implications of child development on the practice of oral care.
Of all patient groups, children represent perhaps the most challenging in the preventive dental practice. While technical skills must be excellent, the interpersonal skills of the clinician are also paramount to successful pediatric dentistry and are affected by where children are in their development. This article reviews the developmental stages that children experience and how age characteristics can be predictors of the dental professional's approach to ensure successful, long-term oral health care.


Purified HLA antigens to probe human alloantibody specificity.
HLA class I antigens were purified in sufficient quantities to probe the antigen specificity of lymphocyte and platelet antibodies. Purification of HLA was achieved by affinity chromatography using the monoclonal W6/32 antibody that recognizes a nonpolymorphic determinant of HLA-A,B,C molecules. Pooled platelets from a large number of donors were used as source of antigen. A highly purified HLA preparation was obtained that produced a dose-dependent inhibition of the binding of the W6/32 antibody to lymphocytes as measured by flow cytometry. The binding of monoclonal antibodies to T-lymphocyte antigens or to HLA class II antigens was not affected. The purified HLA also inhibited the binding of lymphocyte alloantibodies from renal transplant patients, providing a direct and definitive way to probe HLA specificity. HLA also inhibited the binding of the same antibodies to platelets but it did not interfere with the binding of alloantibodies to the platelet-specific PLA1 antigen. This preparation, therefore, can conclusively probe the HLA specificity of both alloantibodies for clinical investigation purposes and monoclonal antibodies for screening purposes, and has the potential of becoming a reagent for routine use in clinical and research laboratories.


Succinic acid production from hemicellulose hydrolysate by an Escherichia coli mutant obtained by atmospheric and room temperature plasma and adaptive evolution.
Atmospheric and room temperature plasma and adaptive evolution were combined to generate Escherichia coli mutants, which can simultaneously and efficiently utilize glucose and xylose to produce succinic acid in chemically defined medium under exclusively anaerobic condition. Compared to the parent strain BA305, a pflB, ldhA, ppc, and ptsG deletion strain overexpressing ATP-forming phosphoenolpyruvate (PEP) carboxykinase (PEPCK), the sugar consumption rate and succinic acid productivity of mutant BA408 were significantly improved with a marked increase in the key enzyme activities. Subsequent anaerobic fermentation of BA408 with corn stalk hydrolysate produced a final succinic acid concentration of 23.1 g L(-1) with a yield of 0.85 g g(-1) sugar mixture. The observed synthesis of succinic acid from the corn stalk hydrolysate showed a great potential usage of renewable biomass as a feedstock for an economical succinic acid production using E. coli.


9-cis-retinoic acid analogues with bulky hydrophobic rings: new RXR-selective agonists.
Stille cross-coupling of aryltriflates 10 and dienylstannane 11, oxidation and Horner-Wadsworth-Emmons reaction afforded stereoselectively retinoates 15. Saponification provided the carboxylic acids 8a and 8b, retinoids that incorporate a bulky hydrophobic ring while preserving the 9-cis-geometry of the parent system. In contrast to the pan-RAR/RXR agonistic profile of the lower homologue of 8a, compound 7 (LG100567), retinoids 8 showed selective binding and transactivation of RXR, devoid of significant RAR activation. In PLB985 leukemia cells that require RXR agonists for differentiation compounds 8 induced maturation in the presence of the RAR-selective pan-agonist TTNPB; this effect was blocked by an RXR-selective antagonist.


[Evaluation of abdominal visceral obesity from anthropometric parameters using receiver operating characteristic curves].
To evaluate the best cut-off point, sensitivity and specificity of body mass index (BMI), waist circumference (WC) and Waist-to-hip ratio (WHR) in predicting of abdominal visceral obesity. Abdominal visceral fat area (VA) was measured with magnetic resonance image (MRI) in 690 subjects (men: 305, women: 385). Meanwhile, BMI, WC, WHR were assessed. Receiver operating characteristic (ROC) curve was used as index for analysis. 1) 61.7% of over-weight/obesity (OW/OB) and 14.2% of normal weight (NW) individuals were abdominal visceral obesity (VA >/= 100 cm(2)) by MRI diagnosis. 2) VA was significantly positively correlated with anthropometric variables (BMI, WC, WHR), in which WC was the best (r = 0.73 - 0.77, P < 0.001). 3) The best cut-off points of these anthropometric parameters in assessing abdominal visceral obesity were as follow: BMI: 26 kg/m(2), WC: 90 cm, WHR: 0.93. Among them WC showed most sensitive and specific. 4) 95% men and 90% women appeared abdominal visceral obesity in subjects with BMI >/= 28 kg/m(2) or WC >/= 95 cm. BMI, WC, WHR can all predict abdominal visceral obesity, with WC the best.


