Attenuation of MPTP neurotoxicity by rolipram, a specific inhibitor of phosphodiesterase IV.
Rolipram, a specific inhibitor of the phosphodiesterase IV (PDE IV), has recently been shown to exert neuroprotective effects in an Alzheimer transgenic mouse model and in hypoxic-ischemic damage in the rat brain. It activates the cAMP-dependent protein kinase (PKA)/cAMP regulatory element-binding protein (CREB) signaling pathway and it inhibits inflammation. We tested the neuroprotective effects of the specific PDE IV inhibitor rolipram in C57BL/6 mice treated with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). We found that rolipram administered at 1.25 mg/kg or 2.5 mg/kg doses significantly attenuated MPTP-induced dopamine depletion in the striatum, and reduced the loss of tyrosine hydroxylase-positive neurons in the substantia nigra. There was a bell-shaped dose effect with greater efficacy at the 1.25 mg/kg dose than 2.5 mg/kg and a higher dose of rolipram, 5 mg/kg, had no protective effect and even increased the mortality of animals when co-administered with MPTP. Rolipram did not interact with MPTP in its absorption into the brain and in its metabolism to 1-methyl-4-phenylpyridinium (MPP(+)). Our data show a neuroprotective effect of the PDE IV specific inhibitor rolipram against dopaminergic neuron degeneration, suggesting that PDE IV inhibitors might be a potential treatment for Parkinson's disease.


Clinical implications of self-neglect among patients in community settings.
The consequences of self-neglect can be wide-reaching and devastating, not only for patients themselves but also for their wider community, including assisting health practitioners and social care staff. Supporting patients in the context of self-neglect requires extensive multi-agency collaboration in order to gain a full understanding and a workable management strategy for the individual. Because community nurses see patients in their own homes, they are well placed to identify and address self-neglect. This article explores the definition, signs and causes of self-neglect, with issues of particular relevance for community nursing staff. The understanding and assessment of mental capacity, which is often complex and challenging, is also discussed, as well as the involvement of the safeguarding team where necessary.


Robot-assisted laparoscopic Mitrofanoff appendicovesicostomy technique and outcomes of extravesical and intravesical approaches.
With growing experience in pediatric robotic surgery, select centers are now performing robot-assisted, laparoscopic Mitrofanoff appendicovesicostomy (RALMA). We present our technique and outcomes of RALMA with or without enterocystoplasties and compare stomal outcomes between two different approaches of the appendicovesical anastomosis: an extravesical (EV) anterior bladder approach and an intravesical (IV) posterior bladder approach. Data from 18 children who have undergone RALMA since 2008 were retrospectively reviewed. RALMA was performed by one surgeon in an academic setting. The appendix was anastomosed on the posterior wall of the bladder intravesically when concomitant enterocystoplasty was done. Otherwise, the appendix was anastomosed extravesically on the anterior wall of the bladder. The primary outcome measured was the overall continence rate. Secondary outcomes included the overall complication rate and stomal complications. The entire cohort included 18 patients (10 IV, 8 EV). The mean overall operative time was 494.1 min. The mean overall length of hospitalization was 5.2 d. There were five immediate, postoperative complications (all Clavien grade 1): three postoperative ilea, one stomal site infection, and one clogged suprapubic catheter. Median follow-up was 24.2 mo. The overall stomal continence rate was 94.4%. One patient from the IV group required dextranomer/hyaluronic acid copolymer for stomal incontinence. Among the eight patients in the EV cohort, there was one stomal complication of stomal stenosis (Clavien grade 1). Among the 10 patients in the IV cohort, there were two stomal complications requiring revisions (both Clavien grade 3): parastomal hernia and stomal stenosis. Limitations of the study include retrospective design, small number of patients, and lack of direct comparison of approaches given the nature of the surgery. Our updated outcomes of RALMA with or without enterocystoplasty continue to be encouraging, with a 94.4% continence rate. We believe that anterior EV reimplantation is a feasible option in isolated RALMA.


Alteration in the sensitivity of GABA(A) receptors to allosteric modulatory drugs in rat hippocampus after chronic intermittent ethanol treatment.
Chronic intermittent ethanol (CIE)-treated rats exhibited a kindling-like persistent increase in withdrawal hyperexcitability. The alteration of GABA(A) receptor (GABA(A)R) function in the hippocampus was suggested as a possible mechanism underlying the hyperexcitability observed in CIE rats, because (1) GABA(A)R agonist (muscimol)-evoked 36Cl- efflux was decreased; (2) paired-pulse inhibition in the CA1 area, predominantly due to GABA(A)R-mediated recurrent inhibition, was persistently decreased; and (3) GABA(A)R subunit expression was altered in the hippocampus from CIE rats. To further characterize the functional alteration of GABA(A)R after CIE treatment, their sensitivity to acute ethanol, a steroid anesthetic (alphaxalone), and a benzodiazepine inverse agonist (DMCM; methyl-6,7-dimethoxy-4-ethyl-beta-carboline-3-carboxylate) were studied using either synaptically evoked GABA(A)R responses or exogenously applied muscimol-evoked responses in hippocampal slices. Bath application of ethanol (60 mM) enhanced the area of GABA(A)R-mediated inhibitory postsynaptic potentials in the hippocampal CA1 region from control and CIE rats, and this potentiation was significantly (p = 0.027) greater in CIE rats (98%) than in control rats (53%). The positive modulatory effect of alphaxalone (1 microM) on GABA(A)R-inhibitory postsynaptic potentials was not significantly different between control and CIE rats (p = 0.375), whereas alphaxalone allosterically increased [3H]flunitrazepam binding in the CA1 area only in CIE rats (by 20 to 25%, p < 0.01), but not in controls. On the other hand, the negative modulatory effect of DMCM (1 microM) on muscimol-evoked responses was significantly larger in CIE rats (p = 0.002). These results suggest that the sensitization of GABA(A)R to acute ethanol and benzodiazepine inverse agonists, and possibly neurosteroids, may underlie ethanol dependence after multiple ethanol withdrawal episodes. These altered pharmacological properties are most consistent with changes in the subunit composition in the CA1 area of this rat model of alcohol dependence.


Identification of insulin receptors on the mucosal surface of colon epithelial cells.
Brush-border membranes were isolated from the mucosal surface of rabbit proximal colon epithelial cells by a procedure involving Ca2+ precipitation. Ouabain-insensitive K+-phosphatase, a marker enzyme for the colon brush-border membrane, was enriched 17-fold by this technique, while no enrichment was observed in the activity of ouabain-sensitive K+-phosphatase, a marker for the basal-lateral membrane. Insulin binding studies revealed a dose-dependent inhibition of 125I-insulin binding with porcine insulin and approximately 4 X 10(-9) M insulin was required to produce 50% inhibition of 125I-insulin binding, while desoctapeptide insulin, insulin-like growth factor I, and A chain of insulin had less effect on 125I-insulin binding. This is the first demonstration of the existence of high-affinity insulin binding sites on the brush-border membrane of mammalian colon epithelial cells. Subsequent studies with the cross-linking agent disuccinimidyl suberate confirmed the presence of insulin binding sites in these membranes and autoradiography of polyacrylamide gels revealed that the binding subunit of the colon epithelial cell brush-border insulin receptor is similar in size to that observed in hepatic tissue. Interestingly, the insulin binding capacity/mg of protein of this preparation is high, suggesting that large numbers of insulin receptors are present in vivo on the mucosal surface of colon epithelial cells. The potential physiological role of these previously unrecognized insulin receptors is discussed.


Investigation of a screening programme and the possible identification of biomarkers for early disseminated histiocytic sarcoma in Bernese Mountain dogs.
The aim of the study was to construct a screening programme for disseminated histiocytic sarcoma (DHS) in Bernese Mountain dogs using diagnostic imaging and blood analysis and evaluate blood borne biomarkers as early disease detection biomarkers. Healthy Bernese Mountain dogs were screened on four occasions in an attempt to detect early disease. Eleven blood borne biomarkers were examined for their worth as early tumour biomarkers. During 2.5 years, five dogs with early DHS were identified; four of these by diagnostic imaging. No dogs developed symptomatic DHS without being detected within 6 months of the screening programme. Only serum ferritin showed potential as a blood borne marker of the disease. Median survival times for the dogs with early DHS were 226 days. Screening programmes every 6 months for Bernese Mountain dogs over 4 years of age including diagnostic imaging and ferritin measurements may identify early DHS.


In vivo and in vitro metabolism of dexamethasone in the camel.
The metabolism of dexamethasone (DXM) in the camel was assessed by in vivo and in vitro techniques. Liver samples were collected at the abattoir from camels of either sex, and microsomes were isolated and characterized as to their protein and haemoprotein content as well as for their ability to metabolise several cytochrome P450 model substrates. The expression of different P450 enzymes was evaluated by means of immunoblotting, and the glucuronidating capacity was assessed with 1-naphthol as the substrate. The activity of 11 beta-hydroxysteroid dehydrogenase type 1 was assayed using metyrapone as a model substrate. To examine the in vitro metabolism of DXM, microsomes were incubated with the corticoid in the presence of either a NADPH-generating system or of uridindiphosphoglucuronic acid. In vivo metabolism of DXM was studied in two male camels, injected with a bolus intravenous dose of DXM (0.2 mg/kg body weight) and DXM metabolites were evaluated in urine samples collected at different times after the administration. DXM and metabolites were extracted using solid phase and liquid-liquid extraction, and analysed by liquid chromatography mass spectrometry (LC/MS) and by LC/MS/MS. Comparative results were obtained by in vitro and in vivo studies. Two phase I metabolites were detected: the major one resulted from reduction of the 3-carbonyl group in ring A and the minor metabolite from ring hydroxylation of ring A. Glucuronidation involved both phase I metabolites as well as the parent compound.


Establishment and first experiences of the National Serum Depot in the Netherlands.
Since 2008, a National Serum Depot is operational in the Netherlands, guaranteeing antivenom supply, 24 h per day, during medical emergencies. In this article the organisation structure, choice of antivenoms, problems encountered during the establishment, and the results from establishment in 2008 till December 2011 are discussed. The Serum Depot is organised by the National Institute for Public Health and the Environment in cooperation with the Dutch National Poisons Information Center. During establishing and maintaining of the Serum Depot several antivenom purchase difficulties were encountered. Some antivenom producers did not respond upon (initial) contact and some antivenoms were (temporarily) unavailable. Good contacts with professional herpetologists are necessary in order to keep the content of the depot up-to-date. At the same time, it is important to remain well informed concerning the safety and efficacy of the currently available antivenoms and development of new antivenoms. During the first four years of the National Serum Depot, the Dutch National Poisons Information Center was consulted on average 10 times a year about exotic venomous bites and stings in which antivenom treatment might play a role. Almost half of these consultations were related to bites by venomous exotic snakes, the other half to scorpion and fish stings. Antivenom was delivered in five cases, all after a bite by an exotic venomous snake, and actually administered twice because of the severity of local effects. To reduce costs and extend coverage of the Serum Depot of antivenoms for more unfamiliar snake species, international cooperation between the various owners of the antivenom Serum Depots in Europe is recommended.


