On-demand therapy in gastroesophageal reflux disease: a comparison of the early effects of single doses of fast-dissolving famotidine wafers and ranitidine tablets.
In this double-masked, double-dummy, randomized, single crossover study, we compared single doses of a fast-dissolving wafer formulation of famotidine with a conventional tablet formulation of ranitidine in patients with gastroesophageal reflux disease (GERD). Patient preference time until symptomatic relief, and predictive characteristics of early responders were assessed. Eligible patients had a clinical diagnosis of GERD and symptoms of GERD of sufficient severity to require relief. The study treatment was one dose of famotidine (20-mg wafer) and one dose of ranitidine (150-mg tablet), which were given in a randomized order and taken as needed. The patients were instructed to measure the symptomatic effects on a seven-point categorical scale (1 = worse to 7 = free of symptoms) at 15, 30, 45, 60, 120, and 180 minutes. After the clinical phase of the trial, the patients indicated their global assessment of efficacy and their preference for the wafer or the tablet. Of the 829 patients who completed the study, significantly more preferred the wafer to the tablet. While there was no significant difference in the global assessment of efficacy, the famotidine wafer provided significantly better relief than the ranitidine tablet during the first hour after dosing. However, at 120 and 180 minutes, the degree of relief was similar for the two drugs. The time until a clinically significant effect was also similar for the two drugs, and approximately one half of the patients experienced such improvement within 3 hours. Multivariate analyses disclosed no predictive characteristics of early symptomatic effect.


Diglyceride prodrug strategy for enhancing the bioavailability of norfloxacin.
Prodrug approach using diglyceride as a promoiety is a promising strategy to improve bioavailability of poorly absorbed drugs and the same was explored in the present work to improve oral bioavailability of norfloxacin; a second generation fluoroquinolone antibacterial. The prodrug was synthesized by standard procedures using dipalmitine as a carrier and the structure was confirmed by spectral analysis. Higher LogP indicated improved lipophilicity. The ester linkage between norfloxacin and dipalmitine would be susceptible to hydrolysis by lipases to release the parent drug and carrier in the body. In vivo kinetic studies in rats indicated 53% release of norfloxacin in plasma at the end of 8h. The prodrug exhibited improved pharmacological profile than the parent compound at equimolar dose that indirectly indicated improved bioavailability.


In Vivo Validation of CRISPR Reagents in Preimplantation Mouse Embryos.
The CRISPR/Cas9 system has enjoyed enormous success and has now become the standard method of generating gene-modified mouse models. The tools for predicting the activity of CRISPR reagents in the mouse embryo are currently limited and not particularly accurate in predicting if a given reagent will be active. Given the time and cost of generating genetically modified mice, it is highly desirable to use CRISPR reagents that are known to be active in the mouse embryo. In this chapter, we provide a detailed procedure for empirically testing the activity of CRISPR reagents via electroporation into cultured preimplantation mouse embryos. This platform has proven to be rapid, efficient, and applicable to a variety of mouse strains, and can be used for assessing on- and off-target activity through a variety of molecular assays.


Critical material content in modern conventional U.S. vehicle electronics.
Critical materials (CMs) are vital to modern technology. Components of modern vehicles can be recycled to recover and reuse the CMs to help ensure a supply of these materials. Electronic components from a 2015 GMC Sierra truck (21 components) and 2016 Toyota Camry sedan (10 components) were analyzed for CMs. The components were processed via size reduction, aqua regia leaching and dissolution, and final solutions were analyzed for metal content. It was found that most electronic components of both vehicles contain CMs. The most concentrated CMs in the components were Sn, Nb, and Tb. Nd and Co were found in several of the magnetic components. CM economic value was found to be low compared to the overall value of the components, and the CM content would not allow for a viable pathway for recycling. Remanufacturing of components may be a more economic option of reuse in the future.


Substitution controlled aryne insertion: synthesis of diarylmethane/chromones.
Aryne insertion reaction with 2-aroyl malonates/cyanoesters lead to the formation of diarylmethane or chromones depending on the substitution on the aryne ring. The presence of an electronegative atom at the ortho position of arynes generates chromones, whereas other arynes lead to the formation of diarylmethanes, via a cascade double aryne insertion.


ATP-induced calcium mobilization in human neutrophils.
Extracellular ATP at 10 microM increased the concentration of cytoplasmic free Ca2+ ( [Ca2+]i) 3-fold in human neutrophils. The [Ca2+]i was measured by fura-2 fluorescence. The effect was rapid but transient: [Ca2+]i reached a maximum within 10 s and then returned to its resting value after 2-3 min. The rise in [Ca2+]i elicited by ATP was unaffected by the removal of extracellular Ca2+, indicating that the primary source of Ca2+ is from intracellular stores. In contrast to ATP, neither ADP nor AMP, at concentrations as high as 100 microM, caused any detectable changes in [Ca2+]i. Among other nucleotide triphosphates tested, UTP was as effective as ATP in causing a transient rise in [Ca2+]i, and prevented a subsequent response to ATP. Similarly, ATP prevented a subsequent response to UTP but the second response could be obtained when the initially added ATP was removed by the addition of hexokinase. Phorbol myristate acetate, the activator of Ca2+, phospholipid-dependent protein kinase, completely inhibited the ATP-induced increases in [Ca2+]i without affecting the basal [Ca2+]i level. The results suggest that extracellular ATP stimulates human neutrophils by causing the release of calcium from intracellular storage pools by mechanisms which can be inhibited by phorbol myristate acetate.


Immunoglobulin germline gene variation and its impact on human disease.
Immunoglobulins (Ig) play an important role in the immune system both when expressed as antigen receptors on the cell surface of B cells and as antibodies secreted into extracellular fluids. The advent of high-throughput sequencing methods has enabled the investigation of human Ig repertoires at unprecedented depth. This has led to the discovery of many previously unreported germline Ig alleles. Moreover, it is becoming clear that convergent and stereotypic antibody responses are common where different individuals recognise defined antigenic epitopes with the use of the same Ig V genes. Thus, germline V gene variation is increasingly being linked to the differential capacity of generating an effective immune response, which might lead to varying disease susceptibility. Here, we review recent evidence of how germline variation in Ig genes impacts the Ig repertoire and its subsequent effects on the adaptive immune response in vaccination, infection, and autoimmunity.


Regenerable immuno-biochip for screening ochratoxin A in green coffee extract using an automated microarray chip reader with chemiluminescence detection.
Ochratoxin A (OTA) can contaminate foodstuffs in the ppb to ppm range and once formed, it is difficult to remove. Because of its toxicity and potential risks to human health, the need exists for rapid, efficient detection methods that comply with legal maximum residual limits. In this work we have synthesized an OTA conjugate functionalized with a water-soluble peptide for covalent immobilization on a glass biochip by means of contact spotting. The chip was used for OTA determination with an indirect competitive immunoassay format with flow-through reagent addition and chemiluminescence detection, carried out with the stand-alone automated Munich Chip Reader 3 (MCR 3) platform. A buffer model and real green coffee extracts were used for this purpose. At the present, covalent conjugate immobilization allowed for at least 20 assay-regeneration cycles of the biochip surface. The total analysis time for a single sample, including measurement and surface regeneration, was 12 min and the LOQ of OTA in green coffee extract was 0.3 μg L(-1) which corresponds to 7 μg kg(-1).


Predicting patient decompensation from continuous physiologic monitoring in the emergency department.
Anticipation of clinical decompensation is essential for effective emergency and critical care. In this study, we develop a multimodal machine learning approach to predict the onset of new vital sign abnormalities (tachycardia, hypotension, hypoxia) in ED patients with normal initial vital signs. Our method combines standard triage data (vital signs, demographics, chief complaint) with features derived from a brief period of continuous physiologic monitoring, extracted via both conventional signal processing and transformer-based deep learning on ECG and PPG waveforms. We study 19,847 adult ED visits, divided into training (75%), validation (12.5%), and a chronologically sequential held-out test set (12.5%). The best-performing models use a combination of engineered and transformer-derived features, predicting in a 90-minute window new tachycardia with AUROC of 0.836 (95% CI, 0.800-0.870), new hypotension with AUROC 0.802 (95% CI, 0.747-0.856), and new hypoxia with AUROC 0.713 (95% CI, 0.680-0.745), in all cases significantly outperforming models using only standard triage data. Salient features include vital sign trends, PPG perfusion index, and ECG waveforms. This approach could improve the triage of apparently stable patients and be applied continuously for the prediction of near-term clinical deterioration.


The M694V mutation in Armenian-Americans: a 10-year retrospective study of MEFV mutation testing for familial Mediterranean fever at UCLA.
Familial Mediterranean fever (FMF), inherited in an autosomal recessive manner, is a systemic auto-inflammatory disorder characterized by recurrent attacks of fever with peritonitis, pleuritis, synovitis and erysipeloid rash. The marenostrin-encoding fever (MEFV) gene, located on chromosome 16p13.3, is the only gene in which mutations are currently known to cause FMF. To correlate specific genotypes with adverse phenotypes of affected populations residing in the Western United States, a retrospective case series review was conducted of all MEFV gene mutation testing completed at UCLA Clinical Molecular Diagnostic Laboratory between February 2002 and February 2012, followed by clinical chart review of all subjects who either have a single or double mutation. All 12 common mutations in the MEFV gene were analyzed and the M694V variant was found to be associated with an adverse FMF clinical outcome in the Armenian-American population, manifested by earlier onset of disease, increased severity of disease, and renal amyloidosis.


Is it Necessary to Measure Blood Glucose Level Before and After Colonoscopy in Diabetic and Nondiabetic Patients?
The aim of this study was to examine the necessity of measuring the blood glucose level before and after a colonoscopy in diabetic and nondiabetic patients. A total of 200 patients who were over the age of 18 with an American Society of Anesthesiologists (ASA) score I-IV and were to undergo an elective colonoscopy procedure were included in this randomized, controlled, prospective trial. In the study group, 100 patients were diabetic and 100 were nondiabetic. Patient age, sex, body mass index, ASA classification, comorbid diseases, daily medications, and the length of preprocedure fasting were recorded. Before the procedure, the capillary glucose level was measured and recorded as an initial value. This glucose assessment was repeated and recorded 15 minutes after the beginning of the colonoscopy and 60 minutes after the procedure. All complications related to the anesthesia or the colonoscopy were recorded. The sex and age distribution was not statistically significant in a comparison of the diabetic and nondiabetic groups. The body mass index value and presence of comorbid diseases, particularly hypertension, was statistically significantly higher in the diabetic group. There was no significant difference in complications between the groups. The mean fasting time in the diabetic group was statistically significantly shorter than that of the nondiabetics. The blood glucose level of the diabetic patients was consistently higher than that of the nondiabetics. Blood glucose measurement is necessary for diabetic patients before and after a colonoscopy procedure; however, assessment is not necessary for nondiabetics.


