Loss of cholinergic innervation differentially affects eNOS-mediated blood flow, drainage of Aβ and cerebral amyloid angiopathy in the cortex and hippocampus of adult mice.
Vascular dysregulation and cholinergic basal forebrain degeneration are both early pathological events in the development of Alzheimer's disease (AD). Acetylcholine contributes to localised arterial dilatation and increased cerebral blood flow (CBF) during neurovascular coupling via activation of endothelial nitric oxide synthase (eNOS). Decreased vascular reactivity is suggested to contribute to impaired clearance of β-amyloid (Aβ) along intramural periarterial drainage (IPAD) pathways of the brain, leading to the development of cerebral amyloid angiopathy (CAA). However, the possible relationship between loss of cholinergic innervation, impaired vasoreactivity and reduced clearance of Aβ from the brain has not been previously investigated. In the present study, intracerebroventricular administration of mu-saporin resulted in significant death of cholinergic neurons and fibres in the medial septum, cortex and hippocampus of C57BL/6 mice. Arterial spin labelling MRI revealed a loss of CBF response to stimulation of eNOS by the Rho-kinase inhibitor fasudil hydrochloride in the cortex of denervated mice. By contrast, the hippocampus remained responsive to drug treatment, in association with altered eNOS expression. Fasudil hydrochloride significantly increased IPAD in the hippocampus of both control and saporin-treated mice, while increased clearance from the cortex was only observed in control animals. Administration of mu-saporin in the TetOAPPSweInd mouse model of AD was associated with a significant and selective increase in Aβ40-positive CAA. These findings support the importance of the interrelationship between cholinergic innervation and vascular function in the aetiology and/or progression of CAA and suggest that combined eNOS/cholinergic therapies may improve the efficiency of Aβ removal from the brain and reduce its deposition as CAA.


Lumbar spinal stenosis-diagnosis and management of the aging spine.
Low back pain and lumbar spinal stenosis (LSS) is an extensive problem in the elderly presenting with pain, disability, fall risk and depression. The incidence of LSS is projected to continue to grow as the population ages. In light of the risks, costs and lack of long-term results associated with surgery, and the positive outcomes in studies utilizing physical therapy interventions for the LSS patient, a non-invasive approach is recommended as a first line of intervention. This Masterclass presents an overview of LSS in terms of clinical examination, diagnosis, and intervention. A focused management approach to the patient with LSS is put forward that emphasizes a defined four-fold approach of patient education, manual physical therapy, mobility and strengthening exercises, and aerobic conditioning.


New algorithm for the treatment of gastro-oesophageal reflux disease.
Gastro-oesophageal reflux disease (GERD) is associated with a variety of typical and atypical symptoms. Patients often present in the first instance to a pharmacist or primary care physician and are subsequently referred to secondary care if initial management fails. Guidelines usually do not provide a clear guidance for all healthcare professionals with whom the patient may consult. To update a 2002-treatment algorithm for GERD, making it more applicable to pharmacists as well as doctors. A panel of international experts met to discuss the principles and practice of treating GERD. The updated algorithm for the management of GERD can be followed by pharmacists, for over-the-counter medications, primary care physicians, or secondary care gastroenterologists. The algorithm emphasizes the importance of life style changes to help control the triggers for heartburn and adjuvant therapies for rapid and adequate symptom relief. Proton pump inhibitors will remain a prominent treatment for GERD; however, the use of antacids and alginate-antacids (either alone or in combination with acid suppressants) is likely to increase. The newly developed algorithm takes into account latest clinical practice experience, offering healthcare professionals clear and effective treatment options for the management of GERD.


The Association Between Professional Burnout and Engagement With Patient Safety Culture and Outcomes: A Systematic Review.
In the last 20 years, there have been numerous successful efforts to improve patient safety, although recent research still shows a significant gap. Researchers have begun exploring the impact of individual level factors on patient safety culture and safety outcomes. This review examines the state of the science exploring the impact of professional burnout and engagement on patient safety culture and safety outcomes. A systematic search was conducted in CINAHL, PubMed, and Embase. Studies included reported on the relationships among burnout or engagement and safety culture or safety outcomes. Twenty-two studies met inclusion criteria. Ten studies showed a relationship between both safety culture and clinical errors with burnout. Two of 3 studies reported an association between burnout and patient outcomes. Fewer studies focused on engagement. Most studies exploring engagement and safety culture found a moderately strong positive association. The limited evidence on the relationship between engagement and errors depicts inconsistent findings. Only one study explored engagement and patient outcomes, which failed to find a relationship. The burnout/safety literature should be expanded to a multidisciplinary focus. Mixed results of the relationship between burnout and errors could be due to a disparate relationship with perceived versus observed errors. The engagement/safety literature is immature, although high engagement seems to be associated with high safety culture. Extending this science into safety outcomes would be meaningful, especially in light of the recent focus on an abundance-based approach to safety.


Rare-variant pathogenicity triage and inclusion of synonymous variants improves analysis of disease associations of orphan G protein-coupled receptors.
The pace of deorphanization of G protein-coupled receptors (GPCRs) has slowed, and new approaches are required. Small molecule targeting of orphan GPCRs can potentially be of clinical benefit even if the endogenous receptor ligand has not been identified. Many GPCRs lack common variants that lead to reproducible genome-wide disease associations, and rare-variant approaches have emerged as a viable alternative to identify disease associations for such genes. Therefore, our goal was to prioritize orphan GPCRs by determining their associations with human diseases in a large clinical population. We used sequence kernel association tests to assess the disease associations of 85 orphan or understudied GPCRs in an unselected cohort of 51,289 individuals. Using rare loss-of-function variants, missense variants predicted to be pathogenic or likely pathogenic, and a subset of rare synonymous variants that cause large changes in local codon bias as independent data sets, we found strong, phenome-wide disease associations shared by two or more variant categories for 39% of the GPCRs. To validate the bioinformatics and sequence kernel association test analyses, we functionally characterized rare missense and synonymous variants of GPR39, a family A GPCR, revealing altered expression or Zn2+-mediated signaling for members of both variant classes. These results support the utility of rare variant analyses for identifying disease associations for GPCRs that lack impactful common variants. We highlight the importance of rare synonymous variants in human physiology and argue for their routine inclusion in any comprehensive analysis of genomic variants as potential causes of disease.


Pharmacokinetic analysis of chloral hydrate and its metabolism in B6C3F1 mice.
Chloral hydrate (CH) and its metabolites, trichloroacetate (TCA) and dichloroacetate (DCA), have been shown to induce liver tumors in male B6C3F1 mice. The pharmacokinetics of CH and its metabolites play an important role in its toxicity. This study was designed to characterize the kinetics of CH metabolism, and the formation and elimination of TCA, DCA, trichloroethanol (TCOH), and trichloroethanol glucuronide (TCOG) in male B6C3F1 mice. Mice were dosed with 67.8, 678, and 2034 micromol/kg of CH through the tail vein. At selected time points, mice were killed, and blood and liver samples were collected. Samples were assayed by GC for CH, TCOH, TCOG, TCA, and DCA concentrations. After intravenous administration, CH rapidly disappeared from blood with a terminal half-life ranging from 5 to 24 min. Systemic clearance decreased from 36.0 to 7.6 liters/kg-hr with increasing CH dose, demonstrating dose-dependent pharmacokinetics. TCOH, TCOG, TCA, and DCA were detected over the study period. Formation and metabolism of CH metabolites seemed to be dose-dependent. The terminal half-lives of TCOH and TCOG were similar, ranging from 0.2 to 0.7 hr. TCA and DCA were formed rapidly from the metabolism of CH and cleared slowly from systemic circulation. The area under the blood concentration-time curve for DCA was 10-20% of that for TCA. Both TCA and DCA were slowly eliminated from systemic circulation. The concentration-time profile of DCA seemed to be driven by the blood concentration of TCA, suggesting the possibility of DCA formation from TCA metabolism.


Clinical Relevance of Liquid Biopsy in Melanoma and Merkel Cell Carcinoma.
Melanoma and Merkel cell carcinoma are two aggressive skin malignancies with high disease-related mortality and increasing incidence rates. Currently, invasive tumor tissue biopsy is the gold standard for their diagnosis, and no reliable easily accessible biomarker is available to monitor patients with melanoma or Merkel cell carcinoma during the disease course. In these last years, liquid biopsy has emerged as a candidate approach to overcome this limit and to identify biomarkers for early cancer diagnosis, prognosis, therapeutic response prediction, and patient follow-up. Liquid biopsy is a blood-based non-invasive procedure that allows the sequential analysis of circulating tumor cells, circulating cell-free and tumor DNA, and extracellular vesicles. These innovative biosources show similar features as the primary tumor from where they originated and represent an alternative to invasive solid tumor biopsy. In this review, the biology and technical challenges linked to the detection and analysis of the different circulating candidate biomarkers for melanoma and Merkel cell carcinoma are discussed as well as their clinical relevance.


Large-scale sequencing of plant genomes.
The large number of ESTs generated for Arabidopsis and rice in recent years now act as an important complement to whole genome sequencing projects. The Arabidopsis Genome Initiative has begun a coordinated effort to sequence the entire genome and, as a result, increasing numbers of large sequence entries can be found in the public databases. In addition, the mitochondrial genome of Arabidopsis has been completely sequenced. Genome sequencing studies and the public sequence databases have begun to influence the direction of diverse areas of research from physiology to evolution.


Histopathologic features of the acetabular labrum in femoroacetabular impingement.
This paper summarizes clinical and histopathologic findings derived from 25 patients who had surgery for symptomatic femoroacetabular impingement. We explored if observed pathologic features were consistent with hypothesized mechanisms of injury, if severity of osteoarthritis and labral degeneration were associated, and if labral refixation would present an alternative. Clinically, all patients presented with limited range of motion at the hip attributable to pain and a positive impingement test. Magnetic resonance arthrography and surgical observations showed degenerated or ruptured labra or both in the anterior and/or superior regions of the acetabular rim (24 of 25 specimens) which correlated with pain provocation, limited range of motion, and anatomic deformities. Histologically, labra were mostly hyperplastic with disorganized cystic matrices. No inflammation was observed. Spatial distribution of degenerated labral matrices was not different for the two femoroacetabular impingement mechanisms. Labral degeneration and severity of osteoarthritis observed on radiographs did not correlate. In patients having only joint debridement, the labral matrix at the tip, near its vascular supply, was normal. Femoroacetabular impingement is a gentle chronic irritation of the labra located at the site of rupture that elicits a degenerative reaction. In early stages of the disease, the labral tip is not involved, providing the possibility of labral refixation after resection of the degenerated portion.