[Therapeutic effectiveness of gentamycin and rifampicin in experimental staphylococcal-Pseudomonas aeruginosa infection and their effect on immunological processes].
The survival level of the experimental animals with infection caused by Staphylococcus and Ps. aeruginosa was the highest when the animals were treated with a combination of gentamicin and rifampicin as compared to the use of every antibiotic alone. The combination had a more favourable effect on the plasmocytic reaction and production of the antibody-forming cells in the lymphoid organs which correlated with the therapeutic efficacy of the antibiotics.


The effect of epithelium removal on leukotriene E4-induced histamine hyperresponsiveness in guinea-pig tracheal smooth muscle.
1. Removal of the epithelium resulted in a threefold increase in guinea-pig tracheal sensitivity to histamine without increasing the maximal response. 2. Preincubation of epithelially-denuded guinea-pig tracheal smooth muscle with leukotriene E4 (LTE4) in vitro increased the subsequent maximal response of the tissues to histamine. The sensitivity of the tissues to histamine was unaffected by LTE4 pretreatment. 3. Pretreatment of the epithelially-denuded tissues with the LTE4-analogue, 20-COOH LTE4, did not affect the maximal response to histamine. 4. LTE4 pretreatment increased the maximal response of the epithelially-denuded tissues to substance P (SP) but did not affect the maximal response to carbachol, KCl nor to the beta-adrenoceptor agonist, isoprenaline. 5. LTE4-induced airway histamine hyperresponsiveness was blocked by indomethacin (5 microM), GR32191 (3 microM) and atropine (1 microM). 6. Both LTE4 and U46619 pretreatment increased the contractile response of tracheal smooth muscle to electrical field stimulation. 7. It is proposed that LTE4 induces an increased maximal response of epithelially-denuded guinea-pig airway smooth muscle to both histamine and substance P via a facilitation of cholinergic neurotransmission, which is dependent upon the secondary generation of prostanoid mediator(s) acting on TP-receptors situated on cholinergic nerve terminals. Further, it is suggested that the increased maximal response of the epithelially-intact tissues to both histamine and substance P, after LTE4 pretreatment, may be suppressed by an epithelially-derived factor.


Factors predicting age at menopause among Iranian women in the Bandare-Kong cohort study (a cross-sectional survey of PERSIAN cohort study).
Menopause is a natural period in women's life and can be affected by several factors. The aim of this study was to identify the associated factors for age of natural menopause and among women with early and premature menopause based on a cohort study in Iran. This population-based study was conducted on 894 post menopause women between 35 and 70 years old who participated in the Bandare-Kong Non-Communicable Diseases (BKNCD) Cohort Study, a part of Prospective Epidemiological Research Studies in Iran (PERSIAN) from March 2016 to February 2019. All women completed a standard self-reported questionnaire. Data were analyzed using chi-square test, independent t test, and ANOVA as well as a multivariable linear regression model. The mean age at natural menopause was 48.31 ± 6.34 years. After adjusting other variables, gravida, history of cardiac disease, socioeconomic status and residence status were predictive of age at menopause (P < 0.001). Among the premature menopause group, the mean age at menopause was significantly higher among women with diabetes compared to women without diabetes group (35.68 ± 2.92 vs. 33.82 ± 3.06; P = 0.043), while the mean age at menopause was significantly lower in women with infertility compared to women without infertility (29.13 ± 5.22 vs. 34.84 ± 2.826; P = 0.048). This study suggests that the predictors of menopausal age differed in women with premature menopause compared to overall menopause age. Prospective studies are needed to evaluation the effects of these factors on menopausal age.


In search of optimal resilience ratios: Differential influences of neurobehavioral factors contributing to stress-resilience spectra.
The ability to adapt to stressful circumstances, known as emotional resilience, is a key factor in the maintenance of mental health. Several individual biomarkers of the stress response (e.g., corticosterone) that influence an animal's position along the continuum that ranges from adaptive allostasis to maladaptive allostatic load have been identified. Extending beyond specific biomarkers of stress responses, however, it is also important to consider stress-related responses relative to other relevant responses for a thorough understanding of the underpinnings of adaptive allostasis. In this review, behavioral, neurobiological, developmental and genomic variables are considered in the context of emotional resilience [e.g., explore/exploit behavioral tendencies; DHEA/CORT ratios and relative proportions of protein-coding/nonprotein-coding (transposable) genomic elements]. As complex and multifaceted relationships between pertinent allostasis biomediators are identified, translational applications for optimal resilience are more likely to emerge as effective therapeutic strategies.


[Study of the effect of dopamine on renal excretion in chronic renal failure (author's transl)].
The effects of dopamine on renal excretory function were studied in 20 patients with chronic renal failure (plasma creatinine higher than 30 mg/i). Effects were marked at a dose of 2 micrograms/kg/mn and were no greater at a dose of 5 micrograms/kg/mn (10 subjects in each case). In general, creatinine clearance increased by 28%, urea excretion by 45%, urine output by 77% and urinary sodium output by 164%. In ten patiens with terminal renal failure (plasma creatinine greater than 100 mg/i), the effects of dopamine were maintained. In these individuals, furosemide (250 mg by single intravenous injection) resulted in a higher total urine and urinary sodium output but had a less favourable effect upon creatinine.


The first isolation of Newcastle disease virus (NDV) from free-flying birds in Israel: comparative studies on NDV strain isolated from migrating starlings (Sturnus vulgaris) wintering in Israel.
An NDV strain was isolated in Israel from a starling suffering from severe neurological affections. The strain appeared to be lentogenic to chickens, its hemagglutinin being thermostable and active toward horse erythrocytes. Comparative studies including LaSota and B1 NDV reference strains showed that the isolate is not a vaccinal strain used for vaccination in the country.


Thoracoplasty for treatment of asphyxiating thoracic dysplasia in a newborn.
In our case report and literature review, we report about a female newborn with severe asphyxiating thoracic dysplasia of the spondylocostal dysostosis classification to whom an expandable thoracoplasty with metal implants offered survival and discharge at home from newborn to infancy.


Model-Free Linkage Analysis of a Quantitative Trait.
Model-free methods of linkage analysis for quantitative traits are a class of easily implemented, computationally efficient and statistically robust approaches to searching for linkage to a quantitative trait. By "model-free" we refer to methods of linkage analysis that do not fully specify a genetic model (i.e., the causal allele frequency, and penetrance functions). In this chapter we briefly survey the methods that are available, and then we discuss the necessary steps to implement an analysis using the programs GENIBD, SIBPAL and RELPAL in the S.A.G.E. (Statistical Analysis for Genetic Epidemiology) software suite.


Sporulation and spore stability of Bacillus megaterium enhance Ketogulonigenium vulgare propagation and 2-keto-L-gulonic acid biosynthesis.
Bacillus spp. is widely used as the companion bacterium in the two-step biosynthesis of 2-keto-L-gulonic acid (2-KLG), which is the direct precursor in the production of vitamin C by Ketogulonigenium vulgare. To understand the effects of sporulation and spore stability on 2-KLG production, the spo0A and spoVFA deletion mutants of Bacillus megaterium were constructed. The sorbose conversion rates of spo0A and spoVFA mutant co-culture systems were 33% and 70% lower, respectively, than that of the wild-type co-culture system. In addition, K. vulgare cell numbers in the two mutant systems declined by 15% and 49%, respectively, compared to the value in the wild-type system. Correlation analysis indicated that the 2-KLG concentration is positively related to sorbose dehydrogenase activity and the K. vulgare cell number. This study demonstrated that sporulation and spore stability of the wild-type companion play key roles in the enhancement of K. vulgare propagation and 2-KLG biosynthesis.


Rare fetal monster in Holstein crossbred cow.
This report describes a rare case of conjoined female twin monster (Monocephalus Thoracopagus Tetrabrachius Tetrapus Dicaudatus) in a Holstein Friesian pluriparous crossbred cow.


Nanoparticles deliver triplex-forming PNAs for site-specific genomic recombination in CD34+ human hematopoietic progenitors.
Triplex-forming peptide nucleic acids (PNAs) are powerful gene therapy agents that can enhance recombination of short donor DNAs with genomic DNA, leading to targeted and specific correction of disease-causing genetic mutations. Therapeutic use of PNAs is severely limited, however, by challenges in intracellular delivery, particularly in clinically relevant targets such as hematopoietic stem and progenitor cells. Here, we demonstrate efficient and nontoxic PNA-mediated recombination in human CD34(+) cells using poly(lactic-co-glycolic acid) (PLGA) nanoparticles for intracellular oligonucleotide delivery. Treatment of progenitor cells with nanoparticles loaded with PNAs and DNAs targeting the β-globin locus led to levels of site-specific modification in the range of 0.5-1% in a single treatment, without detectable loss in cell viability, resulting in a 60-fold increase in modified and viable cells as compared to nucleofection. As well, the differentiation capacity of the progenitor cells treated with nanoparticles did not change relative to untreated progenitor cells, indicating that nanoparticles are safe and minimally disruptive delivery vectors for PNAs and DNAs to mediate gene modification in human primary cells. This is the first demonstration of the use of biodegradable nanoparticles to deliver genome-editing agents to human primary cells, and provides a strong rationale for systemic delivery of complex nucleic acid mixtures designed for gene correction.


Novel variants of CYP21A2 in Vietnamese patients with congenital adrenal hyperplasia.
Congenital adrenal hyperplasia (CAH) (OMIM #201910) is a complex disease most often caused by pathogenic variant of the CYP21A2 gene. We have designed an efficient multistep approach to diagnose and classify CAH cases due to CYP21A2 variant and to study the genotype-phenotype relationship. A large cohort of 212 Vietnamese patients from 204 families was recruited. We utilized Multiplex Ligation-dependent Probe Amplification to identify large deletion or rearrangement followed by complete gene sequencing of CYP21A2 to map single-nucleotide changes and possible novel variants. Pathogenic variants were identified in 398 out of 408 alleles (97.5%). The variants indexed span across most of the CYP21A2 gene regions. The most common genotypes were: I2g/I2g (15.35%); Del/Del (14.4%); Del/I2g (10.89%); p.R356W/p.R356W (6.44%); and exon 1-3 del/exon 1-3 del (5.44%). In addition to the previously characterized and documented variants, we also discovered six novel variants which were not previously reported, in silico tools were used to support the pathogenicity of these variants. The result will contribute in further understanding the genotype-phenotype relationship of CAH patients and to guide better treatment and management of the affected.