Role of sex hormones in modulating breast and ovarian cancer associated pain.
According to the National Cancer Institute in 2020 there will be an estimated 21,750 new ovarian cancer cases and 276,480 new breast cancer cases. Both breast and ovarian cancer are hormone dependent cancers, meaning they cannot grow without the presence of hormones. The two most studied hormones in these two cancers are estrogen and progesterone, which are also involved in the modulation of pain. The incidence of pain in breast and ovarian cancer is very high. Research about mechanisms involved in modulation of pain by hormones are still being debated, as some studies find estrogen to be anti-nociceptive and others pro-nociceptive in pain studies. Moreover, analgesic treatments for breast and ovarian cancer-associated pain are limited and often ineffective. In this review, we will focus on estrogen and progesterone mechanisms of action in modulation of pain and cancer. We will also discuss new treatment options for these types of cancer and associated-pain.


Green and gold kiwifruit peel ethanol extracts potentiate pentobarbital-induced sleep in mice via a GABAergic mechanism.
Kiwifruit is one of the most popular fruits worldwide, and it has various biological properties, including antioxidant, anti-allergic, and cardiovascular protective effects. The peel of kiwifruit, which is a by-product of processing, is a good source of flavonoids; however, its bioactivity has not been widely investigated. In this study, we evaluated the hypnotic effects of green (GRPE, Actinidia deliciosa) and gold (GOPE, Actinidia chinensis) kiwifruit peel ethanol extracts and their solvent fractions, and the possible underlying mechanisms. Oral GRPE and GOPE administration (125-1000mg/kg) produced a dose-dependent decrease in sleep latency and an increase in sleep duration in pentobarbital-treated mice. Among three different solvent fractions of GRPE and GOPE, ethyl acetate (EA) fractions had the greatest effect on sleep duration at 250mg/kg. The total flavonoid contents of solvent fractions were proportional to sleep duration. Like diazepam (a GABA(A)-benzodiazepine (BZD) receptor agonist), the hypnotic effects of GRPE, GOPE, and their EA fractions were fully inhibited by flumazenil (a GABA(A)-BZD receptor antagonist). These results suggest that potentiation effects of GRPE and GOPE on pentobarbital-induced sleep in mice may be modulated by a GABAergic mechanism.


[Olecranon fractures].
Olecranon fractures represent a common elbow injury and they are usually treated operatively. Depending on fracture morphology conservative therapy can be considered in geriatric patients. When surgical treatment is performed the anatomical features of the proximal ulna have to be taken into consideration. Tension band wiring is considered a standard procedure for simple fractures and provides good clinical results. Plate osteosynthesis is indicated for more complex fracture patterns. Nowadays, many surgeons prefer plate fixation over tension band wiring even for simple fractures as it leads to a more stable fixation. Both methods frequently require hardware removal for persisting soft tissue irritation. The use of modern low-profile plates could reduce the need for implant removal due to better soft tissue coverage. The available clinical data regarding low-profile plates are promising but limited.


[Management of Gitelman syndrome during pregnancy reporting 12 cases].
Gitelman syndrome is a rare hereditary renal tubulopathy, responsable of hypokalemia and hypomagnesaemia-related ionic disorders, which management is poorly codified during pregnancy. We report 12 cases of pregnancies with Gitelman syndrome and we compare our data with those of literature. It is a report of 12 pregnancies in 5 patients with Gitelman syndrome between 2002 and 2016. Follow up and outcome of pregnancy, delivery modalities and maternal-fetal prognosis have been collected. In our serie, maximum kaliemie observed was 3.4mmol/L, with an average potassium, over all pregnancies of 2.3mmol/L. Oral potassium and magnesium supplementation at the end of pregnancy were 8900mg/day and 460mg/day, respectively. There were no serious maternal complications. Two pregnancies were complicated by intrauterine growth retardation in a context of preeclampsia. There is a large disparity in the methods of anesthetic management of these patients. Materno-fetal prognosis at 1 month post-partum is good. Gitelman syndrome is a rare pathology where there is a lack of homogeneity in management of pregnancy. Monitoring of monthly ionogram is necessary. The goal is to obtain stable, non-symptomatic kaliemias, which will never be standardized even in increasing treatment. The most important is to inform and detect situations at risk of decompensation, including vomiting or the use of certain anesthetics. In agreement with literature data, monitoring of fetal growth and the amount of amniotic fluid in the third trimester is still warranted. These pregnancies require the development of a common care in multidisciplinary consultation meeting.


Divergent extremes but convergent recovery of bacterial and archaeal soil communities to an ongoing subterranean coal mine fire.
Press disturbances are stressors that are extended or ongoing relative to the generation times of community members, and, due to their longevity, have the potential to alter communities beyond the possibility of recovery. They also provide key opportunities to investigate ecological resilience and to probe biological limits in the face of prolonged stressors. The underground coal mine fire in Centralia, Pennsylvania has been burning since 1962 and severely alters the overlying surface soils by elevating temperatures and depositing coal combustion pollutants. As the fire burns along the coal seams to disturb new soils, previously disturbed soils return to ambient temperatures, resulting in a chronosequence of fire impact. We used 16S rRNA gene sequencing to examine bacterial and archaeal soil community responses along two active fire fronts in Centralia, and investigated the influences of assembly processes (selection, dispersal and drift) on community outcomes. The hottest soils harbored the most variable and divergent communities, despite their reduced diversity. Recovered soils converged toward similar community structures, demonstrating resilience within 10-20 years and exhibiting near-complete return to reference communities. Measured soil properties (selection), local dispersal, and neutral community assembly models could not explain the divergences of communities observed at temperature extremes, yet beta-null modeling suggested that communities at temperature extremes follow niche-based processes rather than null. We hypothesize that priority effects from responsive seed bank transitions may be key in explaining the multiple equilibria observed among communities at extreme temperatures. These results suggest that soils generally have an intrinsic capacity for robustness to varied disturbances, even to press disturbances considered to be 'extreme', compounded, or incongruent with natural conditions.


Synchronized electrochemical detection of hydroquinone and catechol in real water samples using a Co@SnO2-polyaniline composite.
The conductive composite Co@SnO2-PANI was successfully synthesized using hydrothermal/oxidative synthesis. Using differential pulse voltammetry, a glassy carbon electrode modified with a CoSnO2-PANI (polyaniline)-based electrochemical biosensor has been created for the quick detection of two phenolics, hydroquinone (Hq) and catechol (Cat). Differential pulse voltammetry (DPV) measurements revealed two well-resolved, strong peaks for GCE@Co-SnO2-PANI, which corresponded to the oxidation of Hq and Cat at 275.87 mV and +373.76 mV, respectively. The oxidation peaks of Hq and Cat mixtures were defined and separated at a pH of 8.5. High conductivity and remarkable selectivity reproducibility was tested by electrochemical impedance spectroscopy, chronoamperometry, and cyclic voltammetry techniques in standard solution and real water samples. The proposed biosensor displayed a low detection limit of 4.94 nM (Hq) and 1.5786 nM (Cat), as well as a large linear range stretching from 2 × 10-2 M to 2 × 10-1 M. The real-sample testing showed a good recovery for the immediate detection of Hq (96.4% recovery) and Cat (98.8% recovery) using the investigated sensing apparatus. The synthesized biosensor was characterized by XRD, FTIR, energy dispersive spectroscopy and scanning electron microscopy.


Visual motion, binocular correspondence and binocular rivalry.
Human observers dichoptically viewed displays consisting of isotropic random dots, with the dots in each eye's view all moving in a given direction or appearing stationary. When the interocular difference in direction of motion was less than 30 deg, a stable, fused percept resulted. Once this interocular difference was exceeded, binocular rivalry ensued. Rivalry was also obtained when dots seen by the two eyes moved in identical directions but at different velocities. Under this condition, the proportion of time that rivalry was experienced increased with the interocular difference in velocity. Moving dots predominated over stationary ones, and when both sets of dots moved there was no clear advantage of one speed of motion over the other. Contrary to some earlier reports, these results show that motion is not immune to binocular rivalry. Evidently the process responsible for establishing binocular correspondence between images received by the two eyes is sensitive to disparities in direction and velocity of motion.


Effect of individual or comorbid antenatal depression and anxiety on birth outcomes and moderation by maternal traumatic experiences and resilience.
Although antenatal depression and anxiety (e.g., negative antenatal mental health; NAMH) are individually associated with preterm birth (PTB) and infant neurological impairment, few studies account for comorbidity. Understanding how NAMH impacts PTB and infant neurological functioning by either singular (depression or anxiety) or comorbid status, as well as the way in which these effects can be moderated by additional risk or protective factors (traumatic experiences and trait resiliency) can contribute further understanding of NAMH effects on birth outcomes. The sample included 3042 mother-infant dyads from U.S. and South Africa cohorts of the Safe Passage Study (N = 3042). A four-category NAMH variable was created to categorize depression-only, anxiety-only, comorbid, or no NAMH statuses. There were no NAMH main effects on PTB, however, anxiety-only and comorbid NAMH increased odds of PTB for mothers with higher rates of traumatic life experiences. Anxiety-only and comorbid NAMH were associated with increased odds of newborn neurological impairment, and the effect of comorbid NAMH was stronger for mothers with higher rates of traumatic experiences. Resiliency decreased odds of neurological impairment for mothers who reported depression-only or anxiety-only NAMH. Limitations included potential artefacts of two cohorts that differed in rates of almost all variables, a single time point for measuring NAMH, and lack of pregnancy-specific NAMH measures. Especially when compared to mothers with no NAMH, comorbidity or singular-condition NAMH statuses associate with negative birth outcomes in nuanced ways, especially when considering additional contexts that may foster or protect against NAMH.