Pharmacological studies on experimental nephritic rats (9). Changes in activities of urinary enzymes in the modified type of Masugi's nephritis and their sources.
Using a modified model of Masugi's nephritis of rats, various enzymatic activities in urine, serum and renal tissue (glomeruli or cortex) were determined at appropriate intervals after the administration of anti-kidney serum and compared with the urinary protein content and the kidney weight. In the urine, alkaline phosphatase (Al-Phosase), acid phosphatase (Ac-Phosase) and N-acetyl-beta-glucosaminidase (NA-beta-Gase) activities remarkably increased after the induction of nephritis, reached their peaks on the 10th day and reverted to almost the normal levels on the 30th day. The patterns of time course of these enzymatic activities were similar to patterns seen in the urinary protein content and the kidney weight. In the serum, the Al-Phosase activity decreased slightly, while NA-beta-Gase activity increased slightly. The Ac-Phosase activity in serum remained at normal levels during the experimental periods. In the glomeruli, the bound activities of these three enzymes decreased with nephritis, showing a negative correlation with results in the urine. On the other hand, fibrinolytic activities in the urine (plasmin-like enzyme) and renal cortex (plasminogen activator) also paralleled the urinary protein content and the kidney weight in the course of the disease. These results suggest that the Al-Phosase, Ac-Phosase and NA-beta-Gase excreted into urine in cases of nephritis may be mostly derived from damaged renal cells and one part of Al-Phosase may also come from the plasma. Moreover, the increase of plasmin-like enzyme in urine is considered to be due to the increase of plasminogen activator in the renal cortex. Thus, the determination of these enzymatic activities in the urine should be useful for evaluating effects of drugs for the treatment of nephritis.


Complex macroevolution of pterosaurs.
Pterosaurs, the earliest flying tetrapods, are the subject of some recent quantitative macroevolutionary analyses from different perspectives.1-2 Here, we use an integrative approach involving newly assembled phylogenetic and body size datasets, net diversification rates, morphological rates, and morphological disparity to gain a holistic understanding of the pterosaur macroevolution. The first two parameters are important in quantitative analyses of macroevolution, but they have been rarely used in previous pterosaur studies.1,3,4,2,5,6,7,8,9,10,11,12 Our study reveals an ∼115-Ma period-from Early Triassic to Early Cretaceous-of multi-wave increasing net diversification rates and disparity, as well as high morphological rates, followed by an ∼65-Ma period-from Early Cretaceous to the end of the Cretaceous-of mostly negative net diversification rates, decreasing disparity, and relatively low morphological rates in pterosaur evolution. Our study demonstrates the following: (1) body size plays an important role in pterosaur lineage diversification during nearly their whole evolutionary history, and the evolution of locomotion, trophic, and ornamental structures also plays a role in different periods; (2) birds, the other major flying tetrapod group at the time, might have affected pterosaur macroevolution for ∼100 Ma; and (3) different mass extinction events might have affected pterosaur evolution differently. Particularly, the revealed decline in pterosaur biodiversity during the Middle and Late Cretaceous periods provides further support for the possible presence of a biodiversity decline of large-sized terrestrial amniotes starting in the mid-Cretaceous,13,14 which may have been caused by multiple factors including a global land area decrease during these periods.


Integrated Behavioral Health Collaborative Practice Embedded Within the Pediatric Residency Continuity Clinic: Incorporating a Multicultural Lens.
Pediatric patients often work with multiple health care providers for complex presenting concerns. This complexity has called for pediatric health care providers to strengthen interdisciplinary relationships with mental health providers to meet patient needs. Integrated behavioral health collaborative practice models, using the Interprofessional Education Collaborative competencies, provide the necessary scaffolding to train medical and mental health professionals. A multicultural framework can be integrated into the interprofessional education curricula to better equip health care professionals to provide culturally competent services that decenter hierarchy, power, privilege, and implicit bias, resulting in improved access and quality of comprehensive health care services.