A novel anaerobic filter membrane bioreactor: prototype start-up and filtration assays.
Anaerobic digestion allows efficient treatment of high loaded wastewater, and membrane technology allows obtaining high quality effluents with complete biomass retention. However, high biomass concentration interferes with membrane fouling. In the present work, a new bioreactor that integrates an attached biomass anaerobic culture on a fixed bed and a submerged membrane has been started up. The recirculation between the digestion and filtration chambers is coupled to the gas-lift effect of the bubbling employed for the scouring of the membranes, avoiding the use or electromechanical pumps that damage the suspended biomass. The support material retains the biomass in the digestion tank despite the downwards flow, avoiding the submerged membrane contacting with a high concentrated suspension. This novel system, called an anaerobic filter membrane bioreactor was immediately started up, achieving chemical oxygen demand (COD) removal efficiencies of 96% at an organic loading rate (OLR) of 7 kg COD/m3·d. In order to select filtration flux, specific gas demand and filtration cycle duration, the results of 15 short term assays, eight hours for each one, is presented for fluxes between 15.7 and 17.7 L/m2·h, cycle duration between 10 and 30 minutes, and three levels of scouring. It was checked that reversible and irreversible fouling were directly related when dTMP/dt > 2.5 mbar/min.


p3k14c, a synthetic global database of archaeological radiocarbon dates.
Archaeologists increasingly use large radiocarbon databases to model prehistoric human demography (also termed paleo-demography). Numerous independent projects, funded over the past decade, have assembled such databases from multiple regions of the world. These data provide unprecedented potential for comparative research on human population ecology and the evolution of social-ecological systems across the Earth. However, these databases have been developed using different sample selection criteria, which has resulted in interoperability issues for global-scale, comparative paleo-demographic research and integration with paleoclimate and paleoenvironmental data. We present a synthetic, global-scale archaeological radiocarbon database composed of 180,070 radiocarbon dates that have been cleaned according to a standardized sample selection criteria. This database increases the reusability of archaeological radiocarbon data and streamlines quality control assessments for various types of paleo-demographic research. As part of an assessment of data quality, we conduct two analyses of sampling bias in the global database at multiple scales. This database is ideal for paleo-demographic research focused on dates-as-data, bayesian modeling, or summed probability distribution methodologies.


Morphological evaluation of the incisive canal with reference to gender and age: A cone-beam computed tomography study.
The incisive canal (IC) is an important anatomical structure in the premaxilla that should be considered during many dental procedures. The objective of this study is to associate the IC morphology and dimensions with reference to gender and age by means of cone-beam computed tomography (CBCT). A retrospective study was conducted using archived CBCT records of patients who sought treatment at the Faculty of Dentistry, King Abdulaziz University, Jeddah, Saudi Arabia. OnDemand 3D Imaging software was utilized in image reconstruction and measurement determination. The parameters evaluated were the IC shape and dimensions in a sagittal and coronal view at two levels: palatal opening and nasal opening. The variables were compared according to age and gender using one-way Analysis of Variance (ANOVA) and Kruskal Wallis tests. Confidence level was obtained at P < 0.05. Out of the 370 CBCT images assessed, only 100 images fulfilled the inclusion criteria; 50 males and 50 females. No substantial variance in IC shapes was found in both the sagittal and coronal perspectives with reference to age and gender. Likewise, there was no statistical variation in IC dimensions with reference to age. On the other hand, there was a statistical difference in IC length when correlated with gender as the male subjects had longer IC as compared to females (P < 0.01). There is no association between IC morphology, age and gender. However, substantial variation in IC length was observed between genders.


The effect of short-term fasting, apolipoprotein E gene polymorphism, and sex on plasma lipids.
The effect of 1 wk of supervised fasting on plasma lipid concentrations in subjects with different apolipoprotein E (apo E) phenotypes was studied in 58 healthy free-living volunteers. The participants consumed an 870-kJ(208 kcal)/d liquid diet containing fruit and berry juices, tea, and water. The decline in plasma total cholesterol during 1 wk of fasting was 0.46 mmol/L in women and 0.35 mmol/L in men. The decreases were significant in both women and men. The response patterns of plasma total cholesterol were not significantly different between the sexes. In men, the changes in plasma low-density-lipoprotein cholesterol during the fast differed significantly (P = 0.0181) between the apo E phenotypes, whereas in women there were no differences due to phenotype (P = 0.695). The magnitude of the change in plasma triacylglycerol during the fast was different between the sexes (P = 0.0099). The changes in plasma triacylglycerols differed significantly between apo E phenotype groups in men (P = 0.0295) but not in women (P = 0.0661). Statistical comparison between different apo E phenotypes was performed with and without the small apo E3,2+E2,2 group, with essentially similar results. During fasting, plasma high-density-lipoprotein cholesterol concentrations decreased slightly but not significantly. The study shows significant differences in the associations of apo E alleles and sex on plasma lipid responses during fasting and illustrates the importance of gene-diet interactions in the regulation of lipid metabolism in humans.


Vaccine receipt and vaccine card availability among children of the apostolic faith: analysis from the 2010-2011 Zimbabwe demographic and health survey.
Vaccine hesitancy and refusal continue to be a global challenge to reaching immunization targets, especially among those in traditional or fundamentalist religions. The apostolic faith in Zimbabwe has been historically associated with objection to most medical interventions, including immunization. We conducted a descriptive analysis of socio-demographic characteristics and vaccine coverage among apostolic and non-apostolic adults aged 15-49 years and children aged 12-23 months using the Demographic and Health Survey conducted in Zimbabwe during 2010-2011. We used logistic regression models to estimate associations between the apostolic religion and receipt of all four basic childhood vaccinations in the Expanded Program on Immunization, receipt of no vaccinations, and availability of child vaccination card. Among children aged 12-23 months, 64% had received all doses of the four basic vaccinations, and 12% had received none of the recommended vaccines. A vaccination card was available for 68% of children. There was no significant association between Apostolic faith and completion of all basic vaccinations (aOR = 0.90, 95% CI: 0.69-1.17), but apostolic children were almost twice as likely to have received no basic vaccinations (aOR = 1.83, 95% CI: 1.22-2.77) than non-Apostolic children, and they were 32% less likely to have a vaccination card that was available and seen by the interviewer (aOR = 0.68, 95% CI: 0.52-0.89). Disparities in childhood vaccination coverage and availability of vaccination cards persist for apostolic in Zimbabwe. Continued collaboration with apostolic leaders and additional research to better understand vaccine hesitancy and refine interventions and messaging strategies are needed.


[Cardiovascular stress protection following anesthesia induction. Comparison of clonidine and esmolol].
Alpha-2-adrenoceptor-agonists as well as cardioselective betareceptor-antagonists have been shown to blunt stress response due to tracheal intubation. The purpose of our study was to investigate,whether clonidine or esmolol is more efficient to attenuate stress response due to intubation.44 patients were randomly assigned to receive either clonidine (n=22; 3 microg/kg) or esmolol (n=22; 2 mg/kg) immediately prior to a standardized induction of anaesthesia. Heart rate, arterial blood pressure, cardiac output, epinephrine and norepinephrine plasma concentrations were measured before,during and 10 min after intubation. Blood pressure was measured invasively and cardiac output was determined by transthoracic echocardiography. Absolute values and increase of mean arterial pressure and norepinephrine plasma concentrations were significantly less in the clonidine group (p<0,05). Clonidine (3 microg/kg) is more efficient than esmolol (2 mg/kg) in blunting stress response due to endotracheal intubation.


Prognostic Value of Ambulatory Blood Pressure Load in Pediatric CKD.
Elevated BP load is part of the criteria for ambulatory hypertension in pediatric but not adult guidelines. Our objectives were to determine the prevalence of isolated BP load elevation and associated risk with adverse outcomes in children with CKD, and to ascertain whether BP load offers risk discrimination independently or in conjunction with mean ambulatory BPs. We studied 533 children in the CKD in Children (CKiD) Study to determine the prevalence of normotension, isolated BP load elevation (≥25% of all readings elevated but mean BP normal), and ambulatory hypertension. We examined the association between these categories of BP control and adverse outcomes (left ventricular hypertrophy [LVH] or ESKD). We used c-statistics to determine risk discrimination for outcomes by BP load used either independently or in conjunction with other BP parameters. Overall, 23% of the cohort had isolated BP load elevation, but isolated BP load elevation was not statistically significantly associated with LVH in cross-section (odds ratio, 1.8; 95% CI, 0.8 to 4.2) or time to ESKD (hazard ratio, 1.2; 95% CI, 0.7 to 2.0). In unadjusted cross-sectional analysis, every 10% higher systolic BP load was associated with 1.1-times higher odds of LVH (95% CI, 1.0 to 1.3), but discrimination for LVH was poor (c=0.61). In unadjusted longitudinal analysis, every 10% higher systolic BP load was associated with a 1.2-times higher risk of ESKD (95% CI, 1.1 to 1.2), but discrimination for ESKD was also poor (c=0.60). After accounting for mean systolic BP, systolic BP load was not statistically significantly associated with either LVH or ESKD. Findings were similar with diastolic BP load. BP load does not provide additive value in discriminating outcomes when used independently or in conjunction with mean systolic BP in children with CKD. This article contains a podcast at https://www.asn-online.org/media/podcast/CJASN/2020_03_11_CPOD10130819.mp3.