Is gender related to the stage of colorectal cancer at initial presentation in young patients?
The incidence of colorectal cancer (CRC) in young adults is rising, and young age is a predictor of poor survival. The purpose of this study was to examine factors leading to increased mortality in patients ≤ 50 years of age, and to examine this population for characteristics that could lead to benefit from CRC screening. Charts of patients 50 years of age and under, diagnosed with CRC from 1998 through 2007, at our community teaching hospital, were reviewed retrospectively. Demographics, social and family history, staging, treatment and death were evaluated. Mann Whitney, Fisher Exact, and χ(2) tests were used with P <0.05 considered statistically significant. Forty-five young patients with CRC were identified. Twenty-five patients were female and 20 male; the mean age was 43.6 y. Most patients presented with rectal bleeding. Right-sided cancers had a higher presenting stage (P < 0.05). Men had both a higher presenting stage (P = 0.35) and a higher incidence of smoking compared with women (P = 0.001). Female patients were more likely to have left-sided CRC (65%) compared with men (35%). Ninety-six percent of patients underwent surgical resection; 14 patients died. CRC in young adults is not common, but is often advanced when discovered. Diagnostic efforts should be aggressive in young patients who have rectal bleeding, especially young male smokers. Sigmoidoscopy is not adequate for comprehensive diagnosis of CRC in young patients, as the majority have right-sided colon cancers, which often result in subsequent presentation of the disease at a higher stage, risk, and mortality rate.


Short- and long-term agreement and reproducibility of 48-hours intraocular pressure measurements in glaucoma patients.
Glaucomatous eyes often show strong intraocular pressure (IOP) fluctuations and individual measurements at different time points are necessary for personalized therapy. To survey IOP variations 48-hours diurnal and nocturnal IOP measurements were performed on two consecutive days. Aims of this study were to investigate the short-term repeatability of 48-hours measurements within one patient's IOP profile and long-term repeatability between two separate IOP profiles of the same patient. A retrospective cohort study was performed evaluating data of 90 glaucoma patients in a German university medical center between 2006 and 2013. All patients underwent two separate diurnal IOP profiles of 48 h. IOP was measured at 8 am, 2 pm, 6 pm, 9 pm using Goldmann applanation tonometry and at 12 midnight using Perkins tonometry in supine position on two consecutive days. Intraclass correlation coefficients (ICC) were calculated to evaluate agreement for the same time points (each time point agreement) and for consecutive measurements within the IOP profiles (between time point agreement). ICC ≤ 0.4 was defined as poor agreement, 0.4-0.75 as moderate and ≥ 0.75 as excellent. Differences between time points were investigated by Bland Altman plots. Each time point measurements of profile 1 showed moderate to excellent agreement (ICCs 0.62-0.93). There was a moderate to excellent agreement for measurements between time points of profile 1 (ICCs day one 0.57-0.86, day two 0.71-0.90). Profile 2 was performed at a median interval of 12.0 months (quartiles 11.0 to 21.0). Each time point agreements within profile 2 showed ICCs from 0.23 to 0.81. It showed moderate to excellent agreement for changes between time points (ICCs 0.53-0.94). Day two demonstrated ICCs from 0.74 to 0.88. Long term IOP repeatability (over both pressure profiles) showed moderate to good agreement (ICCs 0.39-0.67). Short and long-term agreement of IOP measurements evaluated by diurnal IOP profiles is moderate to good. Due to mostly moderate agreements, which we believe represent IOP fluctuations, we conclude that it is necessary to perform 48-hours IOP profiles to gain a better overview of the individual IOP fluctuations.


Neuropsychological models of stuttering--II. Interhemispheric interference.
The performance of male adult stutterers and fluent speakers was compared on repetitive sequential finger tapping and index finger tapping with one hand while carrying out concurrent paced tasks with the other hand. For the theoretically meaningful condition of right-hand sequential tapping and left-hand concurrent task performance, there was more interference on the tapping task among stutterers than fluent speakers. The data were interpreted as being consistent with a neuropsychological model of stuttering that includes as an element enhanced left-hemisphere vulnerability to interference by concurrent right-hemisphere activity.


Trajectory of livestock genomics in South Asia: A comprehensive review.
Livestock plays a central role in sustaining human livelihood in South Asia. There are numerous and distinct livestock species in South Asian countries. Several of them have experienced genetic development in recent years due to the application of genomic technologies and effective breeding programs. This review discusses genomic studies on cattle, buffalo, sheep, goat, pig, horse, camel, yak, mithun, and poultry. The frontiers covered in this review are genetic diversity, admixture studies, selection signature research, QTL discovery, genome-wide association studies (GWAS), and genomic selection. The review concludes with recommendations for South Asian livestock systems to increasingly leverage genomic technologies, based on the lessons learned from the numerous case studies. This paper aims to present a comprehensive analysis of the dichotomy in the South Asian livestock sector and argues that a realistic approach to genomics in livestock can ensure long-term genetic advancements.


MLKL and other necroptosis-related genes promote the tumor immune cell infiltration, guiding for the administration of immunotherapy in bladder urothelial carcinoma.
The involvement of necroptosis in the immunosuppressive tumor microenvironment has been established and has been shown to contribute to the growth of pancreatic ductal adenocarcinoma, indicating its role in promoting tumor development. However, the relationship between necroptosis and bladder urothelial carcinoma (BUC) has yet to be fully understood. To shed light on this issue, our study aimed to uncover the impact of necroptosis on immune cell infiltration and immunotherapy response in BUC patients. We conducted an analysis of 67 necroptosis genes to assess their expression and genomic changes across pan-cancer and identified 12 necroptosis genes that are prognostically relevant and associated with immune subtypes and tumor stemness in BUC. Using a public database of 1841 BUC samples, we then performed Unsupervised Cluster Analysis and discovered two distinct necroptotic phenotypes in BUC. These phenotypes showed significant differences in molecular subtypes, immune infiltration patterns, and gene mutation profiles. We confirmed this discovery in BUC through qPCR and WB experiments. To evaluate the impact of necroptosis on prognosis, chemotherapy sensitivity, and immunotherapy response (such as anti-PD-L1), we developed a principal component analysis model called NecroScore. Finally, we validated the effects of RIPK3 and MLKL through a nude mouse transplantation model for BUC. Our study has uncovered that necroptosis plays a role in shaping the tumor immune microenvironment in BUC. The high necroptosis phenotype (Cluster B) was characterized by a higher abundance of tumor immunosuppressive cells and more key biological processes driving tumor progression, while the low necroptosis group (Cluster A) had higher FGFR3 mutations. We found that the infiltration levels of immune cells, including CD8+ T cells, were significantly different between FGFR3 mutated and wild-type (WT) samples. Our results confirmed the reliability of NecroScore as a comprehensive assessment tool for evaluating the immunotherapeutic effect and prognosis of BUC patients, with high NecroScore values favoring basal-like differentiation and lower FGFR3 alterations. We also observed that high expression of MLKL had a significant inhibitory effect on tumor growth and increased neutrophil infiltration in vivo. In our study, we uncovered the regulation pattern of necroptosis in the tumor immune microenvironment of BUC. Additionally, we developed a scoring tool called NecroScore that can be utilized to predict the most suitable chemotherapy and immunotherapy strategy for bladder urothelial carcinoma patients. This tool can effectively guide the chemotherapy and immunotherapy regimens for patients with advanced BUC.


Nasopharyngeal teratoma causing airway obstruction in the neonate.
Teratomas are the most common congenital tumours, but teratomas of the nasopharynx are rare in neonates. The present report concerns a premature 30-week-old infant girl with an extensive nasopharyngeal teratoma protruding from the oral cavity. The tumour completely obstructed the airway and necessitated immediate intubation. The tumour was successfully resected directly via the transoral route without needing external incisions. Histological examination of the specimen revealed it to be a mature teratoma. The management and differential diagnosis is discussed, accompanied by a review of the literature.


Identification of alternatively spliced isoforms of interleukin-2/15 receptor β chain in ducks.
Interleukin (IL)-2 and IL-15 receptor β (IL-2/15Rβ, CD122) play important roles in signal transduction for biological functions of IL-2 and IL-15. We found that ducks possess three different IL-2/15Rβ transcripts, a conventional form (duIL-2/15Rβ) and two variants. Comparisons between the cDNA and genomic sequences revealed that the two variants, duIL-2/15Rβ-d7 and duIL-2/15Rβ-d9, were novel spliced transcripts resulting from skipping exons 7 and 9, respectively. Expression profiles of duIL-2/15Rβ and its isoforms were examined in healthy tissues, concanavalin A (ConA)-stimulated splenic lymphocytes and in livers and spleens of Riemerella anatipestifer-infected ducks using quantitative real-time PCR (qRT-PCR). Generally, duIL-2/15Rβ-d9 expression was undetectable in healthy tissues, ConA-activated samples, and R. anatipestifer-infected ducks. Expression levels of duIL-2/15Rβ transcript were relatively high to moderate in all healthy tissues tested, while duIL-2/15Rβ-d7 expression was low. Compared to untreated controls, expression levels of duIL-2/15Rβ were elevated in ConA-activated splenic lymphocytes and in livers on day 7 in R. anatipestifer-infected ducks, while duIL-2/15Rβ-d7 expression was unchanged. Additionally, COS-7 cells transfected with duIL-2/15Rβ, duIL-2/15Rβ-d7, or duIL-2/15Rβ-d9 constructs generated 73 kilodalton (kDa), 31kDa, and 40kDa proteins, respectively. This study identified three different IL-2/15Rβ transcripts, including two isoforms generated by alternative splicing and their gene expression patterns in stimulated conditions.


The definition of precision medicine in neurodegenerative disorders and the one disease-many diseases tension.
Precision medicine is a patient-centered approach that aims to translate new knowledge to optimize the type and timing of interventions for the greatest benefit to individual patients. There is considerable interest in applying this approach to treatments designed to slow or halt the progression of neurodegenerative diseases. Indeed, effective disease-modifying treatment (DMT) remains the greatest unmet therapeutic need in this field. In contrast to the enormous progress in oncology, precision medicine in the field of neurodegeneration faces multiple challenges. These are related to major limitations in our understanding of many aspects of the diseases. A critical barrier to advances in this field is the question of whether the common sporadic neurodegenerative diseases (of the elderly) are single uniform disorders (particularly related to their pathogenesis) or whether they represent a collection of related but still very distinct disease states. In this chapter, we briefly touch on lessons from other fields of medicine that might be applied to the development of precision medicine for DMT in neurodegenerative diseases. We discuss why DMT trials may have failed to date, and particularly the importance of appreciating the multifaceted nature of disease heterogeneity and how this has and will impact on these efforts. We conclude with comments on how we can move from this complex disease heterogeneity to the successful application of precision medicine principles in DMT for neurodegenerative diseases.