Depression in type 2 diabetes: A systematic review and meta-analysis of blood inflammatory markers.
The prevalence of depression is higher among people with type 2 diabetes (T2DM). Individually, both conditions are associated with systemic inflammation. This study aimed to summarize the clinical data comparing peripheral inflammatory markers in blood between people with T2DM, with and without comorbid depression. From 2187 records, we identified 20 original peer-reviewed articles from which blood inflammatory marker concentrations could be combined and compared between people with T2DM and comorbid depression (D) vs. no depression (ND) as standardized mean differences (SMD) in random effects meta-analysis. Concentrations of C-reactive protein (CRP; ND/NND = 1742/15244, SMD = 0.31 95% confidence interval [0.16, 0.45], Z16 = 4.03, p < 0.01; I2 = 84.0%) and interleukin-6 (IL-6; ND/NND = 677/4349, SMD = 0.17 [0.04, 0.30], Z4 = 2.58, p = 0.01; I2 = 48.1%), were higher, and concentrations of brain derived neurotrophic factor (BDNF; ND/NND = 358/1512, SMD = -0.37 95% confidence interval [-0.64,-0.10], Z2 = -2.68, p = 0.01; I2 = 61.2%) were lower, among those with depression. Depression in T2DM was associated with systemic inflammation and lower peripheral blood BDNF concentrations. Inconsistency between studies suggests the need to explore further population heterogeneity and pathophysiological elements. PROSPERO (CRD42020188509).


Extracellular ectonucleotidases are differentially regulated in murine tissues and human polymorphonuclear leukocytes during sepsis and inflammation.
Sepsis is life-threatening organ dysfunction caused by a dysregulated inflammatory and immune response to infection. Sepsis involves the combination of exaggerated inflammation and immune suppression. During systemic infection and sepsis, the liver works as a lymphoid organ with key functions in regulating the immune response. Extracellular nucleotides are considered damage-associated molecular patterns and are involved in the control of inflammation. Their levels are finely tuned by the membrane-associated ectonucleoside triphosphate diphosphohydrolase (E-NTPDase) enzyme family. Although previous studies have addressed the role of NTPDase1 (CD39), the role of the other extracellular NTPDases, NTPDase2, -3, and -8, in sepsis is unclear. In the present studies we identified NTPDase8 as a top downregulated gene in the liver of mice submitted to cecal ligation-induced sepsis. Immunohistochemical analysis confirmed the decrease of NTPDase8 expression at the protein level. In vitro mechanistic studies using HepG2 hepatoma cells demonstrated that IL-6 but not TNF, IL-1β, bacteria, or lipopolysaccharide are able to suppress NTPDase8 gene expression. NTPDase8, as well as NTPDase2 and NTPDase3 mRNA was downregulated, whereas NTPDase1 (CD39) mRNA was upregulated in polymorphonuclear leukocytes from both inflamed and septic patients compared to healthy controls. Although the host's inflammatory response of polymicrobial septic NTPDase8 deficient mice was no different from that of wild-type mice, IL-6 levels in NTPDase8 deficient mice were higher than IL-6 levels in wild-type mice with pneumonia. Altogether, the present data indicate that extracellular NTPDases are differentially regulated during sepsis.


The role of verbal labels in the judgment of orientation and location.
In an earlier study it was found that judgments of right-left orientations and locations were more difficult than judgments of up-down only when spatial words were used in the tasks. Experiments are reported in which pictures of many objects were presented to eliminate the possibility that subjects in previous studies had used strategies specific to single-stimulus tasks. In experiment 1, right-left orientations were judged more slowly than up-down orientations both when the spatial words were used and when arbitrary letters replaced the spatial words. In experiment 2, judgments of the right-left locations of pictures took longer than judgments of their up-down locations only when spatial words were used in the task; the right-left difficulty was eliminated when arbitrary letters replaced the words. The differential effect of words and letters in location judgments seems to be due to the different coding strategies adopted by subjects under the two conditions. It is concluded that a right-left difficulty does not depend on the use of spatial terms: word and letter conditions yield different results only when the task permits different judgments to be made under the two conditions.