Progesterone and estrogen regulate oxidative metabolism in brain mitochondria.
The ovarian hormones progesterone and estrogen have well-established neurotrophic and neuroprotective effects supporting both reproductive function and cognitive health. More recently, it has been recognized that these steroids also regulate metabolic functions sustaining the energetic demands of this neuronal activation. Underlying this metabolic control is an interpretation of signals from diverse environmental sources integrated by receptor-mediated responses converging upon mitochondrial function. In this study, to determine the effects of progesterone (P4) and 17beta-estradiol (E2) on metabolic control via mitochondrial function, ovariectomized rats were treated with P4, E2, or E2 plus P4, and whole-brain mitochondria were isolated for functional assessment. Brain mitochondria from hormone-treated rats displayed enhanced functional efficiency and increased metabolic rates. The hormone-treated mitochondria exhibited increased respiratory function coupled to increased expression and activity of the electron transport chain complex IV (cytochrome c oxidase). This increased respiratory activity was coupled with a decreased rate of reactive oxygen leak and reduced lipid peroxidation representing a systematic enhancement of brain mitochondrial efficiency. As such, ovarian hormone replacement induces mitochondrial alterations in the central nervous system supporting efficient and balanced bioenergetics reducing oxidative stress and attenuating endogenous oxidative damage.


Natural and cross-inducible anti-SIV antibodies in Mauritian cynomolgus macaques.
Cynomolgus macaques are an increasingly important nonhuman primate model for HIV vaccine research. SIV-free animals without pre-existing anti-SIV immune responses are generally needed to evaluate the effect of vaccine-induced immune responses against the vaccine epitopes. Here, in order to select such animals for vaccine studies, we screened 108 naïve female Mauritian cynomolgus macaques for natural (baseline) antibodies to SIV antigens using a Bio-Plex multiplex system. The antigens included twelve 20mer peptides overlapping the twelve SIV protease cleavage sites (-10/+10), respectively (PCS peptides), and three non-PCS Gag or Env peptides. Natural antibodies to SIV antigens were detected in subsets of monkeys. The antibody reactivity to SIV was further confirmed by Western blot using purified recombinant SIV Gag and Env proteins. As expected, the immunization of monkeys with PCS antigens elicited anti-PCS antibodies. However, unexpectedly, antibodies to non-PCS peptides were also induced, as shown by both Bio-Plex and Western blot analyses, while the non-PCS peptides do not share sequence homology with PCS peptides. The presence of natural and vaccine cross-inducible SIV antibodies in Mauritian cynomolgus macaques should be considered in animal selection, experimental design and result interpretation, for their best use in HIV vaccine research.


Highland games: A benchmarking exercise in predicting biophysical and drug properties of monoclonal antibodies from amino acid sequences.
Biopharmaceutical product and process development do not yet take advantage of predictive computational modeling to nearly the degree seen in industries based on smaller molecules. To assess and advance progress in this area, spirited coopetition (mutually beneficial collaboration between competitors) was successfully used to motivate industrial scientists to develop, share, and compare data and methods which would normally have remained confidential. The first "Highland Games" competition was held in conjunction with the October 2018 Recovery of Biological Products Conference in Ashville, NC, with the goal of benchmarking and assessment of the ability to predict development-related properties of six antibodies from their amino acid sequences alone. Predictions included purification-influencing properties such as isoelectric point and protein A elution pH, and biophysical properties such as stability and viscosity at very high concentrations. Essential contributions were made by a large variety of individuals, including companies which consented to provide antibody amino acid sequences and test materials, volunteers who undertook the preparation and experimental characterization of these materials, and prediction teams who attempted to predict antibody properties from sequence alone. Best practices were identified and shared, and areas in which the community excels at making predictions were identified, as well as areas presenting opportunities for considerable improvement. Predictions of isoelectric point and protein A elution pH were especially good with all-prediction average errors of 0.2 and 1.6 pH unit, respectively, while predictions of some other properties were notably less good. This manuscript presents the events, methods, and results of the competition, and can serve as a tutorial and as a reference for in-house benchmarking by others. Organizations vary in their policies concerning disclosure of methods, but most managements were very cooperative with the Highland Games exercise, and considerable insight into common and best practices is available from the contributed methods. The accumulated data set will serve as a benchmarking tool for further development of in silico prediction tools.


A simple terahertz spectrometer based on a low-reflectivity Fabry-Perot interferometer using Fourier transform spectroscopy.
A simple terahertz (THz) Fourier transform spectrometer is theoretically and experimentally demonstrated with a low-reflectivity Fabry-Perot interferometer. Composed with only two parallel low reflectivity surfaces, this simple spectrometer has the ability to measure the spectrum over more than one octave with a controllable resolution. The emission spectra of a wavelength-tunable photonic transmitter excited by an optical coherent control system are determined by the spectrometer. With a simple algorithm for the spectral reconstruction and a compact structure with easy alignment, the demonstrated spectrometer will meet the needs of many important applications where a compact and convenient spectrometer is required in the frequency range from sub-THz wave up to even visible light.


Adjunctive Use of Platelet Concentrates for Hard- and Soft-Tissue Grafting.
During healing after injury, platelets are natural reservoirs of growth factors and cytokines that play a critical role in the formation, maturation, and repair of soft and hard tissues. Platelet concentrates (PCs) have long been used to improve such healing in multiple applications throughout medicine and dentistry. Platelet-rich plasma and platelet-rich fibrin are autologous PCs derived from patients' blood. Because of the readily available source of blood after a simple venipuncture and the high level of patient acceptance of autologous materials, the use of autologous PCs for dental and oral surgical procedures is increasing in practice. Many indications for their use in dental procedures have been described, including hard- and soft-tissue regeneration. This article reviews the properties of currently available autologous platelet concentrates used in dentistry and identifies clinical applications for their adjunctive use to improve regeneration of oral tissues.


Endoscopic ultrasound after preoperative chemoradiation can help identify patients who benefit maximally after surgical esophageal resection.
We investigated whether differences in postoperative survival exist based on the presence and site of residual tumor (esophagus vs regional lymph nodes) after preoperative chemoXRT in patients with esophageal cancer. Based on these data, we reevaluated the role of EUS in identifying patients who maximally benefit from surgical esophageal resection after preoperative chemoXRT. We studied 97 consecutive esophageal cancer patients treated with preoperative chemoXRT and a potentially curative surgical procedure between 1998 to 2001. All patients had EUS examination prior to chemoXRT and 53 had a repeat EUS examination after chemoXRT but prior to surgery. Surgical resection specimens were analyzed for absence or presence of residual tumor and its location. Patients with residual tumor in the esophagus (pathT1-3N0) and patients without residual tumor (pathT0N0) had similar cumulative survival (p= 0.92). Patients with residual cancer in lymph nodes showed a trend toward shorter cumulative survival compared to patients without residual tumor in lymph nodes (p= 0.086). The actuarial survival in pathN1 group was lower than pathN0 group at 1, 2, and 3 yr. Patients with significant residual lymphadenopathy detected by EUS after therapy had significantly worse postoperative survival compared to patients with no residual lymphadenopathy (p= 0.028). In eight patients, we found that reliable cytologic identification of residual malignancy was technically feasible by EUS-FNA after chemoradiation therapy. Following preoperative chemoXRT and surgery, patients with residual tumor in the regional lymph nodes have lower actuarial survival at 1, 2, and 3 yr after surgery, compared to patients with path CR or with residual tumor only in the esophagus. EUS and EUS-guided FNA can be helpful in identifying residual tumor in the lymph nodes after preoperative chemoXRT to select patients who benefit maximally from surgery.


The metabotropic glutamate receptor, mGluR5, is a key determinant of good and bad spatial learning performance and hippocampal synaptic plasticity.
Hippocampal synaptic plasticity is expressed to very different extents in distinct rat strains in vivo. This may correlate with differences in learning ability. We investigated whether the metabotropic glutamate receptor mGluR5 contributes to differences in long-term potentiation (LTP) and learning in freely moving hooded Lister (HL) and Wistar rats. High-frequency tetanization (HFT) generated robust CA1 LTP in Wistar rats (> 24 h) and incremental potentiation in HL rats. The mGluR5 antagonist 2-methyl-6-(phenylethynyl) pyridine (MPEP; 1.8 microg), applied intracerebrally, impaired LTP from approximately 60 min onwards in Wistar and from 24 h in HL rats. HFT generated LTP in the dentate gyrus (DG) of Wistar rats (> 24 h), which was blocked by MPEP, and MPEP-resistant short-term depression in HL rats. Training for 10 days in an eight-arm radial maze revealed no working memory differences, but better reference memory performance in Wistar compared with HL rats. Daily application of MPEP (1.8 microg) impaired working and reference memory in Wistar rats. In HL rats, working memory was impaired but reference memory was unaffected. Western blot analysis revealed lower expression of mGluR5 in HL compared with Wistar rats. MGluR1 expression was equivalent. These data reveal striking mGluR5-dependent differences in spatial learning in different rat strains, which correlate to synaptic plasticity and mGluR5 expression levels.


Do HIV-infected women want to discuss reproductive plans with providers, and are those conversations occurring?
The purpose of the study is to assess frequency and determinants of discussions between HIV-infected women and their HIV providers about childbearing plans, and to identify unmet need for reproductive counseling. We conducted a cross-sectional, audio computer-assisted self-interview (ACASI) among 181 predominately African American HIV-infected women of reproductive age receiving HIV clinical care in two urban health clinics. We used descriptive statistics to identify unmet need for reproductive counseling by determining the proportion of women who want to, but have not, discussed future reproductive plans with their primary HIV care provider. Multivariate analysis determined which factors were associated with general and personalized discussions about pregnancy. Of the 181 women interviewed, 67% reported a general discussion about pregnancy and HIV while 31% reported a personalized discussion about future childbearing plans with their provider. Of the personalized discussions, 64% were patient initiated. Unmet reproductive counseling needs were higher for personalized discussions about future pregnancies (56%) than general discussions about HIV and pregnancy (23%). Younger age was the most powerful determinant of provider communication about pregnancy. A significant proportion of HIV-infected women want to talk about reproductive plans with their HIV provider; however, many have not. HIV care providers and gynecologists can address this unmet communication need by discussing reproductive plans with all women of childbearing age so that preconception counseling can be provided when appropriate. Providers will miss opportunities to help women safely plan pregnancy if they only discuss reproductive plans with younger patients.