Predicting gestational trophoblastic neoplasia (GTN): is urine hCG the answer?
Previous studies on the significance of hCG to predict gestational trophoblastic neoplasia (GTN) have been too small for robust conclusions to be reached. Our aim in this study was to analyse the significance of urine hCG in predicting GTN in a large population. Details of 3926 patients were available for analysis. Information regarding age, dates of diagnosis and registration, urine hCG levels, antecedent pregnancy and chemotherapy were prospectively collected and used for analyses. Patients were stratified into different groups according to urine hCG level (IU/L); < 50, 50-99, 100-249, 250-499, 500-999, 1000-9999 and ≥10,000. Multivariate analyses were used to identify the prognostic indicators of GTN. Urine hCG and antecedent pregnancy were the most powerful indicators for developing GTN (P<0.01). None of the patients with partial mole and urine hCG <50 IU/L (Normal level=40 IU/L) developed GTN. The risk of GTN was >35% in all patients with urine hCG ≥500 IU/L. GTN developed in 70% of patients with complete mole and urine hCG ≥10,000 IU/L. Urine hCG is sensitive test for GTN. Urine hCG level is a powerful prognostic indicator for the GTN. Patients with partial mole could be safely discharged from the surveillance programme once their hCG have normalised. Patients with urine hCG ≥249 IU/L, whether partial or complete molar pregnancy, appear to benefit from intensive surveillance. Prophylactic chemotherapy could be considered when there are problems with surveillance.


[Development without dormancy of prospective diapause eggs ofBombyx mori in paraffin oil with or without chorion].
Prospective diapause eggs ofBombyx mori become permeable to water in or after contact with paraffin, and they die before reaching diapause. If the eggs are hindered from drying up, their germ anlagen develop to diapausing germ bands. Prospective diapause eggs opened in paraffin, always develop without egg diapause, but their degree of organogenesis depends on the chorion: When eggs are completely dechorionized most of them develop to hatching or nearly hatching larvae; when eggs are completely dechorionized, but their chorion remains in the paraffin, the degree of organogenes is issignificantly lower; and when the opened eggs keep 1/2-3/4 of the chorion, their organogenesis is significantly lower than in the two previous experiments.It is discussed that nondormancy development ofprospective diapause eggs in vitro is not a specific effect of culture media containing water but is possible in paraffin oil too. It is not only possible to stop but also to prevent egg diapause. Nothing, as yet, can be said about the prospective significance of the chorion's reducing factor in organogenesis.


Neighborhood poverty and children's exposure to danger: Examining gender differences in impacts of the Moving to Opportunity experiment.
The Moving to Opportunity (MTO) program offered public housing residents in distressed communities a chance to move to low-poverty neighborhoods. The present study examined whether the resulting decline in neighborhood poverty led to lower levels of exposure to danger among children and youth ages 8-19years old (n=4606), and specifically, if there was a gender difference that matched the pattern of more beneficial program effects for girls and more adverse affects for boys. The study goes beyond previous research by using fixed effects to control for family factors that may influence moving behavior and confound estimates of gender differences in program impacts. Results showed that children experienced a decline in exposure to danger, with one key gender difference. Models based on brother-sister comparisons indicated that MTO had a more beneficial impact on exposure to drug activity for females than males. The findings suggest that neighborhood poverty is tied to children's exposure to danger. Moreover, exposure to drug activity may help explain the gender differences in impacts on children's mental health and risky behavior.


Prognostic Significance of Complete Pathologic Response Obtained with Chemotherapy Versus Chemoradiotherapy in Gastric Cancer.
Few studies have compared the survival advantage of complete pathologic response (cPR) achieved through neoadjuvant chemotherapy (nCT) versus neoadjuvant chemoradiotherapy (nCRT) in gastric adenocarcinoma. Our study utilizes a large national cancer database to address this question. This is a retrospective review of patients with clinical stage I to III gastric adenocarcinoma from 2004 to 2013 who received nCT or nCRT. Patients who achieved cPR were selected. Associations were evaluated using Mann-Whitney U and Fisher's exact tests. Survival information was summarized using standard Kaplan-Meier methods, where estimates of the median and 5-year survival rates were estimated with 95% confidence intervals. A total of 413 patients who had cPR were identified. Eighty-four patients received nCT and 329 patients received nCRT. Patients in the nCRT group had higher clinical stage (88.4% vs. 75.0%) and more proximal location of tumors (95.4% vs. 45.2%). The nCT group (n = 84) had a 94% 5-year survival rate, while the nCRT group's (n = 329) rate was 60% (p < 0.001). On Cox regression modeling using a propensity-weighted approach, nCT treatment was an independent predictor of improved overall survival (nCRT vs. nCT; HR 10.44, p < 0.001). The use of nCT leads to a significant increase in overall survival in patients when compared with nCRT for those who achieved cPR in gastric adenocarcinoma. While this study is limited in identifying the cause for this difference in overall survival, this important finding nonetheless requires further investigation and should be considered in the development of future gastric cancer trials.


Vitreous fluorophotometric recordings in HIV infection.
Fluorophotometry was performed in 10 patients. Five of these were affected by AIDS and five ARC (AIDS Related Complex). All patients had normal fundi detectable by standard examination and by fluorescein angiography. In spite of the normal condition of the fundus, vitreous fluorophotometry readings were constantly above normal. We believe that the disturbance of the blood retinal barrier appears before any lesion detectable both clinically and by fluorangiography. It is possible that the first toxic effect of the retrovirus is at the level of the retinal vessels.


The addition of clonidine to ropivacaine in rectus sheath nerve blocks for pediatric patients undergoing laparoscopic appendectomy: A double blinded randomized prospective study.
The primary goal of this study was to determine if the addition of clonidine to ropivacaine prolonged periumbilical numbness compared to ropivacaine alone in pediatric patients receiving ultrasound guided rectus sheath nerve blocks for laparoscopic appendectomy. The secondary goals were to evaluate differences in perioperative pain scores, analgesic consumption, sedation, anxiolysis, and hemodynamic effects from clonidine. This was a single center, randomized, double-blinded prospective study. This study was conducted within the pediatric operating rooms at the Children's Hospital of Pittsburgh, a large university-based academic medical center. Fifty pediatric patients (ages 10-17 years old) without pre-existing cognitive impairment, developmental delay or chronic pain undergoing laparoscopic appendectomy during weekday hours were enrolled and randomized to control versus intervention groups. Ultrasound guided rectus sheath nerve block injections were performed at the beginning of surgery with either ropivacaine 0.5% plus normal saline or ropivacaine 0.5% plus clonidine (2 mcg/kg, maximum of 100 mcg). The duration of periumbilical numbness, Numeric Pain Rating Scale scores, University of Michigan Sedation Scale, State-Trait Anxiety Inventory for Children, analgesic consumption, heart rate, blood pressure, and mean arterial pressures, were recorded for each patient at several time points in the perioperative setting. There were no significant differences in demographic characteristics between groups. The median duration of periumbilical numbness did not significantly differ between the ropivacaine only and the ropivacaine plus clonidine groups 540.0 minutes [360.0 -1015.0] (median [interquartile range (IQR)]) versus 823.5 minutes [509.5- 1080.0], p = 0.451. There were no significant differences in perioperative analgesic consumption, pain and anxiety scores, PACU sedation, or hemodynamic instability. The addition of clonidine did not significantly prolong rectus sheath nerve block duration and was well tolerated in pediatric patients. Perioperative analgesia, hemodynamics, anxiety, and PACU sedation did not differ between groups. Clinical Trials NCT02439281.


Removal of fluoride from wastewater solution using Ce-AlOOH with oxalic acid as modification.
In this paper, Ce-AlOOH were investigated to develop as an adsorbent for removing fluoride. Oxalic acid was selected as an effectively modified reagent to improve the performance of adsorption. Cerium existed in the form of CeO2 and kept good stability during the adsorption process through XRD, TEM, BET, Raman, and Infrared spectra. The adsorption capacity could be improved with the addition of cerium (62.8 mg/g). Specially, the oxalic acid modification significantly promoted the adsorption capacity to 90 mg/g. There adsorption isotherm and kinetics were estimated independently. These adsorption behaviors were in accordance with the Freundlich model and pseudo-second-order model, indicating that chemisorption was the rate-determining step. the obtained adsorbents all exhibited good recycling performance using oxalic acid as the regeneration reagent. The species of tetravalent cerium was the important adsorption sites. The mechanism was carefully explored by XPS analysis. The fluoride adsorption process can be ascribed to the combined effect of the electrostatic action, surface coordination, and ion exchange between M-OH and F-. Furthermore, modification of oxalic acid exhibited a new easier way to quickly increase M-OH content, which contributed to the dominated adsorption sites.


TFCP2 is a transcriptional regulator of heparan sulfate assembly and melanoma cell growth.
Heparan sulfate (HS) is a long, linear polysaccharide that is ubiquitously expressed in all animal cells and plays a key role in many cellular processes, including cell signaling and development. Dysregulation of HS assembly has been implicated in pathophysiological conditions, such as tumorigenesis and rare genetic disorders. HS biosynthesis occurs in a non-template-driven manner in the endoplasmic reticulum and Golgi through the activity of a large group of biosynthetic enzymes. While much is known about its biosynthesis, little is understood about the regulation of HS assembly across diverse tissue types and disease states. To address this gap in knowledge, we recently performed genome-wide CRISPR/Cas9 screens to identify novel regulatory factors of HS biosynthesis. From these screens, we identified the alpha globin transcription factor, TFCP2, as a top hit. To investigate the role of TFCP2 in HS assembly, we targeted TFCP2 expression in human melanoma cells using the CRISPR/Cas9 system. TFCP2 knockout cells exhibited decreased fibroblast growth factor binding to cell surface HS, alterations in HS composition, and slowed cell growth compared to wild-type cells. Additionally, RNA sequencing revealed that TFCP2 regulates the expression of multiple enzymes involved in HS assembly, including the secreted endosulfatase, SULF1. Pharmacological targeting of TFCP2 activity similarly reduced growth factor binding and increased SULF1 expression, and the knockdown of SULF1 expression in TFCP2 mutant cells restored melanoma cell growth. Overall, these studies identify TFCP2 as a novel transcriptional regulator of HS and highlight HS-protein interactions as a possible target to slow melanoma growth.