[Bronchiolar-alveolar carcinoma: From concept to innovative therapeutic strategies].
Bronchioloalveolar carcinoma (BAC) is a primary pulmonary adenocarcinoma (ADC) developped from the terminal respiratory unit. Its restrictive definition adopted by the 1999 WHO pathological classification needs a complete tumor resection to exclude any signs of histological invasion. Although IIIB-IV tumors were excluded from the strict WHO definition of BAC, the first international workshop on BAC in 2004 had focussed on the need to include in the same spectrum of disease pure BAC and ADC with BAC feature (ADC-WBF). BAC and ADC-WBF affect more frequently women, non-smokers and Asian people than other non-small cell carcinoma. Their predominant lepidic and aerogenous tumor progression results in a frequent pneumonic, multifocal or diffuse presentation and explains why death is more frequently related to bilateral pulmonary involvement than extrathoracic metastasis. Natural history is slower and prognosis better than for other ADC. Within this entity, there are different cytological subtypes: mucinous, non-mucinous and mixed and according to them different clinical and biological phenotypes, with different sensitivity to therapeutic agents. At present, the diagnosis, the staging and the therapeutic strategy does not differ from that of non-small lung carcinoma cells. In localized forms, surgical resection remains the best therapeutic option for localized tumors. In diffuse forms, high frequency of epidermal growth factor receptor (EGFR) expression on tumor cells and its gene amplification and/or mutation as well as a particular sensitivity of this entity to EGFR tyrosine kinase inhibitors offer new strategy of therapeutical management in patients with non-resectable tumor. However, the place of chemotherapy has recently been revisited in this entity known until now as chemoresistant tumors. The results are being evaluated. It is necessary to continue therapeutic trials to determine criteria for choosing a first-line TKI or conventional chemotherapy in that entity. Cytological subtype will probably have an important role to play in this choice.


Bibliometric analysis of single-cell sequencing researches on immune cells and their application of DNA damage repair in cancer immunotherapy.
In recent decades, single-cell sequencing technology has developed rapidly and used widely in various fields of life sciences, especially for the detection of immune cells. A bibliometric analysis of single-cell sequencing research work on immune cells published during the 2011-2021 period should provide new insight on the use of single-cell sequencing. We screened 1,460 publications on single-cell sequencing on immune cells according to the publication date, article type, language, and country. The United States published the first and largest number of articles, while China's research started relatively late, but ranked second in the number of publications. T cells were the most commonly studied immune cells by single-cell sequencing, followed by mononuclear macrophages. Cancer biology was the most common field of immune cell research by single-cell sequencing. Single-cell sequencing studies using γδ T cells were mainly in the fields of cancer biology and cell development, and focused over time from cell surface receptor to cell function. Through in-depth analysis of the articles on single-cell sequencing of T cells in the oncology field, our analysis found that immunotherapy and tumor microenvironment were the most popular research directions in recent years. The combination of DNA damage repair and immunotherapy seems to provide a new strategy for cancer therapy.


25-Hydroxycholecalciferol levels in camel, sheep and goat.
1. The plasma levels of 25-hydroxycholecalciferol were measured in female dromedary camels, female sheep and Sinai desert goats. 2. The camels had levels of 443 +/- 96 ng/ml in summer, and 267 +/- 113 ng/ml in winter. 3. The sheep had levels of 40.7 +/- 9.09 ng/ml in summer and 37.1 +/- 8.82 ng/ml in winter, i.e. roughly the same as man in that region. 4. The goats had lower levels: 23.9 +/- 5.67 ng/ml in summer.