Left ventricular assist devices: physiologic assessment using echocardiography for management and optimization.
Left ventricular assist devices (LVAD) are being deployed increasingly in patients with severe left ventricular dysfunction and medically refractory congestive heart failure of any etiology. The United States Food and Drug Administration (FDA) recently approved the use of the Thoratec Heartmate II (Thoratec Corporation, Pleasanton, CA, USA) for outpatient use. Echocardiography is fundamental during each stage of patient management, pre-LVAD placement, during LVAD placement, for postoperative LVAD optimization and long-term follow-up. We present a pragmatic and systematic echocardiographic approach that serves as a guide for the management of left ventricular assist devices.


Prior Lumbar Spinal Fusion is Associated With an Increased Risk of Dislocation and Revision in Total Hip Arthroplasty: A Meta-Analysis.
The biomechanical relationship between the lumbar spine and the hip is well-documented. It follows that fusing the lumbar spine would have implications on the outcomes of total hip arthroplasty (THA). This study aimed to determine the effect of preexisting lumbar spinal fusion surgery on the outcomes of THA by synthesizing the available evidence via systematic review and meta-analysis. A systematic review with meta-analysis was performed in accordance to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Electronic searches were performed in 6 different databases for studies comparing outcomes in patients after THA with or without a history of lumbar fusion. Studies were required to report at least one outcome out of dislocation, revision due to hip instability or patient-reported outcomes. Patients with a history of lumbar spinal fusion are at a significantly increased risk of dislocation (relative risk 2.03, P < .00001) and revision (relative risk 3.36, P = .006) after THA. Patient-reported outcomes were also poorer in patients with prior lumbar fusion compared with those without, although meta-analysis could not be performed due to heterogeneity in the outcome measure used between studies. Previous lumbar spinal fusion increases risk of dislocation and revision, and may negatively impacts patient-reported outcomes after THA. Orthopaedic surgeons should pay particular attention to these patients and could use patient-specific planning, instrumentation, and targeted counselling to optimize clinical and subjective outcomes. Future studies could clarify the impact of prior fusion on patient-reported outcomes after THA.


D1 and D2 dopamine receptor mediation of amphetamine-induced acetylcholine release in nucleus accumbens.
To assess the interaction of dopamine and acetylcholine systems in the rat nucleus accumbens in response to direct D-amphetamine administration, in vivo microdialysis measures of acetylcholine were used during reverse dialysis of amphetamine alone and in combination with D1 and D2 receptor antagonists SCH 23390 and sulpiride, respectively. During a 15-min exposure to amphetamine (50 microM) in the nucleus accumbens, acetylcholine increased to 33% above pre-infusion levels, became maximal at 15 min post-infusion (+41%) and gradually returned to baseline levels by 60 min post-amphetamine. Conversely, amphetamine (1 mM) administration caused a biphasic change in acetylcholine release with a trend toward a decrease (-14%) during exposure followed by a significant increase (+36%) at 30 min post-amphetamine that returned to baseline levels by 60 min after infusion. The increases observed during amphetamine (50 microM) exposure and during recovery from amphetamine (1 mM) were both blocked by co-administration with the D1 antagonist, SCH 23390 (10 microM), but not with the D2 antagonist, sulpiride (10 microM). Co-infusion of sulpiride eliminated the trend toward reduced acetylcholine release observed during 1 mM amphetamine whereas co-administration of SCH 23390 potentiated this decrease. A possible tonic D1 facilitation of nucleus accumbens acetylcholine release was indicated by the consistent reductions in acetylcholine release observed during infusion of SCH 23390. These results suggest that amphetamine administration in the nucleus accumbens induces a bidirectional change in acetylcholine release that is dependent on dose and opposing effects of nucleus accumbens D1 and D2 activation. In general, relatively low doses of amphetamine administered into the nucleus accumbens caused an increase in acetylcholine release that was dependent on dopamine D1 receptors whereas higher doses of amphetamine resulted in a D2-mediated decrease.


(68)Ga-PSMA ligand PET/CT in patients with prostate cancer: How we review and report.
Recently, positron emission tomography (PET) imaging using PSMA-ligands has gained high attention as a promising new radiotracer in patients with prostate cancer (PC). Several studies promise accurate staging of primary prostate cancer and restaging after biochemical recurrence with (68)Ga-PSMA ligand Positron emission tomography/computed tomography (PET/CT). However, prospective trials and clinical guidelines for this new technique are still missing. Therefore, we summarized our experience with (68)Ga-PSMA ligand PET/CT examinations in patients with primary PC and biochemical recurrence. It focuses on the technical and logistical aspects of (68)Ga-PSMA ligand PET/CT examination as well as on the specific background for image reading discussing also potential pitfalls. Further, it includes relevant issues on free-text as well as structured reporting used in daily clinical routine.


Mucosal tonometry as early warning of gastrojejunal leak in laparoscopic Roux-en-y gastric bypass.
The laparoscopic Roux-en-Y gastric bypass (LRYGB) is the standard surgical procedure for morbidly obese patients in many centers worldwide. The gastrojejunal anastomosis (GJA) leak has a 2 % incidence and a 10 % mortality. This prospective study aims to test gastroenteric tonometry as an early warning of GJA leak risk. A nasogastric tube with tonometric capability was used to monitor gastroenteric mucosal carbon dioxide partial pressure (PgeCO2) in 32 consecutive patients during the first 24 to 72 postoperative hours after LRYGB. Sensitivity was 100 %, specificity 96.77 %, likelihood ratio 31, and area under receiver operating characteristic curve 0.984. The only early gastrojejunal leak occurred to the patient with maximal PgeCO2 (13.9 kPa) of the cohort. The remaining patients kept a PgeCO2 below 11 kPa except one; none of these developed early GJA leak. Mucosal gastroenteric tonometry may be a useful predictor of early GJA leak of the LRYGB.


The interaction between mitochondria and oncoviruses.
Mitochondria play important roles in multiple aspects of viral tumorigenesis. Mitochondrial genomes contribute to the host's genetic background. After viruses enter the cell, they modulate mitochondrial function and thus alter bioenergetics and retrograde signaling pathways. At the same time, mitochondria also regulate and mediate viral oncogenesis. In this context, oncogenesis by oncoviruses like Hepatitis B virus (HBV), Hepatitis C virus (HCV), Human papilloma virus (HPV), Human Immunodeficiency virus (HIV) and Epstein-Barr virus (EBV) will be discussed.


Letter to the Editor Concerning Skuk et al., "Parameter-Specific Morphing Reveals Contributions of Timbre and Fundamental Frequency Cues to the Perception of Voice Gender and Age in Cochlear Implant Users".
Purpose The purpose of this letter is to compare results by Skuk et al. (2020) with Meister et al. (2016) and to point to a potential general influence of stimulus type. Conclusion Our conclusion is that presenting sentences may give cochlear implant recipients the opportunity to use timbre cues for voice perception. This might not be the case when presenting brief and sparse stimuli such as consonant-vowel-consonant or single words, which were applied in the majority of studies.


Prevalence, trend and disparities of palliative care utilization among hospitalized metastatic breast cancer patients who received critical care therapies.
Early integration of palliative care (PC) for patients with advanced cancer has been recommended to improve quality of care. This study aims to describe prevalence, temporal trend and predictors of PC use in metastatic breast cancer (mBCa) patients receiving critical care therapies (CCT; included invasive mechanic ventilation, percutaneous endoscopic gastrostomy tube, total parenteral nutrition, tracheostomy and dialysis). The National Inpatient Sample was queried for mBCa patients receiving CCT between 2005 and 2014. Annual percent changes (APC) were calculated for PC prevalence in the overall cohort and subgroups. Multivariable logistic analysis was used to explore predictors of PC use. Of 5833 mBCa patients receiving CCT, 880 (15.09%) received PC. Rate of PC use increased significantly from 2.53% in 2005 to 25.96% in 2014 (APC: 35.75%; p < 0.0001). Higher increase in PC use was observed in South (from 0.65% to 27.11%; APC: 59.42%; p < 0.0001), medium bedsize hospitals (from 3.75% to 26.05%; APC: 38.16%; p = 0.0006) and urban teaching hospitals (from 4.13% to 29.86%; APC: 37.33%; p = 0.0005). Multivariable analysis revealed that year interval, urban teaching hospitals, and invasive mechanical ventilation were associated with increased PC use, while primary diagnosis of gastrointestinal disorders, fractures, metastatic sites from lymph nodes and tracheostomy were associated with lower PC use. PC use in mBCa patients receiving CCT increases significantly over the period. However, it still remains low. Efforts to illustrate disparities in PC use are needed to improve quality of care for mBCa patients receiving CCT, especially for those hospitalized in rural and nonteaching hospitals.


Antibody mimetic drug conjugate manufactured by high-yield Escherichia coli expression and non-covalent binding system.
Antibody-drug conjugates (ADCs) are a major therapeutic tool for the treatment of advanced cancer. Malignant cells in advanced cancer often display multiple genetic mutations and become resistant to monotherapy. Therefore, a therapeutic regimen that simultaneously targets multiple molecules with multiple payloads is desirable. However, the development of ADCs is hampered by issues in biopharmaceutical manufacturing and the complexity of the conjugation process of low-molecular-weight payloads to biologicals. Here, we report antibody mimetic-drug conjugates (AMDCs) developed by exploiting the non-covalent binding property of payloads based on high-affinity binding of mutated streptavidin and modified iminobiotin. Miniprotein antibodies were fused to a low immunogenic streptavidin variant, which was then expressed in Escherichia coli inclusion bodies, solubilized, and refolded into functional tetramers. The AMDC developed against human epidermal growth factor receptor 2 (HER2) effectively killed cultured cancer cells using bis-iminobiotin conjugated to photo-activating silicon phthalocyanine. The HER2-targeting AMDC was also effective in vivo against a mouse KPL-4 xenograft model. This AMDC platform provides rapid, stable, and high-yield therapeutics against multiple targets.


Trauma management in ancient Greece: value of surgical principles through the years.
This article surveys in an interdisciplinary fashion the evolution of ancient Greek medicine and traumatology in particular. In sounding out the key methods and themes of Greek medicine, we cite a range of medical treatises and correlate them to the rich evidence of ancient Greek art (iconography), which often is explicit in its depiction of the management of disease and of trauma in particular. The article begins its survey from Homer, our first source of medical information, and highlights the pioneering work of Hippocrates and the secularized professional guild of the "sons of Aesclepius."