Segmental low-density area on contrast-enhanced CT is a possible clue to diagnosing branch artery fibromuscular dysplasia.
Fibromuscular dysplasia can cause renovascular hypertension. Since fibromuscular dysplasia may be underdiagnosed, precise diagnosis and management are crucial, especially for young women. A 20-year-old woman with hypertension and hypokalemia was referred to our hospital for further evaluation of secondary hypertension. At the previous hospital, her blood pressure was 160/110 mmHg and the serum potassium level was 2.9 mEq/L. The equilibrium phase on contrast-enhanced computed tomography revealed a low-density area in the upper median portion of the right kidney. On admission to our hospital, her blood pressure was 141/96 mmHg under 5 mg of amlodipine. Laboratory tests revealed plasma renin activity of 11.3 ng/mL/h and plasma aldosterone concentration of 117.1 pg/mL. Renal venous sampling of active renin concentration showed a right-to-left renin ratio of 3.13, confirming a significant increase in renin secretion from the right kidney. Selective reno-angiography detected focal stenosis with adjacent aneurysmal dilation and tortuosity in the proximal branch of the right renal artery. She was diagnosed with branch artery fibromuscular dysplasia and successfully treated with percutaneous transluminal angioplasty. After the treatment, she was free from hypertension and hypokalemia without any medications. Since branch artery fibromuscular dysplasia is sometimes difficult to diagnose, contrast-enhanced computed tomography can be a promising diagnostic tool as shown in this case. Concerning treatment, our patient was treated with percutaneous transluminal angioplasty, which should be considered for women of reproductive age because recommended antihypertensive medications can be teratogenic even in the first trimester of pregnancy. Although branch artery fibromuscular dysplasia (FMD) is sometimes difficult to diagnose, it should be considered in patients with high-renin, high-aldosterone hypertension. Branch artery FMD can present with a low-density area of the kidney on contrast-enhanced computed tomography, as shown in this case. Percutaneous transluminal angioplasty (PTA) can be an appropriate treatment for branch artery FMD, especially in young female patients. PTA may immediately improve hypertension and hypokalemia without the need for medications.


Preliminary recognition of whole body vibration risk in private farmers' working environment.
The objective of the study was the preliminary recognition of whole body mechanical vibration risk among farmers in the rural work environment. The study covered 15 farms using cultivated land of the size of over 10 ha, carrying out mixed production (plant-animal), equipped with agricultural tractors, and a basic set of tractor-mounted agricultural machinery, with a partial contribution of self-propelled agricultural machines. The scope of the study covered the measurements of effective vibration RMS acceleration (equivalent, maximum, minimum, peak) frequency corrected on the seats of agricultural vehicles in the three spatial directions of vibration (X, Y, Z). These measurements were realized while performing various field and transport work activities during the period of the whole year. A analysis of the peak, maximum and minimum vibration accelerations confirms that in the agricultural occupational environment there occurs a considerable variation of the vibration values registered. This is also evidenced by high values of the Crest Factor, sometimes exceeding a score of 10. Analysis of the registered equivalent values of vibration acceleration (frequency corrected) from the hygienic aspect showed that vibration occurring on the seats may create risk for farmers' health while performing such work activities as: tending and raking of hay, fertilizers spreading, soil aggregation, grass mowing and cultivation. Analysis of the spatial distribution of the measured, frequency corrected vibration accelerations indicates that considerably the highest acceleration values occur in the vertical plane (direction-Z). Literature data clearly confirm an unfavourable effect of whole body vibration present in agricultural vehicles on discomfort and the occurrence of back pain in the operators, especially in the low back region (lumbar spine), as well as degenerative changes in the spine.


[Carriers of Neisseria meningitidis among children from a primary school].
A cross-sectional and descriptive study was conducted among 318 children from the "Mártires del Corynthia" Primary School under the authorization of the Municipal Division of Education and the informed consent of their parents aimed at knowing the prevalence of meningoccoco carriers in school children, determining the epidemiological markers of the isolated strains and establishing the possible relation existing between the carrier and variables, such as age, sex, acute respiratory infection history, hacinamiento, amigdalectomy, inhibitory effect of of the accompanying flora and the secretory state of ABH antigens in saliva. All of them underwent nasopharyngeal exudate and a saliva sample was taken. In adition, the paents were surveyed about the risks factors to be investigated. 6.9 % of meningoccoco carriers were found and the NA:NT:P1:NST:L3,7,9 strains predominated. The risk factors with statistically significant results regarding the condition of carrier Neisseria meningitidis carrier were age, acute respiratory infection history, and the presence of Streptococcus pneumoniae and Neisseria lactamica of the accompanying bacterial flora in the nasopharynx of the children under study.


Clinicopathological Study of Eosinophilic Cholecystitis: Five Year Single Institution Experience.
Gallbladder diseases are very common in Northern India, most common of which is Chronic Cholecystitis. Rarely, histopathological diagnosis of Eosinophilic Cholecystitis (EC) is given when transmural cellular infiltrate consists of more than 90% eosinophils. To determine the prevalence and clinicopathological profile of eosinophilic cholecystitis at a tertiary care hospital of New Delhi. This was a retrospective clinicopathological study done on twenty two cases of eosinophilic cholecystitis over a period of five years from January 2011- December 2015. In cases diagnosed histopathologically as eosinophilic cholecystitis, clinical details were obtained from hospital records and slides were retrieved. Various histologic features, pattern of the inflammatory infiltrate and association of EC with other medical diseases, drugs and allergic states were evaluated. Out of a total of 1370 cholecystectomy specimens received during five year period, Eosinophilic cholecystitis was diagnosed in 22 (1.6%) of the specimens. Clinically, seven of these patients had a clinical diagnosis of acute cholecystitis. Patient's age ranged from 25-64 years and male to female ratio was 1:2.7. Most common symptom reported was abdominal pain. Most of the cases showed gallstones radiologically (90%) while only two cases showed peripheral eosinophilia (9%). Histologically, mucosal and muscular eosinophilic infiltrate was seen in 72.6% of the cases. No association with drug therapy, allergies or other pre-existing medical conditions was noted. EC is a relatively uncommon entity in which histopathology remains the main stay of diagnosis. Although the presentation may be similar to general cholecystitis, if a postoperative histopathological diagnosis of EC is made, then the patient must be investigated thoroughly to rule out other associated disease conditions, which may have a worse prognosis than cholecystitis itself.


Periodontal considerations in a patient with glucose-6-phosphate dehydrogenase deficiency with associated pancytopenia: A rare case report.
Glucose-6-phosphate dehydrogenase (G6PD) deficiency is the most common enzyme defect in humans. G6PD deficiency is widely distributed in tropical and subtropical parts of the world and a conservative estimate is that at least 500 million people have a G6PD deficient gene. In several of these areas, the frequency of a G6PD deficiency gene may be as high as 20% or more. The vast majority of people with G6PD deficiency remain clinically asymptomatic throughout their lifetime. However, all of them have an increased risk of developing neonatal jaundice and a risk of developing acute hemolytic anemia when challenged by a number of oxidative agents. The most important treatment measure is prevention: Avoidance of the drugs and foods that cause hemolysis.


[Prevalence of diabetic retinopathy using non-mydriatic retinography].
To establish the prevalence of diabetic retinopathy (RD) diagnosed after non-mydriatic retinography and to evaluate its utility as a screening test in the area of San Sebastián. A prospective study including 2,444 diabetic patients sent by their primary attention doctors and/or their endocrinologists. All patients underwent non-mydriatic retinography in the central 45 degrees; visual acuity was explored, as well as IOP through non-contact tonometry. The retinographies and information obtained were sent to our hospital and were revised by an ophthalmologist from the Retina Department. Fifteen point zero two (15.02%) of the patients suffered from diabetes and were under dietary treatment, 62.55% suffered from non-insulin-dependant diabetes, and 22.43% suffered from insulin-dependant diabetes. The prevalence of diabetic retinopathy was 9.36%; 5.27% mild non-proliferative diabetic retinopathy (DR); 2.21% moderate-non-proliferative DR; 1.67 % severe non-proliferative DR; and 0.05% proliferative-diabetic retinopathy. Eight point two two (8.22%) of the sample studied was diagnosed with ocular hypertension. We observed a low prevalence of DR in our sample. Use of non-mydriatic retinopathy in telemedicine plays an important role in the early diagnosis of diabetic retinopathy and it can be applied to other ophthalmic diseases.


Ultrasound Cyclo Plasty for Treatment of Surgery-Naïve Open-Angle Glaucoma Patients: A Prospective, Multicenter, 2-Year Follow-Up Trial.
The purpose of this prospective study was to evaluate the efficacy and safety of the Ultrasound Cyclo Plasty (UCP) procedure using high-intensity focused ultrasound in surgery-naïve open-angle glaucoma patients. prospective, non-randomized, single-arm, multicenter clinical trial. Sixty-six eyes with primary open-angle glaucoma, intraocular pressure (IOP) ≥21 mmHg and with no history of filtering surgery were enrolled. Patients were treated by UCP with a therapy probe comprising six piezoelectric transducers, consecutively activated for 8 s each. Complete ophthalmic examination was performed before the procedure, 1 day after the procedure, and 1, 3, 6, 12, 18 and 24 months after the procedure. Primary outcomes were complete success (defined as IOP lowering from baseline ≥20% without additional glaucoma medications) and vision-threatening complications. Secondary outcomes were the presence of complications and the reduction of the number of medications used. IOP was significantly reduced after one procedure (p < 0.05), from a mean pre-operative value of 24.3 ± 2.9 mmHg (n = 2.3 hypotensive medications) to a mean value of 15.9 ± 3.6 mmHg (n = 2.2 hypotensive medications) at 2 years (mean IOP lowering of 33%). Surgical success was achieved in 74% of eyes. Notwithstanding side effects such as transient anterior chamber inflammation, refractive error changes, transient hypotony and macular edema, no major intra or post-operative complications such as phthisis, induced cataract, neovascularization or significant vision loss were observed. Ultrasound Cyclo Plasty is a valuable, effective and well-tolerated procedure to lower IOP in patients with open-angle glaucoma without previous filtering surgery.