Correction of aortic regurgitation after transcatheter aortic valve implantation of the Medtronic CoreValveTM prosthesis due to a too-low implantation, using transcatheter repositioning.
Transcatheter aortic valve implantation (TAVI) has been introduced for the treatment of severe symptomatic aortic stenosis in patients not suitable for surgical valve replacement. However, a potential problem of TAVI is the development of severe aortic insufficiency after valve implantation due to a too-low implantation of the valve. Since August 2008, a total of 33 TAVI procedures using the 18 Fr Medtronic CoreValve ReValving system has been performed at the authors' institution. Severe post-implantation aortic regurgitation occurred in three patients (9%), due to a too-low implantation. Two of these patients underwent a catheter-based repositioning of the valve using a standard snare; the third patient declined any further intervention. Both repositioning procedures were uneventful, with no significant residual regurgitation. Severe aortic regurgitation after TAVI with the Medtronic CoreValve system is not uncommon. If the valve is implanted too low, a catheter-based valve repositioning may be the method of choice to resolve the problem.


The curiously suspicious: infectious disease may ameliorate an ongoing autoimmune destruction in systemic lupus erythematosus patients.
Systemic lupus erythematosus (SLE) is a chronic autoimmune disease, which can arise from a combination of genetic and environmental factors. In the past, infections (Epstein Barr virus, parvovirus B-19) have been indicated to play a causative role in the development of autoimmune diseases, such as SLE. On the other hand, with the emergence of the "hygiene hypothesis" infections have also shown to play a protective role in autoimmune diseases. Two case studies are presented which provide clinical evidence of SLE patients with severe, long-term disease, despite immunosuppresive therapy. The course of both diseases changed remarkably after they experienced infections with multiple microbes (bacterial, viral and fungal). Surprisingly, their clinical and laboratory signs of SLE normalized and they are now symptom-free after 5 and 3year follow-ups. The second patient has even had a normal pregnancy, which was a trigger factor for disease flare in the past. The infections presumably changed the host immune systems and the mechanisms of their protective effects are most likely multifactorial. Our cases illustrate that infections could be beneficial in SLE patients and re-directing research toward novel innate-based SLE therapy should be explored.


Interaction between sodium dodecyl sulfate and membrane reconstituted aquaporins: a comparative study of spinach SoPIP2;1 and E. coli AqpZ.
This study describes the interaction between sodium dodecyl sulfate (SDS) and membrane proteins reconstituted into large unilamellar lipid vesicles and detergent micelles studied by circular dichroism (CD) and polarity sensitive probe labeling. Specifically, we carried out a comparative study of two aquaporins with high structural homology SoPIP2;1 and AqpZ using identical reconstitution conditions. Our CD results indicate that SDS, when added to membrane-reconstituted aquaporins in concentrations below the SDS critical micelle concentration (CMC, ~8mM), causes helical rearrangements of both aquaporins. However, we do not find compelling evidence for unfolding. In contrast when SDS is added to detergent stabilized aquaporins, SoPIP2;1 partly unfolds, while AqpZ secondary structure is unaffected. Using a fluorescent polarity sensitive probe (Badan) we show that SDS action on membrane reconstituted SoPIP2;1 as well as AqpZ is associated with initial increased hydrophobic interactions in protein transmembrane (TM) spanning regions up to a concentration of 0.1× CMC. At higher SDS concentrations TM hydrophobic interactions, as reported by Badan, decrease and reach a plateau from SDS CMC up to 12.5× CMC. Combined, our results show that SDS does not unfold neither SoPIP2;1 nor AqpZ during transition from a membrane reconstituted form to a detergent stabilized state albeit the native folds are changed.


Management of patients receiving transperineal palladium-103 prostate implants.
To describe the complexities of the medical management of patients undergoing treatment of prostate cancer; discuss the sequelae of treatment options, including surgery, external beam radiation, and brachytherapy; outline the evolution of interstitial prostatic brachytherapy and the current use of transperineal ultrasound-guided prostate implants using palladium-103 (103Pd), and discuss the side effects of the 103Pd prostate implant as well as the nursing management of patients who receive the implants. Published articles and State of Florida administrative codes. Transperineal 103Pd implants are a viable and contemporary treatment for early stage prostate cancer that provide the advantages of an outpatient procedure along with less acute morbidity and better potency preservation. Side effects associated with 103Pd implants are predictable, short-lived, and easily managed. Sexual function is maintained in most men. Patient education greatly reduces patient anxiety. Nurses' roles include preprocedure assessment, intraprocedure care and postimplant monitoring, and patient education for discharge.


Salivary tumor necrosis factor-alpha to detect the severity of erectile dysfunction: A randomized clinical trial.
This study aimed to provide evidence on the impact of chronic periodontitis (CP) on the severity of erectile dysfunction (ED) through the assessment of the salivary level of tumor necrosis factor-alpha (TNF-α). 140 patients with chronic periodontitis and erectile dysfunction were enrolled in this study and then randomly allocated to the control group (70 participants received delayed periodontal treatment) or test group (70 participants were subjected to immediate periodontal therapy). The assessment of the clinical and serological outcomes was done at baseline and 3 months postoperatively. This included pocket depth (PD), visible plaque, clinical attachment level (CAL), bleeding on probing (BOP), level of tumor necrosis factor-alpha (TNF-α), and the severity of erectile dysfunction. Periodontal therapy consists of oral hygiene instructions and single-visit scaling and root planing. There were no significant differences regarding the serological and clinical outcomes at baseline between the two groups (p > .05). At 3-month follow-up, the PD, BOP, CAL, and visible dental plaque means in the control group were significantly higher than those in the test group (PD: 4.94 ± 0.647 mm vs. 4.25 ± 0.619 mm; BOP: 49.03 ± 29.98 vs. 6.20 ± 7.14; CAL: 4.96 ± 0.631 mm vs. 4.31 ± 0.591 mm; visible dental plaque: 48.49 ± 30.07 vs. 5.83 ± 6.51) (p = .00). Compared with baseline findings, both groups showed significant reductions in TNF-α in serum, salivary TNF-α, and severity of erectile dysfunction (p < .001). The non-surgical periodontal therapy could significantly improve the severity of erectile dysfunction in addition to periodontal and serological parameters. Salivary TNF-α could be used as a new diagnostic tool to detect the severity of erectile dysfunction.


Physical activity and frailty as indicators of cardiorespiratory reserve and predictors of surgical prognosis: General and digestive surgery population characterization.
Frailty and low physical activity and cardiorespiratory reserve are related to higher perioperative morbimortality. The crucial step in improving the prognosis is to implement specific measures to optimize these aspects. It is critical to know the magnitude of the problem in order to implement preoperative optimization programmes. To characterize surgical population in a university hospital. All patients undergoing preoperative evaluation for abdominal surgery with admission were prospectively included during a 3-month period. Level of physical activity, functional capacity, frailty and emotional state were assessed using score tests. Additionally, physical condition was evaluated using 5 Times Sit-to-Stand Test. Demographic, clinical and surgical data were collected. One hundred and forty patients were included (60±15yr-old, 56% male, 25% ASA III or IV). Forty-nine percent of patients were proposed for oncologic surgery and 13% of which had received neoadjuvant treatment. Seventy percent of patients presented a low functional capacity and were sedentary. Eighteen percent of patients were considered frail and more than 50% completed the 5 Times Sit-to-Stand Test at a higher time than the reference values adjusted to age and sex. Advanced age, ASA III/IV, sedentarism, frailty and a high level of anxiety and depression were related to a lower functional capacity. The surgical population of our area has a low functional reserve and a high index of sedentary lifestyle and frailty, predictors of postoperative morbidity. It is mandatory to implement preoperative measures to identify population at risk and prehabilitation programmes, considered highly promising preventive interventions towards improving surgical outcome.


Differences in optical coherence tomography of the macula in advanced glaucoma and after a retinal artery occlusion.
Optical coherence tomography (OCT) was used to evaluate the macular thickness in eyes with advanced glaucoma compared with eyes following a retinal artery occlusion. Ten patients with a retinal artery occlusion and 10 patients with severe glaucoma were evaluated with OCT using the macular thickness map protocol. The median thinnest macular sector was 183 microns (range: 152 to 223 microns) in patients with glaucoma versus 143 microns (range: 98 to 177 microns) in patients with arterial occlusion (P = .001). Median macular volume was 5.9 mm3 (range: 5.1 to 6.7 mm3) in patients with glaucoma versus 5.1 mm3 (range: 3.6 to 6.1 mm3) in patients with arterial occlusion (P = .015). OCT demonstrates that patients with a retinal artery occlusion have significantly reduced macular thickness compared with those with severe glaucoma.


A reformulation of the hygiene hypothesis: maternal infectious diseases confer protection against asthma in the infant.
Epidemiological studies have shown an inverse relationship between allergic respiratory diseases and the number of siblings. It was hypothesized that the lower prevalence of allergic respiratory diseases in large sibships was due to cross-infections between siblings. According to this hygiene hypothesis the increase in the prevalence of atopic diseases is caused by a decrease in the exposure to infections. It was believed that early infections were beneficial for health because of their contribution to the maturation of the immune system. However, in this interpretation a possible protective influence of the mother was overlooked. A new hypothesis is therefore proposed. Maternal exposure to infections induces immunological memory, which protects her children against allergic respiratory diseases.


Light exposure mediates circadian rhythms of rhizosphere microbial communities.
Microbial community circadian rhythms have a broad influence on host health and even though light-induced environmental fluctuations could regulate microbial communities, the contribution of light to the circadian rhythms of rhizosphere microbial communities has received little attention. To address this gap, we monitored diel changes in the microbial communities in rice (Oryza sativa L.) rhizosphere soil under light-dark and constant dark regimes, identifying microbes with circadian rhythms caused by light exposure and microbial circadian clocks, respectively. While rhizosphere microbial communities displayed circadian rhythms under light-dark and constant dark regimes, taxa possessing circadian rhythms under the two conditions were dissimilar. Light exposure concealed microbial circadian clocks as a regulatory driver, leading to fewer ecological niches in light versus dark communities. These findings disentangle regulation mechanisms for circadian rhythms in the rice rhizosphere microbial communities and highlight the role of light-induced regulation of rhizosphere microbial communities.