Electrophysiological study of myopia.
To investigate the characteristics of retinal function in myopia using full-field electroretinogram (ERG) and multifocal ERG (MF-ERG) and to determine the correlation among MF-ERG, ocular axis length, retinal thickness and degree of myopia. Twenty emmetropes (20) and sixty-eight myopes (68) underwent manifest refraction, A- and B-scan, fundus examination, fluorescein angiography (FA), optical coherence tomography (OCT), full field ERG and MF-ERG. The amplitudes and implicit times of ERG were determined. The results were further analyzed by comparing ocular axis length, refraction, retinal thickness, and macular function detected by ERG parameters. There was a significant difference in implicit times of MF-ERG of an emmetrope and a moderate and high myopia whereas implicit times of mild myopia patients and emmetropes were similar. There was a statistically significant difference in amplitude densities of first positive peak of MF-ERG P1 wave between an emmetrope and a moderate and high myopia. In central ring and four quadrants, amplitude densities showed negative correlation to ocular axis length and diopter of myopia. There was no statistically significant difference between the average retinal thickness in emmetropic and physiological myopic eyes (low, medium, high), but there was significant difference between physiological and pathological myopia. Decreased foveal function as determined by MF-ERG is associated with high degree of myopia. Retinal function impairment is correlated with increase in the diopter of myopia, decrease of corrected visual acuity (VA), elongation of ocular axis and increased macular degeneration.


Activated Carbon Modification towards Efficient Catalyst for High Value-Added Products Synthesis from Alpha-Pinene.
DT0-activated carbons modified with HCl and HNO3 acids, which were used for the first time in the catalytic process of alpha-pinene isomerization, are presented in this study. The carbon materials DT0, DT0_HCl, DT0_HNO3, and DT0_HCl_HNO3 were examined with the following methods: XRF, SEM, EDX, XPS, FT-IR, XRD, and N2 adsorption at -196 °C. It was shown that DT0_HCl_HNO3-activated carbon was the most active material in the alpha-pinene isomerization process. Detailed studies of alpha-pinene isomerization were carried out over this carbon by changing the reaction parameters such as time (5-180 min) and temperature (60-175 °C). The 100% conversion of alpha-pinene was achieved at the temperature of 160 °C and catalyst content of 5 wt% after 3 h over the DT0_HCl_HNO3 catalyst. Camphene and limonene were the main products of the alpha-pinene isomerization reaction.


Structural organization of the Chromatium vinosum reaction center associated c-cytochromes.
Magnetic interactions operating between the Chromatium vinosum reaction center associated c-cytochromes and the electron carriers of the reaction center have been assayed by comparing the magnetic properties of these components alone, and in various combinations with paramagnetic forms of the reaction center electron carriers. These studies have yielded the following results. 1. The oxidized paramagnetic forms of the high potential cytochromes c-555 produce no discernable alteration of the light-induced (BChl)2.+signal. 2. Similarly, analysis of the lineshape of the light-induced (BChl)2.+signal shows that a magnetic interaction with the oxidized low potential cytochromes c-553 is likely to produce less than a 1 gauss splitting of the (BChl)2.+signal, which corresponds to a minimum separation of 25 +/- 3 A between the unpaired spins if the heme and (BChl)2 are orientated in a coplanar arrangement, suggesting a minimum separation of 15+/- 3A between the heme edge and the (BChl)2 edge. 3. a prominent magnetic interaction is observed to operate between the cytochrome c-553 and c-555, which results in a 30-35 gauss splitting of these spectra, and suggests an iron to iron separation of about 8 A.4. Magnetic interactions are not observed between the c-cytochromes and the reaction center "primary acceptor" (the iron . quinone complex) nor with the reaction center intermediate electron carrier (which involves bacteriopheophytin) suggesting separations greater than 10 A. 5. Magnetic interactions are not discerned between the two cytochrome c-553 hemes, nor between the two cytochrome c-555 hemes, implying that the distance between the cytochromes of the same pair is greater than 10 A. 6. EPR studies of oriented chromatophores have demonstrated that the cytochrome c-553 and c-555 hemes are perpendicular to each other, and suggest that the cytochrome c-553 heme plane lies parallel to the plane of the membrane, while the cytochrome c-555 heme plane lies perpendicular to the plane of the membrane surface.


Recent Advances in the Diagnosis and Treatment of Vestibular Disorders.
Vestibular medicine "embraces a wide approach to the potential causes of vestibular symptoms, acknowledging that vertigo, dizziness, and unsteadiness are non-specific symptoms that may arise from a broad spectrum of disorders, spanning from the inner ear to the brainstem, cerebellum and supratentorial cerebral networks, to many disorders beyond these structures" [...].


[The value of 99mTc-MIBI image axillary lymph node in selecting operative method for breast cancer].
To retain axillary lymph node not infiltrated by cancer cell. Breast cancer was diagnosed by fine needle aspiration cytology (FNA) or tumor biopsy before operation. Axillary lymph node was examined by surgery and (99m)Tc-MIBI image. Pathological examination of the axillary tissue after operation is used as gold standard in comparison of the two examination methods. The sensitivity, specificity, and accuracy of surgical examination are lower than those of (99m)Tc-MIBI image (P < 0.05). (99m)Tc-MIBI image combined with surgical examination can be used as a method for retaining axillary lymph node.


Synthesis of a water-soluble 2,2'-biphen[4]arene and its efficient complexation and sensitive fluorescence enhancement towards palmatine and berberine.
A water-soluble 2,2'-biphen[4]arene (2,2'-CBP4) containing eight carboxylato moieties was synthesized and characterized. Its complexation behavior towards two alkaloids, palmatine (P) and berberine (B), was investigated by means of fluorescence and 1H NMR spectroscopy in aqueous phosphate buffer solution (pH 7.4). In the presence of 2,2'-CBP4, 1H NMR signals of P and B displayed very large upfield shifts, indicating the formation of inclusion complexes with strong binding affinities. Fluorescence titration experiments showed that P and B exhibited dramatic fluorescence enhancement of more than 600 times upon complexation with 2,2'-CBP4. Particularly, the fluorescence intensity is strong enough to be readily distinguished by the naked eye. Although the two guests have similar structures, the association constant of B with 2,2'-CBP4 (Ka = (2.29 ± 0.27) × 106 M-1) is 3.9 times larger than that of P (Ka = (5.87 ± 0.24) × 105 M-1).


Detection of penicillin susceptibility in Streptococcus pneumoniae by pbp2b PCR-restriction fragment length polymorphism analysis.
A PCR-restriction fragment length polymorphism strategy directed against the pbp2b gene was evaluated for identification of penicillin susceptibility. A total of 106 United Kingdom (U.K.), 30 Danish, and 11 Papua New Guinean strains were tested. Of the U.K. strains, all the susceptible and all but one of the resistant isolates were correctly assigned. By using conventional definitions of "not resistant" and "not susceptible," the sensitivities were 97. 5 and 94.4%, the specificities were 100 and 98.9%, the positive predictive values were 100 and 94.4%, and the negative predictive values were 93.1 and 98.9%, respectively. This technique may allow susceptible (MIC, <0.1 mg/liter) and resistant (MIC, >1 mg/liter) isolates to be distinguished in a single PCR.


Associations between executive functioning, personality, and posttraumatic stress symptoms in adolescent solid organ transplant recipients.
Pediatric solid organ transplant recipients are susceptible to posttraumatic stress symptoms (PTSS), given the presence of a life-threatening chronic medical condition and potential for complications. However, little is known about what individual characteristics are associated with an increased risk for PTSS among youth who received an organ transplant. The aim of the current study was to evaluate PTSS and its associations with executive functioning (EF) and personality (i.e., neuroticism and conscientiousness) among adolescents with solid organ transplants. Fifty-three adolescents (Mage = 16.40, SD = 1.60) with a kidney, heart, or liver transplant completed self-report measures of PTSS and personality, whereas caregivers completed a caregiver-proxy report of adolescent EF. Twenty-two percent of adolescent transplant recipients reported clinically significant levels of PTSS. Higher EF difficulties and neuroticism levels, and lower conscientiousness levels were significantly associated with higher PTSS (rs -.34 to .64). Simple slope analyses revealed that adolescents with both high EF impairment and high levels of neuroticism demonstrated the highest PTSS (t = 3.47; p < .001). Most adolescent transplant recipients in the present study did not report clinically significant levels of PTSS; however, those with high neuroticism and greater EF difficulties may be particularly vulnerable to PTSS following organ transplantation. Following transplantation, medical providers should assess for PTSS and risk factors for developing PTSS. Identification of those at risk for PTSS is critical, given the strong associations between PTSS and certain medical outcomes (e.g., medication nonadherence) among these youth.


Monoclonal antibodies for the management of central nervous system diseases: clinical success and future strategies.
Recombinant monoclonal antibodies (mAbs) are highly selective and effective biologicals with proven utility as therapeutics. mAbs have demonstrated substantial promise in the treatment of several central nervous system diseases. Databases including PubMed and Clinicaltrials.gov were used to identify clinical studies of mAbs involving patients with neurological disorders. This manuscript reviews the current status and recent advances in the development and engineering of therapeutic blood-brain barrier (BBB)-crossing mAbs and their potential in treatment of central nervous system diseases, such as Alzheimer's disease (AD), Parkinson's disease (PD), brain tumors, and neuromyelitis optica spectrum disorder (NMSOD). In addition, the clinical implications of recently developed monoclonal antibodies are also discussed, along with the strategies to enhance their BBB permeability. The adverse events associated with the administration of monoclonal antibodies are also presented in the manuscript. There is growing evidence that supports the therapeutic utility of monoclonal antibodies in central nervous system and neurodegenerative diseases. Several studies have offered evidence of clinical efficacy in AD through use of anti-amyloid beta antibodies and anti-tau passive immunotherapy-based strategies. Additionally, ongoing research trials have produced promising findings for the treatment of brain tumors and NMSOD.