A double-sided microscope to realize whole-ganglion imaging of membrane potential in the medicinal leech.
Studies of neuronal network emergence during sensory processing and motor control are greatly facilitated by technologies that allow us to simultaneously record the membrane potential dynamics of a large population of neurons in single cell resolution. To achieve whole-brain recording with the ability to detect both small synaptic potentials and action potentials, we developed a voltage-sensitive dye (VSD) imaging technique based on a double-sided microscope that can image two sides of a nervous system simultaneously. We applied this system to the segmental ganglia of the medicinal leech. Double-sided VSD imaging enabled simultaneous recording of membrane potential events from almost all of the identifiable neurons. Using data obtained from double-sided VSD imaging, we analyzed neuronal dynamics in both sensory processing and generation of behavior and constructed functional maps for identification of neurons contributing to these processes.


Antibacterial activities of plants from Central Africa used traditionally by the Bakola pygmies for treating respiratory and tuberculosis-related symptoms.
The antibacterial activities of 18 plants from 10 different families were investigated for their antimicrobial efficacy, based on the traditional uses of these species by Bakola pygmies living in Central Africa, especially along the Ngoyang area in Cameroon for the treatment of respiratory and tuberculosis-related symptoms. The aim of the study is to test the antimicrobial efficacy of these plants against some pathogens associated with respiratory disease and to determine if there is any validation for the traditional use against Mycobacterium species. Medium polar extracts were prepared in MeOH/DCM (1:1, v/v) from the plant parts of each species used traditionally and were assayed against pathogens associated with respiratory tract ailments [Staphylococcus aureus (ATCC 25923), Klebsiella pneumoniae (ATCC 13883) and Morexella cattarhalis (ATCC 14468)] using the minimum inhibitory concentration (MIC) method. Two additional faster growing Mycobacterium strains [Mycobacterium smegmatis (ATCC 23246) and Mycobacterium aurum (NCTC 10437)] were included in the assay as predictive test organisms for the more pathogenic strain Mycobacterium tuberculosis. Some plant species, such as Alchornea floribunda, Musanga cecropioides (both leaves and stem bark), Tetracera potatoria and Xylopia aethiopica (stem bark), were effective in inhibiting Morexella cattarhalis, having MIC values between 65 and 250 μg/mL. Some noteworthy antimycobacterial inhibition (MIC≤200 μg/mL and as low as MIC 6.5 µg/mL) for 54% of the extracts were observed. While moderate activity was shown for pathogens causing respiratory tract infections, these plant species seems to be selectively targeting Mycobacteria spp. suggesting that the traditional use for treating tuberculosis related symptoms may be indeed be accurate.


SCIENTIFIC AND SOCIAL VALUE JUDGMENTS FOR ORPHAN DRUGS IN HEALTH TECHNOLOGY ASSESSMENT.
We explore how broader aspects of a treatment's value and the impact of the condition on patients not captured by routine health technology assessment (HTA) methods using clinical and economic evidence, defined as "other considerations," may influence HTA processes in different settings. Countries included were England, Scotland, Sweden, and France. Data sources were the publicly available reports on HTA recommendations. Ten drugs with European Medicines Agency orphan designation and appraised in England were selected. Qualitative thematic analysis was used to systematically identify and code all "other considerations" based on a previously developed methodological framework, which also coded whether it was provided by stakeholders, and how it influenced the decision. A classification framework of scientific and social value judgments was developed and used throughout the study. A total of 125 "other considerations" were identified and grouped into ten subcategories based on the information provided. Eighteen to 100 percent of these, depending on the agency, were put forward as one of the main reasons for the final decision potentially contributing to accepting a higher incremental cost-effectiveness ratio or uncertain evidence. Some of these were nonquantified or nonelicited and pertained to the assessor's judgment. A taxonomy of these value judgments was created to be used in future cases. Results also contributed to better defining the determinants of social value and improving accountability for reasonableness. The systematic identification of the scientific and social value judgments enables to better understanding the dimensions of value, which can be used to improve their transparency and consistent use across decisions and settings.


The centrin-based cytoskeleton of Chlamydomonas reinhardtii: distribution in interphase and mitotic cells.
Monoclonal and polyclonal antibodies raised against algal centrin, a protein of algal striated flagellar roots, were used to characterize the occurrence and distribution of this protein in interphase and mitotic Chlamydomonas cells. Chlamydomonas centrin, as identified by Western immunoblot procedures, is a low molecular (20,000-Mr) acidic protein. Immunofluorescence and immunogold labeling demonstrates that centrin is a component of the distal fiber. In addition, centrin-based flagellar roots link the flagellar apparatus to the nucleus. Two major descending fibers extend from the basal bodies toward the nucleus; each descending fiber branches several times giving rise to 8-16 fimbria which surround and embrace the nucleus. Immunogold labeling indicates that these fimbria are juxtaposed to the outer nuclear envelope. Earlier studies have demonstrated that the centrin-based linkage between the flagellar apparatus and the nucleus is contractile, both in vitro and in living Chlamydomonas cells (Wright, R. L., J. Salisbury, and J. Jarvik. 1985. J. Cell Biol. 101:1903-1912; Salisbury, J. L., M. A. Sanders, and L. Harpst. 1987. J. Cell Biol. 105:1799-1805). Immunofluorescence studies show dramatic changes in distribution of the centrin-based system during mitosis that include a transient contraction at preprophase; division, separation, and re-extension during prophase; and a second transient contraction at the metaphase/anaphase boundary. These observations suggest a fundamental role for centrin in motile events during mitosis.


Influence of the inversion of the portal/splenic vein diameter in the results of the surgical treatment of schistossomotic portal hypertension.
To evaluate the morbidity and mortality in surgical treatment of schistosomal portal hypertension in patients with inversion of the Portal/Splenic Vein diameter ratio. We conducted a retrospective cross-sectional study of patients undergoing surgical treatment of portal hypertension in the period between September 1993 and January 2004. The study population was divided into two groups: a) Inversion--splenic vein diameter greater than or equal to portal vein's--and b) control group (portal vein diameter greater than the splenic vein's). Statistical comparisons used the Student t test for averages difference, chi-square test for proportions difference and Fisher's exact test for small samples. 169 patients were analyzed, with follow-up averaging 23.6 months. Twenty-one patients (12.4%) had splenic vein caliber greater of equal than the portal vein's (Inversion--study group). The mean preoperative diameter of the portal and splenic veins were respectively 1.49 and 1.14 cm in the control group, and 0.98 versus 1.07 cm in the inversion group. The portal vein diameter was significantly higher in the control group when compared to the inversion group (p <0.05). Varices in the gastric fundus were found in 33.3% of the inversion group and in 38.5% of patients in the control group. Postoperative rebleeding occurred in 23.1% of patients in the inversion group and in 13.4% of the control group ones (p > 0.05). In the postoperative evaluation with Doppler ultrasonography of portal vessels, no cases of portal vein thrombosis were observed in the inversion group, whilst in the control group portal thrombosis was identified in 16.9% of the patients (p <0.05). Death occurred in one (4.8%) individual from the inversion group; mortality was 4.1% in the control group (p>0.05). The mean serum level of platelets was significantly lower (65,950/mm²) in the inversion group than in the controls (106,647/mm²) (p<0.05). The results suggest that the reversal of portal/splenic vein caliber ratio does not represent a contraindication to surgical treatment of schistosomal portal hypertension.


Simultaneous CRISPR screening and spatial transcriptomics reveals intracellular, intercellular, and functional transcriptional circuits.
Pooled optical screens have enabled the study of cellular interactions, morphology, or dynamics at massive scale, but have not yet leveraged the power of highly-plexed single-cell resolved transcriptomic readouts to inform molecular pathways. Here, we present Perturb-FISH, which bridges these approaches by combining imaging spatial transcriptomics with parallel optical detection of in situ amplified guide RNAs. We show that Perturb-FISH recovers intracellular effects that are consistent with Perturb-seq results in a screen of lipopolysaccharide response in cultured monocytes, and uncover new intercellular and density-dependent regulation of the innate immune response. We further pair Perturb-FISH with a functional readout in a screen of autism spectrum disorder risk genes, showing common calcium activity phenotypes in induced pluripotent stem cell derived astrocytes and their associated genetic interactions and dysregulated molecular pathways. Perturb-FISH is thus a generally applicable method for studying the genetic and molecular associations of spatial and functional biology at single-cell resolution.


Tubular bridges for bronchial epithelial cell migration and communication.
Biological processes from embryogenesis to tumorigenesis rely on the coordinated coalescence of cells and synchronized cell-to-cell communication. Intercellular signaling enables cell masses to communicate through endocrine pathways at a distance or by direct contact over shorter dimensions. Cellular bridges, the longest direct connections between cells, facilitate transfer of cellular signals and components over hundreds of microns in vitro and in vivo. Using various cellular imaging techniques on human tissue cultures, we identified two types of tubular, bronchial epithelial (EP) connections, up to a millimeter in length, designated EP bridges. Structurally distinct from other cellular connections, the first type of EP bridge may mediate transport of cellular material between cells, while the second type of EP bridge is functionally distinct from all other cellular connections by mediating migration of epithelial cells between EP masses. Morphological and biochemical interactions with other cell types differentially regulated the nuclear factor-kappaB and cyclooxygenase inflammatory pathways, resulting in increased levels of inflammatory molecules that impeded EP bridge formation. Pharmacologic inhibition of these inflammatory pathways caused increased morphological and mobility changes stimulating the biogenesis of EP bridges, in part through the upregulation of reactive oxygen species pathways. EP bridge formation appears to be a normal response of EP physiology in vitro, which is differentially inhibited by inflammatory cellular pathways depending upon the morphological and biochemical interactions between EP cells and other cell types. These tubular EP conduits may represent an ultra long-range form of direct intercellular communication and a completely new mechanism of tissue-mediated cell migration.