Final height and body mass index in adult survivors of childhood acute lymphoblastic leukemia treated without cranial radiotherapy: a retrospective longitudinal multicenter Italian study.
Young adult survivors of childhood acute lymphoblastic leukemia (ALL) treated with protocols including cranial radiotherapy demonstrate a persistent weight gain and reduced final height. Published reports on the effects on growth of different oncologic therapies are conflicting and difficult to interpret because they combined children treated with both cranial irradiation and multi-agent chemotherapy. Our study investigated the effect of chemotherapy alone on body mass index (BMI) and on growth at the achievement of final height in a homogeneous cohort of Italian childhood ALL survivors. We retrospectively studied 162 Caucasian patients treated on the Italian Association of Pediatric Hematology and Oncology protocols without radiotherapy between 1989 and 2000 at five Italian centers with 107 inclusions (58 males). Height- and BMI-standard deviation score (SDS) were collected at diagnosis of ALL, at the end of treatment and at the achievement of final height. Changes in height SDS and BMI SDS with time were analyzed using dependent sample Student's t-test. A significant reduction of height-SDS was documented during treatment in both genders. This reduction of height-SDS was not followed by an appropriate catch-up growth, despite the achievement of a mean final height within the normal range. At diagnosis females showed a lower mean BMI-SDS than males. During treatment, in the whole population, BMI-SDS increased significantly. After it, while males lost BMI-SDS, females showed its persistent increase. Survivors of childhood ALL generally seemed to achieve a normal final height with a BMI within the normal range. These parameters appeared to be only minimally affected by chemotherapy. Nevertheless, height catch-up growth was not completed after chemotherapy in both genders and all patients experienced an increase of BMI-SDS during chemotherapy that only females seemed to conserve until the achievement of final height.


Nutritional markers for predicting lower extremity free tissue transfer outcomes in the chronic wound population.
Optimizing nutritional status is critical to maximize flap success and healing. Prealbumin and albumin have been utilized as easily obtained proxies for overall nutritional status. The aim of this study was to investigate whether these markers are correlated with healing time and overall flap healing after lower extremity (LE) free tissue transfer (FTT) in the chronic wound population. A retrospective review of LE chronic wound FTT patients treated by a single surgeon at our institution from 2011 to 2020 was performed. Data collected included demographics, comorbidities, flap characteristics, and perioperative labs. The outcomes of interest were flap healing (FH) and time to flap healing (TFH). We identified 69 patients undergoing LE FTT for limb salvage meeting our inclusion criteria. When using a threshold of <3.5 g/dl for low albumin and < 20 mg/dl for low prealbumin, no significance was found between FH or TFH and preoperative albumin or preoperative prealbumin. With low albumin defined as <2.7 g/dl with the prealbumin threshold unchanged, TFH was significantly increased, and FH was significantly decreased compared with the defined normal preoperative albumin group. Low preoperative albumin, when defined as <3.5 g/dl, and prealbumin did not correlate with TFH or FH. Contrarily, when defined as <2.7 g/dl, low preoperative albumin correlated significantly with increased TFH and decreased FH rates. Further investigation into validated biomarkers and their thresholds is needed to assess the effect of nutritional status on wound healing and guide perioperative optimization.


The role of radiation therapy in melanoma.
Although melanoma was historically thought to be radiation resistant, there are limited data to support the use of adjuvant radiation therapy for certain situations at increased risk for locoregional recurrence. High-risk primary tumor features include thickness, ulceration, certain anatomic locations, satellitosis, desmoplastic/neurotropic features, and head and neck mucosal and anorectal melanoma. Lentigo maligna can be effectively treated with either adjuvant or definitive radiation therapy. Some retrospective and prospective randomized studies support the use of adjuvant radiation to improve regional control after lymph node dissection for high-risk nodal metastatic disease. Consensus on the optimal radiation doses and fractionation is lacking.


Crystal structure of tarocystatin-papain complex: implications for the inhibition property of group-2 phytocystatins.
Tarocystatin (CeCPI) from taro (Colocasia esculenta cv. Kaohsiung no. 1), a group-2 phytocystatin, shares a conserved N-terminal cystatin domain (NtD) with other phytocystatins but contains a C-terminal cystatin-like extension (CtE). The structure of the tarocystatin-papain complex and the domain interaction between NtD and CtE in tarocystatin have not been determined. We resolved the crystal structure of the phytocystatin-papain complex at resolution 2.03 Å. Surprisingly, the structure of the NtD-papain complex in a stoichiometry of 1:1 could be built, with no CtE observed. Only two remnant residues of CtE could be built in the structure of the CtE-papain complex. Therefore, CtE is easily digested by papain. To further characterize the interaction between NtD and CtE, three segments of tarocystatin, including the full-length (FL), NtD and CtE, were used to analyze the domain-domain interaction and the inhibition ability. The results from glutaraldehyde cross-linking and yeast two-hybrid assay indicated the existence of an intrinsic flexibility in the region linking NtD and CtE for most tarocystatin molecules. In the inhibition activity assay, the glutathione-S-transferase (GST)-fused FL showed the highest inhibition ability without residual peptidase activity, and GST-NtD and FL showed almost the same inhibition ability, which was higher than with NtD alone. On the basis of the structures, the linker flexibility and inhibition activity of tarocystatins, we propose that the overhangs from the cystatin domain may enhance the inhibition ability of the cystatin domain against papain.


The influence of systemic immunisation during mammary involution on subsequent antibody production in the mammary gland.
The primary purpose of the experiments reported in this paper was to determine whether a powerful systemic antigenic stimulus, given at the time of mammary involution, would affect the level of specific antibody in milk secreted during the ensuing lactation. The results showed that a single systemic administration of antigen with adjuvant, during mammary involution, is an efficient means of inducing high titres of specific antibody in milk in the subsequent lactation. Furthermore, such antibody belongs mainly to the IgA and IgM classes of immunoglobulin. These results suggest that the antibody is produced locally in the mammary gland by sensitised cells of the lymphocyte-plasma cell series, which infiltrate the tissue during the early stages of mammary involution and then become sessile.


The temporal lobe in schizophrenia from uni- and multiply affected families.
To investigate the effect of genetic loading on brain structure in schizophrenia, we hypothesized that separating families into uniaffected and multiply affected would reveal effects of schizophrenia and family type. Volumes and asymmetries of the amygdala-hippocampus-complex (AHC) and sylvian fissure (SF) were determined using magnetic resonance imaging of subjects with schizophrenia from 12 uniaffected and 14 multiply affected families, and ten healthy controls. AHC volume was reduced in schizophrenia, particularly on the right side in subjects from uniaffected families. AHC asymmetry was disturbed, too. Enlargement of the right SF and disturbed SF asymmetry was demonstrated in subjects from uniaffected families as well. Comparing subjects from uni- and multiply affected families may be a useful strategy to reduce variability for future studies of environmental interactions with genetic risk for schizophrenia.


Distributed Q-Learning Algorithm for Dynamic Resource Allocation With Unknown Objective Functions and Application to Microgrid.
Dynamic resource allocation problem (DRAP) with unknown cost functions and unknown resource transition functions is studied in this article. The goal of the agents is to minimize the sum of cost functions over given time periods in a distributed way, that is, by only exchanging information with their neighboring agents. First, we propose a distributed Q -learning algorithm for DRAP with unknown cost functions and unknown resource transition functions under discrete local feasibility constraints (DLFCs). It is theoretically proved that the joint policy of agents produced by the distributed Q -learning algorithm can always provide a feasible allocation (FA), that is, satisfying the constraints at each time period. Then, we also study the DRAP with unknown cost functions and unknown resource transition functions under continuous local feasibility constraints (CLFCs), where a novel distributed Q -learning algorithm is proposed based on function approximation and distributed optimization. It should be noted that the update rule of the local policy of each agent can also ensure that the joint policy of agents is an FA at each time period. Such property is of vital importance to execute the ε -greedy policy during the whole training process. Finally, simulations are presented to demonstrate the effectiveness of the proposed algorithms.


Diversity and community structure of endophytic Bacillus with antagonistic and antioxidant activity in the fruits of Xisha Wild Noni (Morinda citrifolia L.).
Noni (Morinda citrifolia L.) is a tropical crop with strong antibacterial, antioxidant and other abilities, and its fruit has a strong potential for adjuvant treatment of diseases. This study aimed to explore the dynamic change of endophytic bacteria in Noni fruit at different stages and the correlation between the antagonistic and antioxidant activity of the Bacillus which was screened and the change of the host's growth stage. In this study, though the high-throughput sequencing technology (HTS), 106 endophytic bacteria species were found in A, B, C, D, E and F stages of Noni fruit, among which the dominant group were Pantoea (0.3%-20.9%), and Candidatus_Uzinura (2.3%-35.2%) etc. The endophytic bacteria were isolated by culture-dependent method. Through their antagonistic experiments on Staphylococcus aureus and Escherichia coli, the results of 16S polyphasic taxonomic identification showed that the 34 antagonistic strains belonged to Bacillus. Five species of these Bacillus were identified by gyrA polyphase taxonomy, including Bacillus subtilis (76% of all Bacillus), Bacillus licheniformis (9%), Bacillus amyloliquefaciens (6%), Bacillus velezensis (6%) and Bacillus mojavensi (3%), and the RAPD showed these Bacillus are no signs of stable passage. In C, D, E and F stages, the average total antioxidant activity of Bacillus endophytic antagonists against Noni was 7.812 U/mL, 8.144 U/mL, 7.817 U/mL and 7.144 U/mL, which was much higher than that of Noni fruit, and antioxidant activity of Noni juice and Bacillus bacterial liquid vary with host's growth period showed the same trend, both rose slowly at first, and reached the highest in period E, then declined slightly in period F, it showed that the antagonistic Bacillus of Noni had synergistic function with Noni fruit. This study clarified the relationship of function between Noni fruit and endophytic bacteria, and laid a foundation for future study on the dynamic change of endophytic flora succession and efficacy.