Aerobic training improves insulin sensitivity 72-120 h after the last exercise session in younger but not in older women.
The regular practice of aerobic training (AT) induces an improvement in insulin sensitivity (IS) in healthy younger women that persists until 96-120 h after the last exercise bout. Due to the dearth of research data, it still remains unclear whether a regular AT program can improve IS for such a period of time after the last training bout in healthy older women. To address this issue, we trained 14 younger and 8 older women 3 days per week during 6 months, and measured IS 3-5 days after the last training bout. AT consisted of 25-60 min sessions of running at 60-95% of maximal heart rate. Fat mass decreased (8%) in older women only. VO(2max) and fat-free mass increased in both groups. Only older women decreased bodyweight (4%) and subcutaneous adipose tissue (19%). Visceral adipose tissue decreased in none of the groups. The IS improved only in younger women (relative: 22%; absolute: 24%). The present findings suggest that in older women the improvement in IS following AT is short-lived and results mainly from the acute effect of the last training bout, whereas in younger women the chronic adaptations induced by AT are implicated, as the improvement in IS is maintained beyond the residual effect of the last training bout. From a clinical standpoint, our findings suggest that in older women AT should be performed every day to improve glucose metabolism, whereas in younger women an AT frequency (three times per week) allowing to induce and maintain chronic minimal physiological adaptations would be required.


Localized interleukin-10 gene transfer induces apoptosis of alloreactive T cells via FAS/FASL pathway, improves function, and prolongs survival of cardiac allograft.
We hypothesized that localized IL-10 gene transfer can induce alloreactive T cell apoptosis and tested this hypothesis with liposome-mediated ex vivo intracoronary IL-10 gene transfer using a functional heterotopic allograft heart transplant model in rabbits. Localized IL-10 overexpression prolonged cardiac allograft survival over three folds. In parallel with the time-course of IL-10 overexpression, the percentage of apoptotic CD3+ cells among total CD3+ cells was significantly increased in the gene therapy group (36.5+/-3.9%) compared with that in the control group (6.2+/-2.6%, P<0.01) on postoperative day (POD) 3-6, and it was further increased (45.8+/-5.7%) on POD7-10. Apoptotic CD4+ and CD8+ cells were also significantly increased in the gene group (P<0.01). In contrast, the percentage of apoptotic myocytes significantly decreased from 10.1+/-0.8% in the control group to 3.5+/-0.4% in the gene group on POD7-10 (P<0.01). This reduction was inversely correlated with the increase in the percentages of apoptotic CD4+ and CD8+ cells (P<0.01). The percentage of caspase-3 positive myocytes was significantly reduced, although percentages of caspase-3 positive CD4+ and CD8+ cells were markedly increased in the gene group (P<0.01). Moreover, about 60-80% of apoptotic T lymphocytes expressed Fas in the gene group compared with less than 10% in the control group (P<0.01). These results suggest that localized IL-10 gene transfer induces alloreactive T cell apoptosis via the Fas/FasL pathway that may contribute to the alleviated acute rejection, improved cardiac function, and prolonged survival in the IL-10 gene-treated cardiac allografts.


Peri-Procedural Management of Hemodynamic Instability in Patients Undergoing Carotid Revascularization.
Acute perioperative changes in arterial pressure occur frequently, particularly in patients with cardiovascular disease or those receiving vasoactive medications, or in relation to certain cardiovascular surgical procedures. Hemodynamic Instability (HI) is common in patients undergoing carotid revascularization because of unique patho-physiological and surgical factors. The operation, by necessity, disrupts the afferent pathway of the baroreflex, which can lead to postendarterectomy HI. Poor arterial pressure control is associated with increased morbidity and mortality after carotid revascularization, but good control of arterial pressure is often difficult to achieve in practice. The incidence, implications, and etiology of HI associated with carotid surgery are reviewed, and some recommendations made for its management. Close monitoring and titration of therapy are probably the most important considerations rather than specific choice of agents.


Surgical morbidity and mortality in one hundred and twenty-nine patients with obstructive jaundice.
One hundred and twenty-nine jaundiced patients were operated upon for the relief of benign and malignant bile duct obstruction during a 10-year period, 1977-86. The overall mortality was 4.7 per cent but increased to 9.1 per cent in patients with a serum bilirubin greater than 300 mumol/l. In all, 46.5 per cent of patients had a rise in postoperative creatinine but renal dysfunction occurred in only 4.7 per cent. Wound infection developed in 3.1 per cent of patients and appeared unrelated to infected bile; 3.9 per cent of patients were treated for postoperative septicaemic episodes. The low morbidity and mortality observed suggests that preoperative biliary drainage need not be considered in routine surgical practice if simple measures to maintain urine flow and prevent postoperative sepsis are used.


Genetic dissection of root formation in maize (Zea mays) reveals root-type specific developmental programmes.
Maize (Zea mays) forms a complex root system comprising embryonic and post-embryonic roots. The embryonically formed root system is made up of the primary root and a variable number of seminal roots. Later in development the post-embryonic shoot-borne root system becomes dominant and is responsible together with its lateral roots for the major portion of water and nutrient uptake. Although the anatomical structure of the different root-types is very similar they are initiated from different tissues during embryonic and post-embryonic development. Recently, a number of mutants specifically affected in maize root development have been identified. These mutants indicate that various root-type specific developmental programmes are involved in the establishment of the maize root stock. This review summarizes these genetic data in the context of the maize root morphology and anatomy and gives an outlook on possible perspectives of the molecular analysis of maize root formation.


Extracellular vesicles and their role in peripheral nerve regeneration.
Peripheral nerve injuries often result in sensory and motor dysfunction in respective parts of the body. Regeneration after peripheral nerve injuries is a complex process including the differentiation of Schwann cells, recruiting of macrophages, blood vessel growth and axonal regrowth. Extracellular vesicles (EVs) are considered to play a pivotal role in intercellular communication and transfer of biological information. Specifically, their bioactivity and ability to deliver cargos of various types of nucleic acids and proteins have made them a potential vehicle for neurotherapeutics. However, production, characterization, dosage and targeted delivery of EVs still pose challenges for the clinical translation of EV therapeutics. This review summarizes the current knowledge of EVs in the context of the healthy and injured peripheral nerve and addresses novel concepts for modification of EVs as therapeutic agents for peripheral nerve regeneration.


[COPD in nonsmokers].
The association of chronic obstructive pulmonary disease (COPD) and smoking is well established. However, an increasing number of studies have reported a not inconsiderable prevalence of COPD among nonsmokers. Therefore, other factors, both endogenous and exogenous, may influence the development of this disease. The present article reviews the influence of possible genetic factors, gender and other respiratory diseases (such as chronic asthma and tuberculosis), as well as environmental pollution and occupational exposure in the development of COPD.


Carbon dioxide emissions and the Environmental Kuznets Curve: evidence from the Association of Southeast Asian Nations.
We examined the relationship of carbon dioxide (CO2) emissions with real per capita GDP and energy consumption in the ASEAN region using panel data from 1960 to 2021. We employed various panel unit root tests (IPS, Fisher-ADF, Fisher-PP) and panel cointegration tests (Kao and Pedroni). We find robust empirical evidence supporting the validity of the Environmental Kuznets Curve hypothesis, suggesting the existence of a per capita income turning point (approximately USD 4,808.85) where CO2 emissions and real income begin to decouple. This suggests the presence of an environmentally sustainable economic growth path beyond this threshold. The study highlights the importance of a reduction of fossil fuel use and the adoption of coordinated strategic plans among ASEAN member states to reduce carbon dioxide emissions.


Enhancement of A23187-induced release of enteric vasoactive intestinal polypeptide by phorbol 12,13-dibutyrate.
The effect of phorbol 12,13-dibutyrate on calcium ionophore (A23187)-induced release of vasoactive intestinal polypeptide from enteric nerves was examined. A23187 caused release of vasoactive intestinal polypeptide dose dependently and phorbol 12,13-dibutyrate (100 nM) markedly shifted the dose-response curve of A23187 to the left. The significance of these findings will be discussed in relation to the mechanism of release of vasoactive intestinal polypeptide from enteric nerves.


Distribution and Morphology of Cortical Terminals in the Cat Thalamus from the Anterior Ectosylvian Sulcus.
Two main types of cortical terminals have been identified in the cat thalamus. Large (type II) have been proposed to drive the response properties of thalamic cells while smaller (type I) are believed to modulate those properties. Among the cat's visual cortical areas, the anterior ectosylvian visual area (AEV) is considered as one of the highest areas in the hierarchical organization of the visual system. Whereas the connections from the AEV to the thalamus have been recognized, their nature (type I or II) is presently not known. In this study, we assessed and compared the relative contribution of type I and type II inputs to thalamic nuclei originating from the AEV. The anterograde tracer BDA was injected in the AEV of five animals. Results show that (1) both type I and II terminals from AEV are present in the Lateral Posterior- Pulvinar complex, the lateral median suprageniculate complex and the medial and dorsal geniculate nuclei (2) type I terminals significantly outnumber the type II terminals in almost all nuclei studied. Our results indicate that neurons in the AEV are more likely to modulate response properties in the thalamus rather than to determine basic organization of receptive fields of thalamic cells.


The influences of dark rearing on the transmission characteristics of layer II/III pyramidal cells during the critical period.
The characteristics of synaptic plasticity on layer II/III pyramidal cells in different ages of rats have been studied extensively, and dark rearing is one of the important impact factors. To systematically analyze the influence of dark rearing on synaptic plasticity during the critical period of visual development, we studied the characteristics of short-term and long-term synaptic plasticities of layer II/III pyramidal cells of rats in three rearing conditions during P14 to P37. The paired-pulse ratio (PPR) of inhibitory postsynaptic currents (IPSCs) of layer II/III pyramidal cells was effected by both ages and rearing conditions, but the PPR of excitatory postsynaptic currents (EPSCs) did not change obviously. Moreover, long-term synaptic plasticity of rats in the dark rearing condition did not significantly change with age, while it was elevated during P16 and P21 for rats in the normal rearing condition. These results suggest that visual experience can affect the characteristics of short-term and long-term synaptic plasticities. The IPSC/EPSC ratio increased gradually with aging for NR rats, but the ratio slightly decreased for DR rats, which indicates the relative increase of inhibitory components during the critical period of visual development. The characteristics during P35 and P37 of the 30-day dark-reared (30D×N) group had similar trends with the normal-reared rats during P16 and P21, which emphasizes that dark rearing can postpone the timing of the critical period.