A model for the pattern of deposition of microfibrils in the cell wall of Glaucocystis.
Freeze-fracturing of Glaucocystis nostochinearum Itzigsohn cells during cell-wall microfibril deposition indicates that unidirectionally polarized microfibril ends are localized in a "zone of synthesis" covering about 30% of the sarface area of the plasma membrane. Within this zone there are about 6 microfibril ends/μm(2) cell surface. It is proposed that microfibrils are generated by the passage of their tips over the cell surface and that the pattern of microfibril organization at the poles of the cells, in which microfibrils of alternate layers are interconnected at 3 "rotation centres", results directly from the pattern of this translation of microfibril tips. In a model of the deposition pattern it is proposed that the zone of synthesis may split into 3 sub-zones as the poles are approached, each sub-zone being responsible for the generation of one rotation centre. It is demonstrated that the microfibrillar component of the entire wall could be generated by the steady translation of the microfibril tips (at which synthesis is presumed to occur) over the cell surface at a rate of 0.25-0.5 μm min(-1). Microcinematography indicates that the protoplast rotates during cell-wall deposition, and it is proposed that this rotation may play a role in the generation of the microfibril deposition pattern.


An increase in immature β-cells lacking Glut2 precedes the expansion of β-cell mass in the pregnant mouse.
A compensatory increase in β-cell mass occurs during pregnancy to counter the associated insulin resistance, and a failure in adaptation is thought to contribute to gestational diabetes. Insulin-expressing but glucose-transporter-2-low (Ins+Glut2LO) progenitor cells are present in mouse and human pancreas, being predominantly located in extra-islet β-cell clusters, and contribute to the regeneration of the endocrine pancreas following induced ablation. We therefore sought to investigate the contribution of Ins+Glut2LO cells to β-cell mass expansion during pregnancy. Female C57Bl/6 mice were time mated and pancreata were collected at gestational days (GD) 6, 9, 12, 15, and 18, and postpartum D7 (n = 4/time-point) and compared to control (non-pregnant) animals. Beta cell mass, location, proliferation (Ki67+), and proportion of Ins+Glut2LO cells were measured using immunohistochemistry and bright field or confocal microscopy. Beta cell mass tripled by GD18 and β-cell proliferation peaked at GD12 in islets (≥6 β-cells) and small β-cell clusters (1-5 β-cells). The proportion and fraction of Ins+Glut2LO cells undergoing proliferation increased significantly at GD9 in both islets and clusters, preceding the increase in β-cell mass and proliferation, and their proliferation within clusters persisted until GD15. The overall number of clusters increased significantly at GD9. Quantitative PCR showed a significant increase in Pdx1 presence at GD9 vs. GD18 or control pancreas, and Pdx1 was visualized by immunohistochemistry within both Ins+Glut2LO and Ins+Glut2HI cells within clusters. These results indicate that Ins+Glut2LO cells are likely to contribute to β-cell mass expansion during pregnancy.


Astrocyte regulation of synaptic behavior.
Astrocytes regulate multiple aspects of neuronal and synaptic function from development through to adulthood. Instead of addressing each function independently, this review provides a comprehensive overview of the different ways astrocytes modulate neuronal synaptic function throughout life, with a particular focus on recent findings in each area. It includes the emerging functions of astrocytes, such as a role in synapse formation, as well as more established roles, including the uptake and recycling of neurotransmitters. This broad approach covers the many ways astrocytes and neurons constantly interact to maintain the correct functioning of the brain. It is important to consider all of these diverse functions of astrocytes when investigating how astrocyte-neuron interactions regulate synaptic behavior to appreciate the complexity of these ongoing interactions.


How does equity restriction affect innovation quality? Evidence from listed manufacturing companies in China.
Improving the innovation quality of manufacturing companies has currently received increasing attention in the transformation from "Made in China" to "Created in China". Equity restriction is now one of the most talked about issues in China's corporate governance structures, but we have a limited understanding of the impact of equity restriction on innovation quality. This paper empirically analyzes the relationship and intrinsic mechanism between equity restriction and innovation quality using all A-share listed manufacturing companies in China from 2007 to 2021 as the research sample. First, the Tobit regression model is used to analyze the impact of equity restriction on innovation quality, and the Heckman two-stage model is used for the endogenous test. Then, the three-step regression model with mediating effects is used to validate the intrinsic mechanism of equity restriction to promote innovation quality from two paths, namely equity incentives and R&D investment. The research results show that equity restriction has a significant positive impact on innovation quality; equity incentives and R&D investment play a mediating role between equity restriction and innovation quality. This paper enriches the research on the influencing factors of innovation quality and provides a theoretical basis based on equity restriction for the transformation of manufacturing towards high-quality innovation, and explores the intrinsic mechanisms by which equity restriction affects innovation quality.


DNA Methyltransferase 3b Accelerates the Process of Atherosclerosis.
DNA methylation plays a key role in establishing cell type-specific gene expression profiles and patterns in atherosclerosis. The underlying mechanism remains unclear. Previous studies have shown that DNA methyltransferase 3b (DNMT3b) may play an important role in atherosclerosis. This study aimed to establish the regulatory role of DNMT3b in the development of atherosclerosis. We constructed a viral vector carrying Dnmt3b shRNA to transduce ApoE-/- mice. Meanwhile, healthy human peripheral blood Treg cells were treated with inhibitor of DNMT3b (AZA and EGCG) or transduced with DNMT3b shRNA. It showed that Dnmt3b silencing attenuated atherosclerosis, including decreased lesion size and macrophage content and increased collagen and smooth muscle cells content in ApoE-/- mice. To further investigate the possible mechanisms, combined with previous studies by our group, we showed that Foxp3-TSDR methylation level was significantly reduced Foxp3 expression and peripheral blood Treg levels were significantly increased by Dnmt3b shRNA vector transduction in animals committed to western diet for 12 and 18 weeks. Consistently, inhibition of DNMT3b (AZA and EGCG) decreased the expression levels of DNMT3b, which can increase the expression levels of FOXP3, and increase the levels of TGF-β and IL-10 and decrease the levels of IL-β and IFN-γ. After transduction with DNMT3b shRNA, the effect was more obvious. DNMT3b accelerated atherosclerosis, and may be associated with FOXP3 hypermethylation status in regulatory T cells.


Spontaneous (H)-thymidine uptake in histological subgroups of human B-cell lymphomas.
Spontaneous (3H)-TdR incorporation was studied in cell suspensions from 64 patients with monoclonal B-cell neoplasias. Among various incubation periods a long-term (20 h) assay with (3H)-TdR had the greatest discriminatory power versus non-neoplastic lymph node cell suspensions. The (3H)-TdR uptake correlated positively with cell volume, nuclear volume, and cells in S + G + M phase of the cell cycle. A high degree of heterogeneity with regard to (3H)-TdR incorporation was found within several histological groups of the Kiel classification, especially in low-grade malignant lymphomas of centroblastic/centrocytic origin and in the lymphoplasmacytoid groups. In highly malignant lymphomas (3H)-TdR uptake was statistically, significantly higher than in lymphomas of low-grade malignancy. Patients with localized disease (stages I and II) and those with "B'-symptoms showed increased incorporation of radioactive thymidine as compared to patients with disseminated mined by histopathology and spontaneous uptake of (3H)-TdR.


Size and methylation mosaicism in males with Fragile X syndrome.
Size and methylation mosaicism are a common phenomenon in Fragile X syndrome (FXS). Here, the authors report a study on twelve fragile X males with atypical mosaicism, seven of whom presented with autism spectrum disorder. A combination of Southern Blot and PCR analysis was used for CGG allele sizing and methylation. FMR1 mRNA and FMRP expression were measured by qRT-PCR and by Homogeneous Time Resolved Fluorescence methodology, respectively. DNA analysis showed atypical size- or methylation-mosaicism with both, full mutation and smaller (normal to premutation) alleles, as well as a combination of methylated and unmethylated alleles. Four individuals carried a deletion of the CGG repeat and portions of the flanking regions. The extent of methylation among the participants was reflected in the lower FMR1 mRNA and FMRP expression levels detected in these subjects. Decreased gene expression is likely the main contributor to the cognitive impairment observed in these subjects; although the presence of a normal allele did not appear to compensate for the presence of the full mutation, it correlated with better cognitive function in some but not all of the reported cases emphasizing the complexity of the molecular and clinical profile in FXS.


Temporal and spatial variation of atmospherically deposited organic contaminants at high elevation in Yosemite National Park, California, USA.
Contaminants used at low elevation, such as pesticides on crops, can be transported tens of kilometers and deposited in adjacent mountains in many parts of the world. Atmospherically deposited organic contaminants in the Sierra Nevada Mountains of California, USA, have exceeded some thresholds of concern, but the spatial and temporal distributions of contaminants in the mountains are not well known. The authors sampled shallow-water sediment and tadpoles (Pseudacris sierra) for pesticides, polycyclic aromatic hydrocarbons (PAHs), and polychlorinated biphenyls in four high-elevation sites in Yosemite National Park in the central Sierra Nevada twice during the summers of 2006, 2007, and 2008. Both historic- and current-use pesticides showed a striking pattern of lower concentrations in both sediment and tadpoles in Yosemite than was observed previously in Sequoia-Kings Canyon National Parks in the southern Sierra Nevada. By contrast, PAH concentrations in sediment were generally greater in Yosemite than in Sequoia-Kings Canyon. The authors suggest that pesticide concentrations tend to be greater in Sequoia-Kings Canyon because of a longer air flow path over agricultural lands for this park along with greater pesticide use near this park. Concentrations for DDT-related compounds in some sediment samples exceeded guidelines or critical thresholds in both parks. A general pattern of difference between Yosemite and Sequoia-Kings Canyon was not evident for total tadpole cholinesterase activity, an indicator of harmful exposure to organophosphorus and carbamate pesticides. Variability of chemical concentrations among sites, between sampling periods within each year, and among years, contributed significantly to total variation, although the relative contributions differed between sediment and tadpoles.


Future needs for ERCP: incidence of conditions leading to bile duct obstruction and requirements for diagnostic and therapeutic biliary procedures.
Although the development of endoscopic methods of treatment for biliary obstruction has proceeded rapidly in recent years, endoscopic retrograde cholangiopancreatographic (ERCP) services are patchily distributed. A recent survey by the British Society of Gastroenterology has shown that almost half the district general hospitals questioned did not have a sphincterotomy service available locally. To assess the level of provision required, two investigations have been undertaken. Firstly, an epidemiological study of bile duct obstruction has been carried out in the South Western Region. Secondly, the actual surgical and endoscopic workload in treating obstructive jaundice has been analysed in two health districts. Using present incidence and treatment rates at least 50 ERCPs per 100,000 of the population per year are estimated to be required in the future. Surgical treatment rates can be expected to fall as the number of therapeutic ERCPs increases. The implications of this estimate in equipment and staffing terms are discussed.