A cost-utility analysis of risk model-guided versus physician's choice antiemetic prophylaxis in patients receiving chemotherapy for early-stage breast cancer: a net benefit regression approach.
We assessed the cost-effectiveness of a risk model-guided (RMG) antiemetic prophylaxis strategy compared with the physician's choice (PC) strategy in patients receiving chemotherapy for early-stage breast cancer. We conducted a cost-utility analysis based on a published randomized controlled trial of 324 patients with early-stage breast cancer undergoing chemotherapy at two Canadian cancer centers. Patients were randomized to receive their antiemetic treatments according to either predefined risk scores or the treating physician's preference. Effectiveness was measured as quality-adjusted life years (QALYs) gained. Cost and utility data were obtained from the Canadian published literature. We used generalized estimating equations to estimate the incremental cost-effectiveness ratios (ICERs) and 95% confidence intervals (CIs) over a range of willingness-to-pay values. The lower and upper bounds of the 95% CIs were used to characterize the statistical uncertainty for the cost-effectiveness estimates and construct cost-effectiveness acceptability curves. From the health care system's perspective, the RMG strategy was associated with greater QALYs gained (0.0016, 95% CI 0.0009, 0.0022) and higher cost ($49.19, 95% CI $24.87, $73.08) than the PC strategy, resulting in an ICER of $30,864.28 (95% CI $14,718.98, $62,789.04). At the commonly used threshold of $50,000/QALY, the probability that RMG prophylaxis is cost-effective was >94%; this probability increased with greater willingness-to-pay values. The risk-guided antiemetic prophylaxis is an economically attractive option for patients receiving chemotherapy for early-stage breast cancer. This information supports the implementation of risk prediction models to guide chemotherapy-induced nausea and vomiting prophylaxis in clinical practices.


Asymmetric development of peripheral atherosclerosis in patients with erectile dysfunction: an ultrasonographic study.
Recent literature focused on erectile dysfunction (ED) as a reliable predictive parameter of cardiovascular diseases. ED patients have a higher prevalence of atherosclerotic lesions (increased intima-media thickness and plaques) at carotid site, but data on femoral site are still lacking. Nevertheless, there is accumulating evidence concerning a significant involvement of femoral atherosclerosis in other clinical conditions associated to ED, such as diabetes mellitus and coronary disease. Therefore, we investigated the prevalence of carotid and femoral atherosclerotic lesions and penile peak systolic velocity (PSV) in 238 ED patients by Eco-Colour Doppler ultrasonography (US). We found - irrespective of the presence of cardiovascular risk factors - a significant increase of atherosclerotic lesions in ED group with respect to 52 controls (66.4% versus 36.5%) and a higher prevalence of atherosclerosis at the femoral site (23.1% versus 5.7%), also with respect to the carotid site (8%). Moreover, PSV was significantly lower in ED patients with atherosclerosis compared to those without atherosclerotic lesions (41.9+/-15.3 cm/s versus 55.2+/-17.7 cm/s), and it was particularly low in those with combined carotid and femoral atherosclerosis (34.8+/-13.3 cm/s) and those with isolated carotid atherosclerosis (37.9+/-13.0 cm/s). These data confirm the strong relation between atherosclerosis and ED, an asymmetric development of atherosclerotic lesions in ED patients and suggest to perform an US study of both femoral and carotid district in these subjects.


Epithelial NOTCH Signaling Rewires the Tumor Microenvironment of Colorectal Cancer to Drive Poor-Prognosis Subtypes and Metastasis.
The metastatic process of colorectal cancer (CRC) is not fully understood and effective therapies are lacking. We show that activation of NOTCH1 signaling in the murine intestinal epithelium leads to highly penetrant metastasis (100% metastasis; with >80% liver metastases) in KrasG12D-driven serrated cancer. Transcriptional profiling reveals that epithelial NOTCH1 signaling creates a tumor microenvironment (TME) reminiscent of poorly prognostic human CRC subtypes (CMS4 and CRIS-B), and drives metastasis through transforming growth factor (TGF) β-dependent neutrophil recruitment. Importantly, inhibition of this recruitment with clinically relevant therapeutic agents blocks metastasis. We propose that NOTCH1 signaling is key to CRC progression and should be exploited clinically.


To compare the incubation period following intratracheal and subcutaneous inoculation of bovine leukosis virus infected lymphocytes and to study their clearance from the circulation.
The migration of fluorescein isothiocyanate labelled lymphocytes through the tracheobronchial mucosa has been studied in cattle. Following intratracheal inoculation of labelled non-infected autologous lymphocytes and bovine leukosis virus (BLV) infected heterologous (presumed allogeneic) lymphocytes, the labelled lymphocytes appeared in the blood circulation between 4 and 7 days post inoculation. Following intravenous inoculation of labelled autologous lymphocytes, the cells could be detected in the circulation for 10 days post inoculation whereas BLV infected and non-infected heterologous lymphocytes could be detected for only 2 days. The migration of BLV-infected heterologous lymphocytes through the tracheobronchial mucosa caused a delay in the appearance of labelled lymphocytes in the circulation and a corresponding delay in the appearance of BLV antibodies. Comparison was made of the effect of two different routes of inoculation, subcutaneous and intratracheal on the incubation period as indicated by the detection of antibody. Subcutaneous inoculation of 1 X 10(4), 5 X 10(3), 1 X 10(3) of lymphocytes from a BLV infected cow caused seroconversion whereas 5 X 10(2) cells did not. Intratracheal inoculation of 5 X 10(3) cells caused sero-conversion. One animal did not develop BLV antibody until 30 weeks after inoculation although BLV could be isolated from the blood at 24 and 26 weeks post inoculation.


Using wearable devices for assessing the impacts of hair exposome in Brazil.
Previous studies have shown that physicochemical properties of hair can be impacted by internal and environmental exposures ranging from chemical stressors to weather. Besides the effects on hair, these exposures, termed "exposome", can act on specific organs including skin, as a synergistic damaging effect of UV exposure and pollution on human surfaces. The combination of several environmental factors such as sun exposure, temperature, relative humidity, air pollution and photo-oxidation caused by ground level ozone impacts hair properties such as melanin oxidation, protein content, surface quality and structural components. Therefore, exposome studies can reveal new hypotheses on how epithelia and hair could be affected by daily life environment and routine. The aim of this study was to evaluate the impact of several environmental aggressors on human surfaces, using portable and wearable devices for monitoring exposome. To better understand the underlying mechanisms associated with environmental factors, two subjects wore multiple sensors to capture the meteorological conditions biking through urban areas in summer and winter. Temperature, humidity, UV radiation and ozone concentration were recorded and hair swatches of different types, including natural, bleached/colored, colored and gray, were exposed on the helmets. Silicon wristbands were used on skin to identify main chemical aggressors. After exposure, hair swatches were analyzed by surface microscopy analysis, oxidation markers and more than 1,500 chemicals were evaluated on the bracelets. Correlated with GPS and monitoring data, all these results provide insights on how environmental stressors affect the quality of different hair types and body surface according to exposure routine. Our results suggest extreme climate conditions associated with hair damage and photo-oxidative marker linked to the environmental aggressors. Polycyclic aromatic hydrocarbons (PAH) indicate possible causes of hair damages. This is the first meteorotropic study of its kind, combining environmental aggressors related to hair damage, opening new research hypothesis further studies on exposome.


Assessment of the role of the humoral response to Plasmodium falciparum MSP2 compared to RESA and SPf66 in protecting Papua New Guinean children from clinical malaria.
The prevalence and concentration of naturally acquired humoral response (IgG) to merozoite surface protein 2 (MSP2), RESA, SPf66 and crude schizont extract were measured in a population living in a malaria highly endemic area of Papua New Guinea. A prospective longitudinal study in 0.5-15 year old children was conducted for one year in order to examine the relationship between the humoral response to these antigens and subsequent susceptibility to clinical malaria using a series of clinical definitions. The prevalence and concentration of antibodies to all antigens increased with age. Such correlation with age was most marked for MSP2 recombinant proteins. When age and previous exposure were controlled for, only antibody levels to MSP2 recombinant proteins (3D7 and d3D7) and to RESA predicted a reduction in incidence rate of episodes of clinical malaria. Our results support the inclusion of the recombinant proteins of the 3D7 allelic family of merozoite surface antigen 2 and RESA into a subunit vaccine against malaria.


Comparison of cardiac output estimates by bioreactance and inert gas rebreathing methods during cardiopulmonary exercise testing.
This study assessed the agreement between cardiac output estimated by inert gas rebreathing and bioreactance methods at rest and during exercise. Haemodynamic measurements were assessed in 20 healthy individuals (11 females, nine males; aged 32 ± 10 years) using inert gas rebreathing and bioreactance methods. Gas exchange and haemodynamic data were measured simultaneously under rest and different stages (i.e. 30, 60, 90, 120, 150 and 180 W) of progressive graded cardiopulmonary exercise stress testing using a bicycle ergometer. At rest, bioreactance produced significantly higher cardiac output values than inert gas rebreathing (7·8 ± 1·4 versus 6·5 ± 1·7 l min-1 , P = 0·01). At low-to-moderate exercise intensities (i.e. 30-90 W), bioreactance produced significantly higher cardiac outputs compared with rebreathing method (P<0·05). At workloads of 120 W and above, there was no significant difference in cardiac outputs between the two methods (P = 0·10). There was a strong relationship between the two methods (r = 0·82, P = 0·01). Bland-Altman analysis including rest and exercise data showed that inert gas rebreathing reported 1·95 l min-1 lower cardiac output than bioreactance, with lower and upper limits of agreement of -3·1-7·07 l min-1 . Analysis of peak exercise data showed a mean difference of 0·4 l min-1 (lower and upper limits of agreement of -4·9-5·7 l min-1 ) between both devices. Bioreactance and inert gas rebreathing methods show acceptable levels of agreement for estimating cardiac output at higher levels of metabolic demand. However, they cannot be used interchangeably due to strong disparity in results at rest and low-to-moderate exercise intensity.


Urgent care in the community: an observational study.
This case study describes a community-based urgent care clinic in a general practitioner (GP) super clinic in South East Queensland. This retrospective chart audit describes patient demographic characteristics, types of presentations and management for Sundays in 2015. The majority of patients (97%) did not require admission to hospital or office investigations (95%) and presented with one condition (94%). Of the presentations, 66.5% were represented by 30 conditions. Most patients received a prescription (57%), some were referred to the pathology laboratory (15%) and some were referred to radiology (12%). A majority (54%) of patients presented in the first three hours. Approximately half (51%) of patients presenting were aged under 25. More females (53%) presented than males. A majority (53%) lived in the same postcode as the clinic. The three most common office tests ordered were urinalysis, electrocardiogram (ECG) and urine pregnancy test. Some patients (19%) needed procedures, and only 3% were referred to hospital. The study offers analysis of the client group that can be served by an urgent care clinic in a GP super clinic on a Sunday. The study provides an option for emergency department avoidance. Despite calls for more research into community-based urgent care clinics, little is known in Australia about what constitutes an urgent care clinic. The study proposes a classification system for walk-in presentations to an urgent care clinic, which is comparable to emergency department presentations.