Didelphis albiventris: an overview of unprecedented transcriptome sequencing of the white-eared opossum.
The white-eared opossum (Didelphis albiventris) is widely distributed throughout Brazil and South America. It has been used as an animal model for studying different scientific questions ranging from the restoration of degraded green areas to medical aspects of Chagas disease, leishmaniasis and resistance against snake venom. As a marsupial, D. albiventris can also contribute to the understanding of the molecular mechanisms that govern the different stages of organogenesis. Opossum joeys are born after only 13 days, and the final stages of organogenesis occur when the neonates are inside the pouch, depending on lactation. As neither the genome of this opossum species nor its transcriptome has been completely sequenced, the use of D. albiventris as an animal model is limited. In this work, we sequenced the D. albiventris transcriptome by RNA-seq to obtain the first catalogue of differentially expressed (DE) genes and gene ontology (GO) annotations during the neonatal stages of marsupial development. The D. albiventris transcriptome was obtained from whole neonates harvested at birth (P0), at 5 days of age (P5) and at 10 days of age (P10). The de novo assembly of these transcripts generated 85,338 transcripts. Approximately 30% of these transcripts could be mapped against the amino acid sequences of M. domestica, the evolutionarily closest relative of D. albiventris to be sequenced thus far. Among the expressed transcripts, 2077 were found to be DE between P0 and P5, 13,780 between P0 and P10, and 1453 between P5 and P10. The enriched GO terms were mainly related to the immune system, blood tissue development and differentiation, vision, hearing, digestion, the CNS and limb development. The elucidation of opossum transcriptomes provides an out-group for better understanding the distinct characteristics associated with the evolution of mammalian species. This study provides the first transcriptome sequences and catalogue of genes for a marsupial species at different neonatal stages, allowing the study of the mechanisms involved in organogenesis.


Dynamics of lymphatic regeneration and flow patterns after lymph node dissection.
Knowledge about the mechanisms of regeneration of the lymphatic vasculature after surgical trauma is essential for the development of strategies for the prevention and therapy of lymphedema. However, little is known about the alterations of lymphatic flow directly after surgical trauma. We investigated lymphatic function in mice using near-infrared imaging for a period of 4 weeks after surgeries that mimic sentinel lymph node biopsy (SLNB) or axillary lymph node dissection (ALND), by removal of the popliteal lymph node (LN) alone or together with the popliteal fat pad, respectively. SLNB-like surgery did not cause changes in lymphatic drainage in the majority of cases. In contrast, lymphatic drainage impairment shown by collecting vessel rupture, dermal backflow and rerouting of lymph flow via collateral vessels were observed after ALND-like surgery. All collateral vessels drained to the inguinal LN. These results indicate that less invasive surgery prevents lymphatic decompensation. They also reveal the development and maturation of collateral lymphatic vessels after extensive surgical trauma, which reroute the flow of lymph towards a different LN. These findings might be helpful for the development of strategies to prevent and/or treat post-surgical lymphedema.


Pharmacologic profiling of transcriptional targets deciphers promoter logic.
The blueprint for cellular diversity and response to environmental change is encoded in the cis-acting regulatory sequences of most genes. Deciphering this 'cis-regulatory code' requires multivariate data sets that examine how these regions coordinate transcription in response to diverse environmental stimuli and therapeutic treatments. We describe a transcriptional approach that profiles the activation of multiple transcriptional targets against combinatorial arrays of therapeutic and signal transducing agents. Application of this approach demonstrates how cis-element composition and promoter context combine to influence transcription downstream of mitogen-induced signaling networks. Computational dissection of these transcriptional profiles in activated T cells uncovers a novel regulatory synergy between IGF-1 and CD28 costimulation that modulates NF-kappaB and AP1 pathways through signaling cascades sensitive to cyclosporin A and wortmannin. This approach provides a broader view of the hierarchical signal integration governing gene expression and will facilitate a practical design of combinatorial therapeutic strategies for exploiting critical control points in transcriptional regulation.


Temporal and Microspatial Heterogeneity in Transmission Dynamics of Coendemic Plasmodium vivax and Plasmodium falciparum in Two Rural Cohort Populations in the Peruvian Amazon.
Malaria is highly heterogeneous: its changing malaria microepidemiology needs to be addressed to support malaria elimination efforts at the regional level. A 3-year, population-based cohort study in 2 settings in the Peruvian Amazon (Lupuna, Cahuide) followed participants by passive and active case detection from January 2013 to December 2015. Incidence and prevalence rates were estimated using microscopy and polymerase chain reaction (PCR). Lupuna registered 1828 infections (1708 Plasmodium vivax, 120 Plasmodium falciparum; incidence was 80.7 infections/100 person-years (95% confidence interval [CI] , 77.1-84.5). Cahuide detected 1046 infections (1024 P vivax, 20 P falciparum, 2 mixed); incidence was 40.2 infections/100 person-years (95% CI, 37.9-42.7). Recurrent P vivax infections predominated onwards from 2013. According to PCR data, submicroscopic predominated over microscopic infections, especially in periods of low transmission. The integration of parasitological, entomological, and environmental observations evidenced an intense and seasonal transmission resilient to standard control measures in Lupuna and a persistent residual transmission after severe outbreaks were intensively handled in Cahuide. In 2 exemplars of complex local malaria transmission, standard control strategies failed to eliminate submicroscopic and hypnozoite reservoirs, enabling persistent transmission.


Focal transplantation-based astrocyte replacement is neuroprotective in a model of motor neuron disease.
Cellular abnormalities in amyotrophic lateral sclerosis (ALS) are not limited to motor neurons. Astrocyte dysfunction also occurs in human ALS and transgenic rodents expressing mutant human SOD1 protein (SOD1(G93A)). Here we investigated focal enrichment of normal astrocytes using transplantation of lineage-restricted astrocyte precursors, called glial-restricted precursors (GRPs). We transplanted GRPs around cervical spinal cord respiratory motor neuron pools, the principal cells whose dysfunction precipitates death in ALS. GRPs survived in diseased tissue, differentiated efficiently into astrocytes and reduced microgliosis in the cervical spinal cords of SOD1(G93A) rats. GRPs also extended survival and disease duration, attenuated motor neuron loss and slowed declines in forelimb motor and respiratory physiological functions. Neuroprotection was mediated in part by the primary astrocyte glutamate transporter GLT1. These findings indicate the feasibility and efficacy of transplantation-based astrocyte replacement and show that targeted multisegmental cell delivery to the cervical spinal cord is a promising therapeutic strategy for slowing focal motor neuron loss associated with ALS.


[Current state of training in pharmacy education using a problem-based learning/tutorial model with simulated patients and standardized patients at National University Corporation].
Simulated/standardized patient-based (SP) education and problem-based learning (PBL) tutorial education become a powerful tool to heighten the pharmacy students' will to learn in order to cultivate the responsibility to contribute to public health and welfare as a clinical professional and to facilitate students' competences to solve problems by themselves. What this program is trying to do is: 1) to establish the system to train, educate and supply SP who are effective in the training and education of pharmacy students in close cooperation with the medical schools and their affiliated hospitals; 2) to improve the quality of the current PBL tutorial education and thereby establish it as an advanced education program in the education of senior students. We carried out the questionnaire to National University Corporation which establishes a school of pharmacy, as to the training and education of SP. The analysis of the answers to the questionnaire revealed the present status of SP in the Pharmaceutical Objective Structured Clinical Examination (OSCE) in the Pharmaceutical Common Achievement Test, and the existence of the problems on how to standardize SP as well as how to cover such expenses. Furthermore, the activity of the first year consisted of the exchange and sharing of information regarding the existing method of training and education of SP and PBL tutorial education and the identification of the problems to be solved in order to improve the quality of the educational program.


Can the intraoperative leak test prevent postoperative leakage of esophagojejunal anastomosis after total gastrectomy?
Anastomotic failures that cannot be detected during surgery often lead to postoperative leakage. There have been no detailed reports on the intraoperative leak test for esophagojejunal anastomosis. Our purpose was to investigate the utility of routine intraoperative leak testing to prevent postoperative anastomotic leakage after performing esophagojejunostomy. We prospectively performed routine air leak tests and reviewed the records of 185 consecutive patients with gastric cancer who underwent open total gastrectomy followed by esophagojejunostomy. A positive leak test was found for six patients (3.2 %). These patients with positive leak tests were subsequently treated with additional suturing, and they developed no postoperative anastomotic leakage. However, anastomotic leakage occurred in nine patients (4.9 %) with negative leak tests. A multivariate analysis demonstrated that a patient age >75 years and the surgeon's experience <30 cases were risk factors for anastomotic leakage. Intraoperative leak testing can detect some physical dehiscence, and additional suturing may prevent anastomotic leakage. However, it cannot prevent all anastomotic leakage caused by other factors, such as the surgeons' experience and patients' age.


Immune landscape of periodontitis unveils alterations of infiltrating immunocytes and molecular networks-aggregating into an interactive web-tool for periodontitis related immune analysis and visualization.
Immunity reaction plays an essential role in periodontitis progress and we aim to investigate the underlying regulatory network of immune reactions in periodontitis. CIBERSORT was used to estimate immunocyte fractions in different clinical statuses. Logistic regression was used to assess the immunocyte weight in periodontitis. Immune-related periodontitis subtypes were identified by the Nonnegative Matrix Factorization algorithm. Gene-set enrichment analysis and Gene-set variation analysis were conducted to analyze pathway activities. Immunocytes related gene modules were identified by Weighted gene co-expression network analysis. Altered immunocytes in healthy versus periodontitis, aggressive versus chronic, male versus female and age were identified. Immunocytes enriched in periodontitis were calculated, and their correlation was also explored. Two distinct immune-related periodontitis subtypes were identified and one is characterized by B cell reactions and the other is IL-6 cytokine reactions. 463 statistically significant correlations between 22 immunocytes and pathways were revealed. Immunocytes and clinical phenotypes matched their gene modules, and their functions were annotated. Last, an easy-to-use and user-friendly interactive web-tool were developed for periodontitis related immune analysis and visualization ( https://126.96.36.199:3838/tool-PIA/ ). This study systematically investigated periodontitis immune atlas and caught a glimpse of the underlying mechanism of periodontitis from gene-pathway-immunocyte networks, which can not only inspire researchers but also help them in periodontitis related immune researches.


Immunohistochemical study of the abnormal cells in Langerhans cell histiocytosis (histiocytosis x).
The immunophenotypic properties of the abnormal cells in routine specimens from 16 cases of Langerhans cell histiocytosis (LCH) were examined. In five cases, cryostat sections were also available. The abnormal cells expressed a similar phenotype and were positive for HLA-DR, S-100 protein, peanut agglutinin (PNA), CD1a, CD4 and several macrophage-associated markers, including CD11c, CDw32 and CD68 (the latter detectable in routine sections with antibody KP1). Staining with CD14, CD35 (C3b receptor), and CD11b (C3bi receptor) was negative with the exception of one of the cases in which a proportion of the cells showed faint positivity with CD11b. Staining for pan-T-cell (CD2, CD3, CD5) and pan-B-cell (CD19, CD22) antigens was negative in all lesions. It is concluded that LCH expresses a characteristic phenotype with some heterogeneity with regard to macrophage markers and that immunohistochemical methods in cryostat sections and routine specimens form a useful supplement to other techniques for the diagnosis of this condition.