Obesity, systemic inflammation, and increased risk for cardiovascular disease and diabetes among adolescents: a need for screening tools to target interventions.
Cardiovascular disease (CVD) and type 2 diabetes mellitus have their roots in childhood, particularly in obese children and adolescents, raising important opportunities for early lifestyle intervention in at-risk individuals. However, not all obese individuals are at the same risk for disease progression. Accurate screening of obese adolescents may identify those in greatest need for intensive intervention to prevent or delay future disease. One potential screening target is obesity-related inflammation, which contributes to insulin resistance, metabolic syndrome, and CVD. In adults, the inflammatory marker high-sensitivity C-reactive protein (hsCRP) has utility for risk stratification and treatment initiation in individuals of intermediate CVD risk. In adolescents, hsCRP shares many of the associations of hsCRP in adults regarding the degree of insulin resistance, metabolic syndrome, and carotid artery media thickness. However, long-term data linking increased hsCRP levels-and increased insulin or decreased adiponectin-in childhood to adult disease outcomes are lacking at this time. Future efforts continue to be needed to identify childhood clinical and laboratory characteristics that could be used as screening tests to predict adult disease progression. Such tests may have utility in motivating physicians and patients' families toward lifestyle changes, ultimately improving prevention efforts.


Play Behavior in Two Captive Bottlenose Dolphin Calves (Tursiops Truncatus): Ethogram, Ontogeny, and Individual Differences.
This research focused on different aspects of play behavior including ethogram, ontogeny, and individual differences, in one male and one female captive bottlenose dolphin calves (Tursiops truncatus) from November 2003 to June 2004. We presented the first peer-reviewed description of a play ethogram in bottlenose dolphin calves whose behaviors were grouped into three hierarchical levels: two categories: solitary and social play; four subcategories: locomotor, object, bubble play, and in the presence of humans, and 35 entries. It was conducted in two phases: the descriptive phase - from 3 to 5 months old - with 29 entries and the quantitative phase - from 6 to 10 months old -with six entries. All social and solitary locomotor behaviors appeared when animals were 3 months old meanwhile more complex behaviors concerning playing with objects, bubbles, and in the presence of humans were observed for 6 months old. There were no statistically significant intra-individual and inter-individual differences in the play behavioral diversity, in the time invested in play and in the Shannon's evenness index. However, we observed statistically significant inter-individual but not intra-individual differences for the Shannon's diversity index.


Functional and ecomorphological evolution of orbit shape in mesozoic archosaurs is driven by body size and diet.
The orbit is one of several skull openings in the archosauromorph skull. Intuitively, it could be assumed that orbit shape would closely approximate the shape and size of the eyeball resulting in a predominantly circular morphology. However, a quantification of orbit shape across Archosauromorpha using a geometric morphometric approach demonstrates a large morphological diversity despite the fact that the majority of species retained a circular orbit. This morphological diversity is nearly exclusively driven by large (skull length > 1000 mm) and carnivorous species in all studied archosauromorph groups, but particularly prominently in theropod dinosaurs. While circular orbit shapes are retained in most herbivores and smaller species, as well as in juveniles and early ontogenetic stages, large carnivores adopted elliptical and keyhole-shaped orbits. Biomechanical modelling using finite element analysis reveals that these morphologies are beneficial in mitigating and dissipating feeding-induced stresses without additional reinforcement of the bony structure of the skull.


Effectiveness of an immediate mitomycin C instillation in patients with superficial bladder cancer receiving periodic mitomycin C instillation.
We analyzed the impact of immediate intravesical mitomycin C instillation after transurethral resection of the bladder (TURB) on tumor recurrence and progression in patients with periodic mitomycin C instillation. Between June 2000 and June 2006, a retrospective study was performed in a total of 115 patients with primary bladder tumors receiving a 6-week course of mitomycin C instillation after TURB. The patients were assigned to two groups: 53 patients in the immediate mitomycin C (I-MMC) group were treated by immediate instillation of mitomycin C after TURB and periodic instillation (6 times, 1 time per week), and 62 patients in the MMC group received only periodic instillation. Tumor recurrence and progression were compared in the two groups. During the mean follow-up period of 46.5 months in the I-MMC group and 47.2 months in the MMC group, early recurrence (within 1 year) occurred in 6 of 53 patients (11.3%) in the I-MMC group and in 18 of 62 patients (29.0%) in the MMC group (p<0.02). Although a significantly lower early recurrence rate was observed in the I-MMC group, this difference was not significant for recurrence within 2 or 3 years or for total recurrence. Progression was not significantly different between the two groups regarding the early and total period. Our study confirmed the positive effect of a single, immediate mitomycin C instillation in patients with non-muscle-invasive bladder tumors who received periodic mitomycin C instillation. This benefit was limited to early recurrence and was not maintained with long-term follow-up. This approach can be an alternative to periodic mitomycin C instillation without immediate instillation.