Estimation of cost reduction and increase for the final disposal associated with the categorization of inert waste landfills in Japan.
This study estimates the overall cost savings that have been realized due to disposal of inert wastes in Japan because this material has been deposited in inert waste landfills (IWLs) that are designed exclusively for this purpose, instead of being co-dipsosed with organic wastes in more costly in sanitary landfills (SLs). The total realized cost savings were based on the disposed volume of inert waste and the actual disposal fees for IWLs and SLs for the period 1977-2006. The estimated reduction in expense is 4748 billion JPY for the period. On the other hand, if organic wastes had been deposited in IWLs along with inert wastes, costs would be incurred to clean up the sites because the surrounding environment may be polluted by the decomposition of the non-inert wastes and considerable efforts probably would be required to restore the polluted environment to its normal condition (this is because IWLs typically do not have a barrier system.) The potential cleanup cost was estimated to be 616 to 1226 billion JPY. These estimated costs were compared and it was found that the net reduction in expense was 3522 billion to 4122 billion JPY. Although the expense was reduced substantially, it was noted that a considerable cleanup cost would be generated. In particular, it was found that the increase in cleanup costs becomes most significant after the late 1990s.


Dopamine D1/D2 Receptor Activity in the Nucleus Accumbens Core But Not in the Nucleus Accumbens Shell and Orbitofrontal Cortex Modulates Risk-Based Decision Making.
It is well known that brain dopamine (DA) signals support risk-based decision making; however, the specific terminal regions of midbrain DA neurons through which DA signals mediate risk-based decision making are unknown. Using microinfusions of the D1/D2 receptor antagonist flupenthixol, we sought to explore the role of D1/D2 receptor activity in the rat orbitofrontal cortex (OFC) and core and shell regions of the nucleus accumbens (AcbC and AcbS, respectively) in the regulation of risky choices. A risk-discounting task was used that involves choices between a certain small-reward lever that always delivered 1 pellet or a risky large-reward lever which delivered 4 pellets but had a decreasing probability of receiving the reward across 4 subsequent within-session trial blocks (100%, 50%, 25%, 12.5%). To validate task sensitivity to experimental manipulations of DA activity, we also examined the effects of systemic amphetamine and flupenthixol. Systemic amphetamine increased while systemic flupenthixol reduced risky choices. Results further demonstrate that rats that received intra-AcbC flupenthixol were able to track increasing risk associated with the risky lever but displayed a generally reduced preference for the risky lever across all trial blocks, including in the initial trial block (large reward at 100%). Microinfusions of flupenthixol into the AcbS or OFC did not alter risk-based decision making. Our data suggest that intra-AcbC D1/D2 receptor signaling does not support the ability to track shifts in reward probabilities but does bias risk-based decision making. That is, it increased the rats' preference for the response option known to be associated with higher risk-related costs.


Gas-phase inorganic chemistry: monovalent derivatives of calcium and strontium.
The chemistry and spectroscopy of monovalent derivatives of calcium and strontium are described. Laser-driven chemical reactions of calcium and strontium vapors with a variety of small molecules have provided many new free radicals. In general, these species are analogous to the stable molecules obtained in traditional inorganic or organometallic chemistry, but some new families of molecules have been discovered.


Recommendations to limit life support: a national survey of critical care physicians.
There is debate about whether physicians should routinely provide patient surrogates with recommendations about limiting life support. To explore physicians' self-reported practices and attitudes. A cross-sectional, stratified survey of 1,000 randomly selected US critical care physicians was mailed. We included a vignette to experimentally examine how surrogate desire for a recommendation and physician agreement with the surrogate modified whether physicians would provide a recommendation. Proportion of respondents reporting they routinely provide surrogates with a recommendation and how responses varied based on vignette characteristics. A total of 608 (66%) of 922 eligible physicians participated. Approximately one (22%) in five reported always providing surrogates with a recommendation, whereas 1 (11%) in 10 reported rarely or never doing so. Almost all respondents reported comfort making recommendations (92%) and viewed them as appropriate (93%). Most also viewed recommendations as a critical care physician's duty (87%) and did not view them as unduly influential (80%). Approximately two-fifths (41%) believed recommendations were only appropriate if sought by surrogates. In response to the vignettes, nearly all respondents (91%) provided a recommendation when the surrogate requested a recommendation and the physician agreed with the surrogate's likely decision. Physicians were less likely to provide an unwanted recommendation, both when physicians agreed (29%) and disagreed with the surrogate's likely decision (44%). There is substantial variation among physicians' self-reported use of recommendations to surrogates of critically ill adults. Surrogates' desires for recommendations and physicians' agreement with surrogates' likely decisions may have important influence on whether recommendations are provided.


Erdafitinib treatment in metastatic urothelial carcinoma: a real-world analysis.
Erdafitinib, a fibroblast growth factor receptor (FGFR) inhibitor is a standard post chemotherapy advanced treatment line for metastatic urothelial carcinoma harboring FGFR2/3 genomic alterations. It was approved based on a phase 2 clinical trial, revealing a 40% response rate, and 13.8 months overall survival. These FGFR genomic alterations are uncommon. Thus, real-world data on erdafitinb use is scant. We herein describe erdafitinib treatment outcome in a real world patient cohort. We retrospectively reviewed the data of patients treated with erdafitinib from 9 Israeli medical centers. Twenty-five patients with metastatic urothelial carcinoma (median age 73, 64% male, 80% with visceral metastases) were treated with erdafitinib between January 2020 to October 2022. A clinical benefit (complete response 12%, partial response 32%, stable disease 12%) was seen in 56%. Median progression-free survival was 2.7 months, and median overall survival 6.73 months. Treatment related toxicity ≥ grade 3 occurred in 52%, and 32% discontinued therapy due to adverse events. Erdafitinib therapy is associated with a clinical benefit in the real world setting, and associated with similar toxicity as reported in prospective clinical trials.


Lifestyle interventions for adults with serious mental illness: a systematic literature review.
The promotion of healthy lifestyles among persons with serious mental illness is an integral part of their recovery. The aims of this systematic literature review were to rate the methodological quality of lifestyle intervention outcome studies for persons with serious mental illness, summarize intervention strategies, examine physical health outcomes, and evaluate the inclusion of racial and ethnic minority groups in these studies. Electronic bibliographic database searches were performed to locate studies conducted in the United States. Articles written in English and published in peer-reviewed journals between 1980 and 2009 were included. The authors used a standardized instrument to rate studies' methodological quality. Twenty-three articles were reviewed. Based on studies' methodological quality, three levels of evidence were found: single-group reports, quasi-experimental studies, and randomized controlled trials. Most interventions used behavioral techniques to improve dietary habits and increase physical activity. Twelve studies reported significant improvements in either weight loss or metabolic syndrome risk factors associated with receiving a lifestyle intervention. Persons from racial and ethnic minority groups were underrepresented, especially Hispanics and Asian Americans. Only one study included non-English-speaking participants. Lifestyle interventions adapted to persons with serious mental illness show promise in reducing weight loss and some risk factors for metabolic syndrome. The underrepresentation of persons from racial or ethnic minority groups in this literature limits its generalizability. Implications for research and practice are discussed.


Stability studies on piroxicam encapsulated niosomes.
Drug delivery systems which yield ideal treatments are currently the center of interest for researchers. Niosomes have numerous advantages over other drug delivery systems. However, stability issue is not clear yet and is a serious drawback for niosomes. In this study, the stability of niosomes was the center of interest. Piroxicam which was chosen as the model drug was loaded to niosomes. Niosomes were prepared by thin-film method and different forms (aqueous dispersion, lyophilized powder and lyophilized powder with cryoprotectant) of the original niosome formulation were prepared. The samples were stored either at 5°C±3°C or 25°C±2°C/60% RH±5% RH for 3 months. The drug leakage percent, particle size and distribution, zeta potential, drug release profiles were determined and niosomes were visualized under optic microscope. Niosome formulation provided sustained release of piroxicam. The drug leakage from stored niosomes was observed at the level of 1.56-6.63 %. Individual vesicle images were obtained for all samples by optical microscope. However, particle size of niosomes was increased upon storage. The zeta potential values were neither related to time nor physical form. Drug release profiles and amounts were quite similar for all forms of niosomes and the original formulation but a slight decrease was noticed on drug release amounts by time. This indicates that niosomes become more rigid by time. Although the ideal storage was obtained with lyophilized niosomes at 5±3°C in this study, the usage of suitable cryoprotectant and optimized lyophilization process should be further evaluated.


Environmental epidemiologic investigation of the styrene-butadiene rubber industry. Mortality patterns with discussion of the hematopoietic and lymphatic malignancies.
A retrospective cohort mortality study and an industrial hygiene assessment were undertaken in two styrene-butadiene rubber producing facilities in eastern Texas. Occupational history records were available from 1943 at plant A and from 1950 at plant B to the study cut-off date of 31 March 1976. With a two-sided test statistic, no statistically significant excesses in total or cause-specific mortality were observed for the overall worker population of either plant. However, the plant A study group demonstrated a nonsignificant statistical excess [standardized mortality ratio (SMR) of 203] for the cause-specific category of leukemia and aleukemia. Additional analyses were performed on a subgroup consisting of all white males with at least six months of employment at plant A between the beginning of 1943 and the end of 1945, a time which coincided with process and operational changes. An SMR of 278, also not statistically significant, was demonstrated for the leukemia and aleukemia cause-specific category. Due to the relative modest study population sizes, the power of this study to detect statistically significant excesses in leukemias or other malignancies of the hematopoietic and lymphatic tissues is not very large unless one is interested in substantial excesses, such as those that would correspond to a fourfold increase in risk.