Serum exosomal m6A demethylase FTO promotes gefitinib resistance in non-small cell lung cancer by up-regulating FLRT3, PTGIS and SIRPα expression.
This study investigates the molecular mechanism of FTO m6A demethylase in non-small cell lung cancer (NSCLC) and gefitinib resistance using GEO and TCGA databases. Differentially expressed genes (DEGs) were screened from RNA-seq data sets of serum exosomes of gefitinib-resistant NSCLC patients in the GEO database and the NSCLC data set in the GEPIA2 database. From this analysis, FTO m6A demethylase was found to be significantly upregulated in the serum exosomes of gefitinib-resistant NSCLC patients. To identify downstream genes affected by FTO m6A demethylase, weighted correlation network analysis and differential expression analysis were performed, resulting in the identification of three key downstream genes (FLRT3, PTGIS, and SIRPA). Using these genes, the authors constructed a prognostic risk assessment model. Patients with high-risk scores exhibited a significantly worse prognosis. The model could predict the prognosis of NSCLC with high accuracy measured by AUC values of 0.588, 0.608, and 0.603 at 1, 3, and 5 years respectively. Furthermore, m6A sites were found in FLRT3, PTGIS, and SIRPA genes, and FTO was significantly positively correlated with the expression of these downstream genes. Overall, FTO m6A demethylase promotes gefitinib resistance in NSCLC patients by upregulating downstream FLRT3, PTGIS, and SIRPA expression, with these three downstream genes serving as strong prognostic indicators.


Crystals in hand.
A genetic association of the ENPP1 gene with primary hand osteoarthritis was recently reported in this journal. ENPP1 encodes an enzyme that regulates soft tissue calcification. The study as it stands is far from complete because the actual causal variant(s) within ENPP1 has not been identified and no functional study on the activity of the enzyme in hand osteoarthritis was presented. Nevertheless, the study stimulates interest and will encourage others in the field to test ENPP1 as a possible osteoarthritis susceptibility gene in their cohorts. The genetic basis of osteoarthritis is slowly being uncovered, and this report constitutes another interesting find.


Design and in-vitro testing of a portable patient isolation chamber for bedside aerosol containment and filtration.
The emergence of the SARS-CoV-2 pandemic has imposed a multitude of complications on healthcare facilities. Healthcare professionals had to develop creative solutions to deal with resource shortages and isolation spaces when caring for COVID positive patients. Among many other solutions, facilities have utilized engineering strategies to mitigate the spread of viral contamination within the hospital environment. One of the standard solutions has been the use of whole room negative pressurization (WRNP) to turn a general patient room into an infection isolation space. However, this has not always been easy due to many limitations, such as direct access to the outdoors and the availability of WRNP units. In operating rooms where a patient is likely to go through aerosol-generating procedures, other solutions must be considered because most operating rooms use positive pressure ventilation to maintain sterility. The research team has designed, built, and tested a Covering for Operations during Viral Emergency Response (COVER), a low-cost, portable isolation chamber that fits over a patient's torso on a hospital bed to contain and remove the pathogenic agents at the source (i.e., patient's mouth and nose). This study tests the performance of the COVER system under various design and performance scenarios using particle tracing techniques and compares its efficiency with WRNP units. The results show that COVER can dramatically reduce the concentration of particles within the room, while WRNP is only effective in preventing the room-induced particles from migrating to adjacent spaces.


Alternate PAX3-FOXO1 oncogenic fusion in biphenotypic sinonasal sarcoma.
Biphenotypic sinonasal sarcoma (SNS) is a low grade spindle cell sarcoma that affects middle-aged adults, in which the PAX3-MAML3 chimeric transcription factor induces an aberrant dual myogenic and neuroectodermal phenotype. We report an alternate PAX3-FOXO1 oncogenic fusion in SNS, confirming the crucial role of PAX3 in SNS oncogenesis. The presence of PAX3-FOXO1 in SNS and alveolar rhabdomyosarcoma suggests that these two entities are genetically similar lesions arising from distinct progenitor cell pools. This finding has important implications for the molecular diagnosis of SNS and alveolar rhabdomyosarcoma, and underscores the critical contribution of the cell of origin to the phenotype induced by oncogenic transcription factor reprogramming.


High-power therapeutic ultrasound for treatment of abdominal localized adiposity-double-blind randomized clinical trial.
This study aimed to evaluate the effects of high-power therapeutic ultrasound in the treatment of abdominal localized adiposity in an isolated manner, with the use of neutral gel comparing ultrasonic application with 5% lipolytic active caffeine gel (phonophoresis). A total of 90 healthy women aged between 18 and 40 years were randomized and divided into two groups. The volunteers underwent anamnesis evaluation, perimetry, bioimpedance, ultrasound examination, and blood tests (complete lipidogram, creatinine, and vitamin D) before and after the end of the 10-session ultrasound protocol (3 MHz, 2 W/cm2, and 30w). Comparisons between groups and pre-post evaluation were performed by a two-way repeated-measures analysis of variance. Values of p < 0.05 indicated statistical significance. The results demonstrated a significant reduction in both groups, for the perimetry (p < 0.001) and measurements of adipose tissue thickness (p < 0.001). The examinations exhibited a significant alteration only of the complete lipidogram, but without significance (p > 0.05). When comparing the groups, no statistically significant difference was identified in any of the analyzed parameters. The high-power ultrasonic therapy is efficient in reducing localized adiposity, regardless of whether it is applied with neutral gel or 5% caffeine gel.


Secretoneurin in carcinoids of the appendix-immunohistochemical comparison with chromogranins A,B and secretogranin II.
The aim of the present study was to investigate immunohistochemically the distribution of secretoneurin, a novel 33 amino acid peptide, in comparison to chromogranin A, chromogranin B, and secretogranin II in carcinoids of the appendix. Paraffin-embedded tissues from 47 carcinoids were incubated with antibodies specific for chromogranin A, chromogranin B, the secretogranin II derived peptide LF- 19, and secretoneurin. 44 tumors (94%) were positive for secretoneurin, whereas only 39 tumors (83%) were immunoreactive for chromogranin A. There was no significant correlation between neuropeptide expression and type of carcinoid, tumor size, vascular infiltration, serosal involvement or mesoappendiceal infiltration. Our investigations revealed that secretoneurin is detected more frequently than chromogranin A in carcinoids of the appendix. This supports the theory that tumor cells of appendiceal carcinoids are of a different origin than other midgut carcinoids. No special tumor entity with a characteristic secretoneurin-chromogranin pattern could be identified.


Rhabdoid tumor of the skin.
A tumor in the skin of a 42-year-old man was analyzed by light and electron microscopic study and immunohistochemistry. The tumor cells were large and contained eosinophilic, periodic acid-Schiff (PAS)-positive inclusions in the cytoplasm. Immunohistochemically, the neoplasm was positive for intermediate filaments, cytokeratin, vimentin, desmin, and alpha-1-antichimotrypsin, and negative for S-100 and leukocyte common antigen (LCA). Ultrastructurally, the cytoplasm and cellular processes of the cells were inundated with intermediate filaments, some of which were tightly bundled. Junctional complexes and secretory granules were absent. These features suggest a rhabdoid tumor: a malignant tumor of uncertain origin.


Accumulation and excretion of zinc and their effects on growth and food utilization of Spodoptera litura (Lepidoptera: Noctuidae).
By exposing larvae of the holometabolous insect Spodoptera litura to the artificial diets supplemented with a range of Zinc (Zn) contents, we investigated Zn ingestion, excretion and accumulation in the insect throughout its life cycle. The effects of Zn stress on the survival, growth and food utilization of S. litura were also determined. Zn concentrations in the body (larvae, pupae, and adults), faeces, exuviates, puparium, eggs increased with the increasing Zn concentrations in the diets, while Zn excretion and accumulation by S. litura in 750 mg/kg Zn treatments was lower than the 600 mg/kg Zn treatment. In the 450 mg/kg Zn treatment, the Zn accumulation in S. litura at different developmental stages differed as follows: larvae > pupa > adult. S. litura ingested Zn via feeding and could excrete most of the Zn via faeces (compared with Zn excretion via exuviates) to reduce its internal Zn accumulation (compared with Zn ingestion). Survival and weight were significantly inhibited, and the prolonged period of development (larvae, pupae) and shortened longevity of adults were found in S. litura exposed to Zn stress greater than 450 mg Zn/kg. In the 150-450 mg/kg Zn treatments, the 6th instar larvae increased their relative consumption rate (RCR) and approximate digestibility (AD) (namely, food eaten) to gain weight, which resulted in greater Zn accumulation in the body. Therefore, below the threshold level (being close to 450 mg/kg Zn), S. litura seemed to have a strong homeostatic adjustment ability (increase the amount of food eaten, thereby increasing AD, RCR and Zn excretion via faeces and exuviates) to sustain their weight, and Zn was beneficial and harmless. Although larvae treated with 750 mg/kg Zn had a similar RCR and AD as the control, a reduced weight gain and prolonged larval period resulted in significantly lower relative growth rate (RGR), which indicated surviving insects may allocate more energy from foods for detoxification than for growth.


Investigation of polychlorinated biphenyls in breast milk from two regions in Bulgaria.
Human breast milk is an optimally balanced infant food and a suitable tool for assessing the burden of humans with lipophilic persistent organic pollutants. The aim of this study was to investigate the accumulation profile of polychlorinated biphenyls in breast milk of women living in Bulgaria and to assess the health risk to infants. Breast milk samples were obtained from 72 healthy primiparae and multiparae mothers, living in two regions in northeastern Bulgaria - Varna region and Dobrich region, in the period October 2019-July 2021. Important information for the study, such as age, body mass, smoking and dietary habits, was collected through a questionnaire. Fifteen congeners of PCBs, including six indicator congeners, were determined by capillary gas chromatography system with mass spectrometry detection. The lipid content of the tested samples was in the range from 0.5% to 6.7%, with average value 3.25%. The six indicator PCBs in human milk samples formed up to 89% of the total PCBs levels. The most abundant congener was PCB 153, followed by PCB 138 and PCB 180. Five of the 15 PCB congeners (77, 126, 128, 156, 169) were not detected in any of the milk samples. The arithmetic mean PCB levels in milk samples from Varna (32.7 ng/g lw) were found higher than PCB levels in breast milk of mothers from Dobrich (22.5 ng/g lw). The highest PCB levels were found in milk samples from primiparae mothers in 36-40 age group (for both regions). Infant exposure to PCBs present in human milk was estimated using toxic equivalents (TEQ). The health risk to infants was assessed and was compared to the tolerable daily intake (TDI). Positive correlation was found between the arithmetic mean PCBs levels and two important factors - the age and body mass index of the primiparae group. The mean values of the analyzed PCB congeners in breast milk samples from multiparae were lower than in those from primiparae mothers. The regional differences in PCB concentrations were small, suggesting similar exposures in the studied regions. The levels of PCBs in breast milk were found lower than levels from studies in other European countries. Statistical data does not show any association between PCB levels in milk and dietary habits. The results showed that infants are not at risk of any adverse effects caused by PCBs through breast milk.