Re-mapping Robert Rosen's (M,R)-systems.
The central concern of this paper is to re-evaluate Rosen's replicating (M,R)-systems, presented in his book 'Life Itself ', where M and R signify metabolism and repair, respectively. We look anew at Rosen's model of an organism in the light of extensive research into natural hierarchical systems, and the paper presents conclusions drawn from a comparison between Rosen's relational model and that of a birational complementary natural hierarchy. We accept that Rosen's relational model provides a useful stepping stone to understanding the nature of life, but also suggest that it induces potentially digressive conclusions. We conclude that a binary segregation of relational assemblies into mechanisms and organisms is insufficient, and indicate how a threefold segregation throws new light on Rosen's model. An organism is not 'the complement of a mechanism': the complement of a mechanism is its ecosystem. An organism is the 'complex interface' between mechanism and ecosystem.


Nanomaterials: Exfoliating the inorganics.
A versatile method for the production of sheets of inorganic compounds with atomic thickness has been demonstrated.


Dynamic diffraction and interband transitions in two-dimensional photonic lattices.
We reveal a direct link between two fundamental wave phenomena in periodic media, Pendellösung oscillations and resonant coupling between spectral bands. We experimentally measure the power transfer between laser beams associated with the high-symmetry points in periodic and biased hexagonal photonic lattices. As a result, we demonstrate that Pendellösung oscillations dominate the dynamics of resonant interband transitions on a short propagation scale.


Empiric antibiotic use--aztreonam as a model.
Empiric antibiotic therapy, which accounts for over 90 percent of in-hospital therapeutic antibiotic decisions, may be defined as tentative therapy designed to decrease morbidity and mortality associated with severe infection due to unidentified bacterial pathogens. In the 48- to 72-hour interim between presentation and the availability of reliable culture and sensitivity data that allow for definitive therapy, empiric therapy is extremely important. Aztreonam, the first member of the monobactam class of monocyclic beta-lactam antibiotics, is highly active against most gram-negative aerobic bacteria, including Pseudomonas aeruginosa. Its spectrum of activity is similar to that of the aminoglycosides but without the toxicity associated with those agents. For this reason, aztreonam may play an important role in empiric therapy. Currently, it can be recommended as single-agent empiric therapy only for severe urinary tract infections, but in combination with a variety of other agents, it has proved useful against a wide range of bacterial infections, and in certain subgroups, such as penicillin-allergic patients, it may represent the treatment of choice. It is not yet clear whether aztreonam is superior to other relatively nontoxic agents, such as the third-generation cephalosporins or carbapenems, but there is little doubt that this new agent is a generally safe and effective drug for the treatment of suspected gram-negative sepsis.


Infertility and the Risk of Cardiovascular Disease: Findings From the Study of Women's Health Across the Nation (SWAN).
Cardiovascular disease (CVD) is the leading cause of death in women globally. In recent years, attention has turned to infertility and pregnancy-related events as potential markers for early mortality and future CVD. The Study of Women's Health Across the Nation (SWAN) is an ongoing longitudinal cohort study of women's health. Women aged 42-52 years with a uterus and ≤ 1 intact ovary, a menstrual period, and no hormone medications within 3 months before enrollment were eligible. Infertility was self-reported and defined as the inability to achieve pregnancy after 12 months of trying to conceive, or use of fertility medications for > 1 month. Outcomes included development of metabolic syndrome over a 7-year follow-up, and any atherosclerotic CVD event (ie, stroke, angina, myocardial infarction) over a 10-year follow-up. Cox proportional hazards models were used to calculate hazard ratios (HRs) for metabolic syndrome and CVD events in participants with infertility, with adjustment for relevant covariates. Participants without infertility were used as the comparison group. We included 2370 participants in the analysis of metabolic syndrome risk, and 2809 participants were included in the analysis of CVD event risk. Participants with self-reported infertility did not have a higher risk of developing metabolic syndrome (HR, 0.91; 95% confidence interval, 0.71-1.15) or experiencing CVD events (HR, 0.79; 95% confidence interval, 0.52-1.21) after adjusting for relevant covariates. Infertility was not associated with development of metabolic syndrome or CVD events in women; further research is required to investigate the effects of specific causes of infertility and fertility treatments on CVD outcomes.