Meaning in life and vagally-mediated heart rate variability: Evidence of a quadratic relationship at baseline and vagal reactivity differences.
Higher meaning in life (MIL) consistently predicts better health, but the physiological processes underlying this relationship are not well understood. This study examined the relationship between MIL and vagally-mediated heart rate variability (VmHRV) under resting (N = 77), stressor (n = 73), and mindfulness intervention (n = 72) conditions. Regression was used for MIL-VmHRV analyses at baseline, and longitudinal mixed models were used to examine phasic changes in VmHRV as a function of MIL. Regression revealed a quadratic MIL-VmHRV relationship, and mixed models linked higher MIL to greater stress-reactivity but not enhanced stress-attenuation. MIL and mindfulness did not interact to influence VmHRV recovery after experimental stress. Findings suggest that cardiac vagal tone and cardiac vagal reactivity are linked to MIL, shedding light on the physiology underlying MIL and its health associations.


Dual decline in subjective gait speed and domain-specific cognition is associated with higher risk of incident dementia in older Japanese adults: A 15-year age-specific cohort study.
Dual decline in gait speed and cognition has been found to have higher dementia risk than no decline or pure decline. However, evidence from the Asian population is lacking. Therefore, we aimed to investigate the association of dual decline from age 65 to 70 years with late-life dementia in older Japanese adults with different personal characteristics. Data were collected from an age-specific cohort study conducted in 482 Japanese 65-year-old adults. We investigated participant demographics, medical histories, lifestyles, subjective gait speed, and cognition at both 64/65 and 70/71 years old, and confirmed dementia until age of 85 years. Cox proportion hazard models were used to estimate the risk of dementia, with adjustments for covariates, and death was treated as a competing risk. After a mean follow-up period of 12.5-years, 111 participants developed dementia. Older adults with dual decline are more likely to have hyperlipidemia, diabetes, and smoking habits. And we found that dual decline in gait speed and domain-specific cognition was associated with a higher risk of dementia compared with no decline in most cognitive tests, with the highest risk observed for gait speed combined with memory (sub-distribution hazard ratio:3.89, 95 %, confidence intervals: [1.68-9.01]). However, significant differences only existed in men after stratification by sex. A dual decline in subjective gait speed and cognition may serve as a robust predictor of dementia over a decade prior to its onset, particularly in men. These findings highlighted the importance of screening for dual decline at an early age.


Serial T2*WI studies in the acute phase of cerebral venous thrombosis.
We report a case of a 49-year-old woman with headache who was diagnosed with cerebral venous thrombosis (CVT) of the superior sagittal and right transverse sinuses. Serial gradient recalled-echo T2*-weighted imaging (T2*WI) studies demonstrated dynamic changes of thrombosed segments. T2*WI is useful not only as a diagnostic tool for CVT, but also in evaluating changes to thrombus.


Specific suppression of insulin sensitivity in growth hormone receptor gene-disrupted (GHR-KO) mice attenuates phenotypic features of slow aging.
In addition to their extended lifespans, slow-aging growth hormone receptor/binding protein gene-disrupted (knockout) (GHR-KO) mice are hypoinsulinemic and highly sensitive to the action of insulin. It has been proposed that this insulin sensitivity is important for their longevity and increased healthspan. We tested whether this insulin sensitivity of the GHR-KO mouse is necessary for its retarded aging by abrogating that sensitivity with a transgenic alteration that improves development and secretory function of pancreatic β-cells by expressing Igf-1 under the rat insulin promoter 1 (RIP::IGF-1). The RIP::IGF-1 transgene increased circulating insulin content in GHR-KO mice, and thusly fully normalized their insulin sensitivity, without affecting the proliferation of any non-β-cell cell types. Multiple (nonsurvivorship) longevity-associated physiological and endocrinological characteristics of these mice (namely beneficial blood glucose regulatory control, altered metabolism, and preservation of memory capabilities) were partially or completely normalized, thus supporting the causal role of insulin sensitivity for the decelerated senescence of GHR-KO mice. We conclude that a delayed onset and/or decreased pace of aging can be hormonally regulated.


A general excimer signaling approach for aptamer sensors.
Simple, fast and direct analysis or monitoring of significant molecules in complex biological samples is important for many biological study, clinical diagnosis and forensic investigations. Herein we highlight a general method to tailor aptamer sequence into functional subunits to design target-induced light-switching excimer sensors for rapid, sensitive and selective detection of important molecules in complex biological fluids. Our approach is to split one single strand aptamer into two pieces and each terminally labeled with a pyrene molecule while maintaining their binding affinity to target molecules. In the presence of target molecules, two aptamer fragments are induced to self-assemble to form aptamer-target complex and bring two pyrene molecules into a close proximity to form an excimer, resulting in fluorescent switching from approximately 400 nm to 485 nm. With an anti-cocaine sensor, as low as 1 microM of cocaine can be detected using steady-state fluorescence assays and more importantly low picomole level of target can be directly visualized with naked eyes. Because the excimer has a long fluorescence lifetime, time-resolved measurements were used to directly detect as low as 5 microM cocaine in urine samples quantitatively without any sample pretreatment.


Curbing Tregs' (Lack of) Enthusiasm.
In this issue, Overacre-Delgoffe et al. show that interferon gamma production by a subset of regulatory T cells in the tumor microenvironment triggers Treg instability locally and restores anti-tumor immunity.


Epigenetic and gene regulatory functions of small RNAs.
In this review article, I summarize the intervention I made during the "Hommage à François Gros" held at the Institut Pasteur in Paris on the 25th of April, 2023. I discuss how the discovery of the existence of an RNA intermediate between genetic information and protein translation has changed our perspective on the role of RNA in gene regulation in these past years. I also discuss new emerging paradigms, highlighting the role of RNA in heritable information similar to the well-known DNA function.


A comparative study of the biological properties of venoms from juvenile and adult inland taipan (Oxyuranus microlepidotus) snake venoms.
The biological properties of adult and juvenile inland taipan (Oxyuranus microlepidotus) snake venoms were examined. The enzymatic activities, intravenous median lethal dose and procoagulant activity of the juvenile venom samples were not significantly different from those of the adult venom samples. Also, the juvenile and adult venoms exhibited similar electrophoretic patterns, indicating that they possessed similar protein composition.


Ecthyma gangrenosum secondary to MRSA in a young patient with chronic kidney disease.
Ecthyma gangrenosum (EG) is a well-recognized dermatological condition classically associated with Pseudomonas aeruginosa infection, however, the association with other bacteria, especially gram positive, is rare. There are only a few reported cases of EG caused by staphylococcal infection. Here, we report a case in a young patient with chronic kidney disease (CKD) presenting with EG secondary to Methicillin Resistant Staphylococcus aureus.


The Beneficial Effect of Fesoterodine, a Competitive Muscarinic Receptor Antagonist on Erectile Dysfunction in Streptozotocin-induced Diabetic Rats.
To investigate the possible role of fesoterodine (a competitive muscarinic receptor antagonist) on erectile dysfunction in streptozotocin-induced diabetic rats. A total of 16 adult male Sprague-Dawley rats were equally divided into control and diabetic groups. Diabetes was induced by a single intravenous injection of streptozotocin (25-35 mg/kg). In vivo erectile responses were evaluated by the stimulation of cavernosal nerves, and measurements were repeated after the intracavernosal injection of fesoterodine (1 µM) in rats. The relaxation responses to fesoterodine were examined via incubation with various inhibitors. The relaxant responses of corpus cavernosum (CC) strips were observed in the presence or the absence of fesoterodine (10 µM). Intracavernous administration of fesoterodine restored in vivo erectile response at 5.0- and 7.5-V levels, except for 2.5 V in diabetic rats. Basal intracavernosal pressure (5.4 ± 0.9 mm Hg) in diabetic rats was markedly increased after injection of fesoterodine (33.9 ± 7.9 mm Hg, P <.001). In bath studies, fesoterodine resulted in a relaxation of CC in a concentration-dependent manner, which was reduced in diabetic rats. Nifedipine (l-type Ca2+ channel blocker) inhibited maximum fesoterodine-induced relaxation by 58%. The nonselective K+ channel blocker tetraethylammonium and glibenclamide incubation did not change the relaxant response to fesoterodine. The relaxant responses to acetylcholine (10 µM), electrical field stimulation (10 Hz), and sodium nitroprusside (0.01 µM) in diabetic rats were increased after incubation with fesoterodine (10 µM). Fesoterodine improved erectile function and relaxation of isolated strips of rat CC. The underlying mechanism of fesoterodine is likely due to the blocking of l-type calcium channels independent of the nitric oxide-cyclic guanosine monophosphate pathway. Further investigations are warranted to fully elucidate the restorative effects of fesoterodine on overactive bladder-induced diabetic erectile dysfunction.


The impact of cognitive impairment on perceived workforce performance: results from the International Mood Disorders Collaborative Project.
Cognitive dysfunction and depression severity are key mediators of workplace adjustment in adults with major depressive disorder (MDD). Herein, we sought to determine the extent to which measures of depression severity and cognitive dysfunction were associated with perceived global disability, workplace performance and quality of life. A post hoc analysis was conducted using data from 260 participants with a diagnosis of DSM-IV-TR-defined MDD who were enrolled in the International Mood Disorders Collaborative Project (IMDCP) between January 2008 and July 2013. Measures of workplace function, global disability, depression severity, cognitive function, and quality of life were employed. These data were analyzed using a multiple variable linear regression equations. Perceived global disability was significantly predicted by clinical ratings of depression severity (β=0.54), and perceived inattention (β=0.24), accounting for 37% of the variance. In addition, perceived inattention (β=0.58) and clinical ratings of depression severity (β=0.18), were also significant predictors of perceived workplace productivity/performance, accounting for 38% of the variance. Finally, both clinical ratings of depression severity (β=-0.54), and perceived inattention (β=-0.18) were significant inverse predictors of perceived quality of life, accounting for 34% of the variance. The overarching finding in the analysis herein is that workplace performance variability is explained by subjective measures of cognitive dysfunction to a greater extent than total depression symptom severity. Conversely, total depression symptom severity accounts for a greater degree of variability in global measures of disability relative to cognitive measures. Treatment strategies for adults with major depressive disorder should address issues of cognitive dysfunction to improve workforce participation and performance.