Refractive amblyopia among children aged 4-12 years in a hospital-based setting in Gaza Strip, Palestine.
Refractive amblyopia is the most common cause of amblyopia in the Gaza Strip. However, the pattern of this condition has not yet been studied in this region. This study aimed to determine the pattern of refractive amblyopia in Gazan children aged 4‒12 years. This was a hospital-based cross-sectional study using a purposive sampling method. Children aged 4‒12 years who attended the Children's Unit at Gaza Ophthalmic Hospital, Gaza Strip, Palestine from September 2019 to July 2020, were examined. A comprehensive eye test was conducted for all participants. Those who failed the eye examinations and were diagnosed with refractive amblyopia were included in the study. Demographic data and amblyopic refractive error patterns were analyzed accordingly. Of the 107 children, 72.9% were newly diagnosed with refractive amblyopia. The mean (standard deviation [SD]) of age of the children who participated was 7.85 (1.55) years. Approimately two-thirds of the patients were female (57.9%). Unilateral amblyopia was predominant in 60.7% of the cases. Moderate amblyopia was common (81.9%). A total of 149 amblyopic eyes were examined in total, with a mean (SD) (range) of best-corrected distance visual acuity and spherical equivalent of 0.45 (0.19) (0.2 to 1.3) logarithm of the minimum angle of resolution and + 0.76 (4.51) diopters (- 10.25 to + 11.50). Astigmatism was the most common amblyogenic factor (53.7%) among children with amblyopia. The frequency of refractive amblyopia was 72.9%, and meridional amblyopia accounted for the highest percentage. Girls were more commonly affected than boys. The majority were in the 7-year-old age group. Most cases were unilateral with moderate refractive amblyopia. Our study yields insights into the patterns of refractive amblyopia among children in the Gaza Strip.


Spatiotemporal separability in the human cortical response to visual motion speed: a magnetoencephalography study.
Humans can estimate the speed of an object's motion independently of other visual information. Although speed-related neural activity is known to exist in the primate brain, there has been no physiological study that investigated where and how the speed of motion is represented in the human brain. Nine different combinations of spatial and temporal frequencies were used to make drifting sinusoidal grating of five different speeds (from 1.5 to 24 deg/s). Using the stimuli, we evaluated whether the magnetoencephalographic response property changes were due to a speed-tuned mechanism or to separable spatial and temporal frequency detection mechanisms. The latency change was caused mainly by an inseparable speed-tuned mechanism. In contrast, the amplitude was inversely related to the spatial frequency and was also affected by the temporal frequency differently depending on the frequency. Our results support the view that the human visual system has three sets of mechanisms tuned to spatial frequency, temporal frequency, and speed.


[Changes in leukocyte lysosomal acid and alkaline phosphatase activity in acute surgical diseases of the abdominal cavity organs].
To discriminate initial stages of an inflammation from its destructive forms, the authors studied the leucocyte lysosome activity at different stages of inflammatory processes in abdominal organs. 90 patients and 30 practically healthy individuals were examined. The indices of acid and base phosphotase activity were found to rise together with the progress of an inflammatory process. A nomogram, permitting to determine with a rather high precision the stage and direction of the process, was made up on the grounds of the established reguliarity after the mathematical procession of the obtained figure data.


TRPM1: the endpoint of the mGluR6 signal transduction cascade in retinal ON-bipolar cells.
For almost 30 years the ion channel that initiates the ON visual pathway in vertebrate vision has remained elusive. Recent findings now indicate that the pathway, which begins with unbinding of glutamate from the metabotropic glutamate receptor 6 (mGluR6), ends with the opening of the transient receptor potential (TRP)M1 cation channel. As a component of the mGluR6 signal transduction pathway, mutations in TRPM1 would be expected to cause congenital stationary night blindness (CSNB), and several such mutations have already been identified in CSNB families. Furthermore, expression of TRPM1 in both the retina and skin raises the possibility that a genetic link exists between certain types of visual and skin disorders.


The Notch Ligand DLL4 Defines a Capability of Human Dendritic Cells in Regulating Th1 and Th17 Differentiation.
Notch signaling regulates multiple helper CD4(+) T cell programs. We have recently demonstrated that dendritic cells (DCs) expressing the Notch ligand DLL4 are critical for eliciting alloreactive T cell responses and induction of graft-versus-host disease in mice. However, the human counterpart of murine DLL4(+) DCs has yet to be examined. We report the identification of human DLL4(+) DCs and their critical role in regulating Th1 and Th17 differentiation. CD1c(+) DCs and plasmacytoid DCs (pDCs) from the peripheral blood (PB) of healthy donors did not express DLL4. In contrast, patients undergoing allogeneic hematopoietic stem cell transplantation had a 16-fold more DLL4(+)CD1c(+) DCs than healthy donors. Upon activation of TLR signaling, healthy donor-derived CD1c(+) DCs dramatically upregulated DLL4, as did pDCs to a lesser extent. Activated DLL4(+) DCs were better able to promote Th1 and Th17 differentiation than unstimulated PB DCs. Blocking DLL4 using a neutralizing Ab decreased Notch signaling in T cells stimulated with DLL4(+) DCs, and it reduced the generation of Th1 and Th17 cells. Both NF-κB and STAT3 were crucial for inducing DLL4 in human DCs. Interestingly, STAT3 directly activated DLL4 transcription and inhibiting STAT3 alone was sufficient to reduce DLL4 in activated PB DCs. Thus, DLL4 is a unique functional molecule of human circulating DCs critical for directing Th1 and Th17 differentiation. These findings identify a pathway for therapeutic intervention for inflammatory disorders in humans, such as graft-versus-host disease after allogeneic hematopoietic stem cell transplantation, autoimmunity, and tumor immunity.


Monoclonal antibodies to the extracellular domain of prostate-specific membrane antigen also react with tumor vascular endothelium.
Prostate-specific membrane antigen (PSMA), initially defined by monoclonal antibody (mAb) 7E11, is a now well-characterized type 2 integral membrane glycoprotein expressed in a highly restricted manner by prostate epithelial cells. 7E11 has been shown to bind an intracellular epitope of PSMA that, in viable cells, is not available for binding. Herein, we report the initial characterization of the first four reported IgG mAbs that bind the external domain of PSMA. Competitive binding studies indicate these antibodies define two distinct, noncompeting epitopes on the extracellular domain of PSMA. In contrast to 7E11, these mAbs bind to viable LNCaP cells in vitro. In addition, they show strong immunohistochemical reactivity to tissue sections of prostate epithelia, including prostate cancer. These mAbs were also strongly reactive with vascular endothelium within a wide variety of carcinomas (including lung, colon, breast, and others) but not with normal vascular endothelium. These antibodies should prove useful for in vivo targeting to prostate cancer, as well as to the vascular compartment of a wide variety of carcinomas.


Preparing for the strategic planning process helps ensure implementation success.
Strategic planning in many organizations has been less satisfying and useful than these organizations had hoped. We believe these outcomes may be due to a limited view of planning and the implications of the planning process for the organization. Our belief is that these organizations were not genuinely "ready" to engage in the kind of thinking and work required for strategic planning. Therefore, we propose a model of planning readiness consisting of seven components. Each component offers the organization leader an opportunity to achieve improved levels of planning readiness within the organization.


Neonatal outcomes of prenatally diagnosed congenital pulmonary malformations.
Congenital pulmonary malformations (CPM) are mostly recognized on prenatal ultrasound scans. In a minority of cases, they may impair breathing at birth. The factors predictive of neonatal respiratory distress are not well defined, but an understanding of these factors is essential for decisions concerning the need for the delivery to take place in a tertiary care center. The aim of this study was to identify potential predictors of respiratory distress in neonates with CPM. We selected cases of prenatal diagnosis of hyperechoic and/or cystic lung lesions from RespiRare, the French prospective multicenter registry for liveborn children with rare respiratory diseases (2008-2013). Prenatal parameters were correlated with neonatal respiratory outcome. Data were analyzed for 89 children, 22 (25%) of whom had abnormal breathing at birth. Severe respiratory distress, requiring oxygen supplementation or ventilatory support, was observed in 12 neonates (13%). Respiratory distress at birth was significantly associated with the following prenatal parameters: mediastinal shift (P = .0003), polyhydramnios (P = .05), ascites (P = .0005), maximum prenatal malformation area (P = .001), and maximum congenital pulmonary malformation volume ratio (CVR) (P = .001). Severe respiratory distress, requiring oxygen at birth, was best predicted by polyhydramnios, ascites, or a CVR >0.84. CVR >0.84, polyhydramnios, and ascites increased the risk of respiratory complications at birth in fetuses with CPM, and especially of severe respiratory distress, requiring oxygen supplementation or more intensive intervention. In such situations, the delivery should take place in a tertiary care center.


Flap Reconstruction of Perineal Defects after Pelvic Exenteration: A Systematic Description of Four Choices of Surgical Reconstruction Methods.
The treatment of locally advanced or recurrent anorectal cancer requires radical surgery such as extralevator abdominoperineal resection and pelvic exenteration. Larger defects require flap reconstruction. The authors evaluated outcomes of different perineal reconstruction techniques. A systematic search was performed in the PubMed, Embase, and Cochrane databases. Studies reporting outcomes on perineal flap reconstruction in patients with anal or colorectal cancer were included. Data on patient characteristics, surgical details, perineal and donor-site complications, revision surgery, mortality, and quality of life were extracted. Articles were assessed using the Group Reading Assessment and Diagnostic Evaluation approach. The authors included 58 mainly observational studies comprising 1988 patients. Seventy-three percent of patients had rectal cancer. The majority of 910 abdominoperineal resection patients underwent reconstruction with rectus abdominis flaps (91 percent). Dehiscence (15 to 32 percent) and wound infection (8 to 16 percent) were the most common complications. Partial flap necrosis occurred in 2 to 4 percent and flap loss occurred in 0 to 2 percent. Perineal herniation was seen in 6 percent after gluteal flap reconstruction and in 0 to 1 percent after other types of reconstruction. Donor-site complications were substantial but were reported inconsistently. Clinical outcome data on perineal reconstruction after exenterative surgery are mostly of very low quality. Perineal reconstruction after pelvic exenteration is complex and requires a patient-tailored approach. Primary defect size, reconstruction aims, donor-site availability, and long-term morbidity should be taken into account. This review describes the clinical outcomes of four flap reconstruction techniques. Shared clinical decision-making on perineal reconstruction should be based on these present comprehensive data.