Population biology of infectious diseases: Part II.
In the first part of this two-part article (Nature 280, 361--367), mathematical models of directly transmitted microparasitic infections were developed, taking explicit account of the dynamics of the host population. The discussion is now extended to both microparasites (viruses, bacteria and protozoa) and macroparasites (helminths and arthropods), transmitted either directly or indirectly via one or more intermediate hosts. Consideration is given to the relation between the ecology and evolution of the transmission processes and the overall dynamics, and to the mechanisms that can produce cyclic patterns, or multiple stable states, in the levels of infection in the host population.


[Gastroenteropancreatic neuroendocrine tumors: diagnosis and therapy in nuclear medicine].
The over expression of somatostatin receptors (SSTR) in neuroendocrine tumors (NET) enables diagnosis and targeted therapy using radio-labelled somatostatin analogues. PET with (68)Ga-DOTATATE or (68)Ga-DOTATOC, both with a high affinity to the SSTR subtype 2, enables diagnosis of NET with a very high sensitivity and has a significant influence on the therapeutic management of patients with NET. In particular, therapy with (177)Lu-DOTATATE, which offers a considerably lower nephrotoxicity as compared to (90)Y-DOTATOC, has only few side effects and is usually well tolerated. Up to 46% of patients suffering from GEP-NET show a response to this therapy, which is able to mitigate tumour-related symptoms and significantly improve quality of life.


Modified mRNA-LNP Vaccines Confer Protection against Experimental DENV-2 Infection in Mice.
Dengue virus (DENV) infection is a major global public health concern, and there is no effective vaccine for it. In this study, we describe the design and characterization of three nucleotide-modified mRNA vaccines (prME-mRNA, E80-mRNA, and NS1-mRNA) for DENV-2. Our results showed that vaccination with E80-mRNA alone or a combination of E80-mRNA and NS1-mRNA can induce high levels of neutralizing antibodies and antigen-specific T cell responses; furthermore, these vaccines confer complete protection against DENV-2 challenge in immunocompetent mice. These data provide foundations for further development of a tetravalent DENV vaccine based on nucleotide-modified mRNA.


New heterocyclic ring systems--V synthesis and pharmacological activity of 6H-1,3,4-thiadiazolo [3',2':1,2]-5-oxopyrimido [5,4-b] indole derivatives and of 1-phenyl-6H-1,2,4-triazolo [1',5':1,2]-5-oxopyrimido[5,4-b] indole.
As a part of a study on analgesic and antiinflammatory active condensed heterocyclic compounds containing the pyrimidinic ring, a number of 6H-1,3,4-thiadiazolo [3',2':1,2]-5-oxopyrimido [5,4-b]indole and 1-phenyl-6H-1,2,4-triazolo [1',5':1,2]-5-oxopyrimido [5,4-b] indole were synthesized and tested. The results of pharmacological assays are reported and discussed.


The impact of matrix age on intervertebral disc regeneration.
With the lack of effective treatments for low back pain, the use of extracellular matrix (ECM)-based biomaterials have emerged with undeniable promise for IVD regeneration. Decellularized scaffolds can recreate an ideal microenvironment inducing tissue remodeling and repair. In particular, fetal tissues have a superior regenerative capacity given their ECM composition. In line with this, we unraveled age-associated alterations of the nucleus pulposus (NP) matrisome. Thus, the aim of the present work was to evaluate the impact of ECM donor age on IVD de/regeneration. Accordingly, we optimized an SDS (0.1 %, 1 h)-based decellularization protocol that preserves ECM cues in bovine NPs from different ages. After repopulation with adult NP cells, younger matrices showed the highest repopulation efficiency. Most importantly, cells seeded on younger scaffolds produced healthy ECM proteins suggesting an increased capacity to restore a functional IVD microenvironment. In vivo, only fetal matrices decreased neovessel formation, showing an anti-angiogenic potential. Our findings demonstrate that ECM donor age has a strong influence on angiogenesis and ECM de novo synthesis, opening new avenues for novel therapeutic strategies for the IVD. Additionally, more appropriate 3D models to study age-associated IVD pathology were unveiled.


Contraceptive implant use among inner city teens.
This study develops a clinical profile of urban teens who selected Norplant for contraception; determines which variables identify the subjects most likely to be compliant with the method; and determines the most common reasons for early termination of use. Demographic and health history data and reasons for termination of use were collected prospectively for 122 inner city teens who received Norplant. Life table analysis and the Mantel-Haenszel procedure were used to investigate differences between Norplant retainers and terminators. The sample consisted of black and Hispanic teens between the ages of 13-19 years, the majority of whom had one or more children and were in school. One and two year retention rates were 71% and 62%. The highest removal rates occurred during the 3-6 month interval after insertion. A significant finding was that teens who have experienced induced abortion were more likely to retain Norplant. Common reasons for termination of use included general and social concerns, including pregnancy desire. Norplant retention rates for this teen sample were greater than the compliance rates reported for other conventional methods. Similar to noncompliance with oral contraceptives, discontinuance of the method was most likely to occur in the first 6 months of use. A history of induced abortion identifies those teens most likely to retain Norplant, suggesting that these teens might evaluate contraceptive risks and benefits differently than those with no abortion history. Pregnancy desire was a common reason for terminating Norplant use.


Successive phase transitions of the spin-orbit-coupled metal Cd2Re2O7probed by high-resolution synchrotron x-ray diffraction.
The 5dpyrochlore oxide superconductor Cd2Re2O7(CRO) has attracted significant interest as a spin-orbit-coupled metal (SOCM) that spontaneously undergoes a phase transition to an odd-parity multipole phase by breaking the spatial inversion symmetry due to the Fermi liquid instability caused by strong spin-orbit coupling. Despite the significance of structural information during the transition, previous experimental results regarding lattice deformation have been elusive. We have conducted ultra-high resolution synchrotron radiation x-ray diffraction experiments on a high-quality CRO single crystal. The temperature-dependent splitting of the 0 0 16 and 0 0 14 reflections, which are allowed and forbidden, respectively, in the high-temperature cubic phase I (space groupFd-3m), has been clearly observed and reveals the following significant facts: inversion symmetry breaking and tetragonal distortion occur simultaneously atTs1= 201.5(1) K; the previously believed first-order transition between phase II (I-4m2) and phase III (I4122) atTs2∼120 K consists of two close second-order transitions atTs2= 115.4(1) K andTs3∼ 100 K; there is a new orthorhombic phase XI (F222) in between. The order parameters (OPs) of these continuous transitions are uniquely represented by a two-dimensional irreducible representationEuof theOhpoint group, and the OPs of phase XI are a linear combination of those of phases II and III. Each phase is believed to correspond to a distinct odd-parity multipole order, and the complex successive transitions observed may be the result of an electronic phase transition that resolves the Fermi liquid instability in the SOCM.


Occurrence, distribution and size relationships of plastic debris along shores and sediment of northern Lake Victoria.
Plastic pollution has been reported in sediment, surface water and biota of freshwater systems especially in Europe, North and South America, and Asia with limited studies focussing on African great lakes. This study therefore investigated the occurrence, abundance and distribution of micro-, meso- and macro-plastic debris along shores and sediment of northern Lake Victoria. The abundance of micro-, meso- and macro-plastics measured as particles/kg dry sediment were in range of 0-1102, 0-218 and 0-100 respectively in shoreline sediment and 0-108, 0-33 and 0-77 respectively in lake sediment. The mean abundance of micro-, meso- and macro-plastic debris at fish landing beaches (75.2 ± 50.0, 16.7 ± 8.1 and 18.1 ± 4.6 respectively) were higher than what was recorded at recreational beaches (1.5 ± 0.6, 3.1 ± 3.1 and 3.8 ± 3.8 respectively). Similarly, mean abundance of micro-, meso- and macro-plastic debris in lake sediment were higher in areas of fish landing beaches (9.5 ± 2.6, 2.1 ± 1.5 and 7.7 ± 4.5 respectively) than what was recorded in areas of recreational beaches (0.7 ± 0.7, 0.2 ± 0.1, and 0 ± 0 respectively). Films, filaments, fragments, foam and pellets were the plastic types, with the shoreline sediment dominated by films (>54%) while lake sediment was dominated by filaments (>55%), across size groups (micro-, meso- and macro-plastics). Spearman's rank correlation indicated strong and significant correlation between abundance of micro- and meso-plastics for total plastic, film plastic and fragment plastic in shoreline sediment. Significant correlation between macroplastics in shoreline sediment and microplastics in lake sediment for total plastics was observed. The FTIR analysis revealed that polyethylene, polypropylene, Polyethylene Terephthalate, Polyamide (nylon), and polyvinyl chloride were the major polymers. These results demonstrated that fish landing beaches along Lake Victoria are hotspot areas for plastic pollution of the lake and should therefore be targeted for management of plastic pollution of Lake Victoria.


Ultrasensitive levofloxacin electrochemical biosensor based on semiconducting covalent organic framework/poly-L-cysteine/triangular Ag nanoplates modified glassy carbon electrode.
A novel electrochemical biosensor with excellent performance was fabricated for levofloxacin (LEV) detection, which adopted triangular Ag nanoplates (Tri-AgNP) confined in a poly-L-cysteine (poly-L-Cys) film and a semiconducting covalent organic framework (COF) as the electrochemical sensing material. The developed electrochemical sensor revealed excellent analytical properties because of its good electrical conductivity, fast electron transfer, and abundant bioactive site. Based on this, a linear relationship between the LEV concentration and the peak current response at 0.92 V was obtained under the optimal experimental conditions by differential pulse voltammetry (DPV), with a wide linear range of 0.05 to 600 μM and a low limit of detection (LOD) of 0.0061 μM. The prepared sensor also realized sensitive and accurate determination of LEV in human serum and urine samples by standard addition method, with satisfactory recoveries (97.1 to 104%) and a low relative standard deviation of less than 4.6%. These results indicated that the novel ternary system has a promising application in the development of electrochemical signal probe and electrochemical biosensing platform.