Evaluation of diallate and triallate herbicides for genotoxic effects in a battery of in vitro and short-term in vivo tests.
Commercial-grade preparations of two thiocarbamate herbicides, diallate and triallate, were evaluated for their mutagenic potential in a battery of short-term bioassays. All in vitro bioassays were performed with and without mammalian metabolic activation, and all such tests were repeated after an interval of at least 1 week. Diallate and triallate were tested in the Salmonella/microsome assay over dose ranges of 0.59 to 118.0 micrograms/plate and 6.37 to 1273 micrograms/plate, respectively. Both diallate and triallate gave positive results in S. typhimurium strains TA1535, TA98, and TA100 only in the presence of a rat-liver metabolic activation system. In Saccharomyces cerevisiae strain D7, diallate was tested at concentrations from 1.18 to 29.50 micrograms/ml, and triallate was tested at 0.955 to 9.548 micrograms/ml. Both diallate and triallate gave negative results for mitotic gene conversion, mitotic crossing-over, and reverse mutation. In the mouse lymphoma L5178Y TK+/- assay, diallate was tested at concentrations ranging from 1 to 72 micrograms/ml, and triallate was tested at 0.5 to 60 micrograms/ml. Both herbicides produced mutagenic responses in the mouse lymphoma assay in the presence of metabolic activation. In the Drosophila sex-linked recessive lethal test, flies were exposed to 0.0004% diallate and 0.001% triallate. In this assay, diallate was considered mutagenic, whereas triallate did not produce a detectable mutagenic response.


Alveolar capillary dysplasia associated with duodenal atresia: ultrasonographic findings of enlarged, highly echogenic lungs and gastric dilatation in a third-trimester fetus.
We report a case of alveolar capillary dysplasia, wherein duodenal atresia was diagnosed during the third trimester. A 36-year-old mother was referred to our hospital for polyhydramnios at 31 weeks' gestation. Duodenal atresia was suspected from the ultrasonographic findings, which showed gastric dilation. Other findings noted were enlarged, highly echogenic lungs, a spherical heart and an increased lung-thorax transverse area ratio. A male infant was born at 37 weeks' gestation. The findings of serial radiography of the infant's upper gastrointestinal tract were compatible with the diagnosis of duodenal atresia; however, he developed persistent pulmonary hypertension of the newborn eight hours after birth and died at five days of age. The autopsy revealed alveolar capillary dysplasia and duodenal obstruction. We propose that the detection of duodenal atresia should prompt the physician to conduct a thorough ultrasonographic examination to rule out associated anomalies, such as alveolar capillary dysplasia, which can be detected by the presence of highly echogenic lungs.


Ru(II) complexes of N4 and N2O2 macrocyclic Schiff base ligands: their antibacterial and antifungal studies.
Reactions of [RuCl2(DMSO)4] with some of the biologically active macrocyclic Schiff base ligands containing N4 and N2O2 donor group yielded a number of stable complexes, effecting complete displacement of DMSO groups from the complex. The interaction of tetradentate ligand with [RuCl2(DMSO)4] gave neutral complexes of the type [RuCl2(L)] [where L=tetradentate macrocyclic ligand]. These complexes were characterized by elemental, IR, 1H, 13C NMR, mass, electronic, thermal, molar conductance and magnetic susceptibility measurements. An octahedral geometry has been proposed for all complexes. All the macrocycles and macrocyclic Ru(II) complexes along with existing antibacterial drugs were screened for antibacterial activity against Gram +ve (Bacillus subtilis, Staphylococcus aureus) and Gram -ve (Escherichia coli, Klebsiella pneumonia) bacteria. All these compounds were found to be more active when compared to streptomycin and ampicillin. The representative macrocyclic Schiff bases and their complexes were also tested in vitro to evaluate their activity against fungi, namely, Aspergillus flavus and Fusarium species.