Logistics of neuronal protein turnover: Numbers and mechanisms.
Research in the past twenty years or so has revealed that neurons synthesize and degrade proteins at their synapses to enable synaptic proteome remodelling on demand and in real-time. Here we provide a quantitative overview of the decentralized neuronal protein-turnover logistics. We first analyse the huge neuronal protein turnover demand that arises from subcellular compartments outside the cell body, followed by an overview of key quantities and modulation strategies in neuronal protein turnover logistics. In the end, we briefly review recent progress in neuronal local protein synthesis and summarize diverse protein-degradation mechanisms that are found near synapses.


Environmental Control of Single-Molecule Junction Evolution and Conductance: A Case Study of Expanded Pyridinium Wiring.
Environmental control of single-molecule junction evolution and conductance was demonstrated for expanded pyridinium molecules by scanning tunneling microscopy break junction method and interpreted by quantum transport calculations including solvent molecules explicitly. Fully extended and highly conducting molecular junctions prevail in water environment as opposed to short and less conducting junctions formed in non-solvating mesitylene. A theoretical approach correctly models single-molecule conductance values considering the experimental junction length. Most pronounced difference in the molecular junction formation and conductance was identified for a molecule with the highest stabilization energy on the gold substrate confirming the importance of molecule-electrode interactions. Presented concept of tuning conductance through molecule-electrode interactions in the solvent-driven junctions can be used in the development of new molecular electronic devices.


The microRNA-1278/SHP-1/STAT3 pathway is involved in airway smooth muscle cell proliferation in a model of severe asthma both intracellularly and extracellularly.
This study investigated the regulatory effects of microRNA-1278 (miR-1278) on airway inflammation, airway reconstruction, and the proliferation and apoptosis of airway smooth muscle cells (ASMCs) induced by transforming growth factor β1 (TGF-β1). The results showed that miR-1278 was upregulated in the blood and lung tissues (LTs) of patients with asthma compared with that in healthy volunteers; miR-1278 expression was also upregulated in asthmatic mice, and miR-1278 inhibition improved the LTs of asthmatic mice. Moreover, miR-1278 inhibited inflammation in asthmatic mice and counteracted the effect of TGF-β1 of induced proliferation and reduced apoptosis in ASMCs. DLRA indicated that miR-1278 targeted the 3'-UTR of Src-homology 2-containing phosphatase 1 (SHP-1). Furthermore, miR-1278 promoted ASMC proliferation, in which TGF-β1 played an important role by regulating the SHP-1/STAT3 signaling pathway. In conclusion, this study showed that miR-1278 played a critical role in the processes of airway remodeling and reduction of apoptosis by targeting SHP-1.


[French version of The Ottawa Statement on the Ethical Design and Conduct of Cluster Randomized Trials, in a French law context].
There is growing evidence on the ethical challenges raised by cluster randomized trials. This specificity is not reflected in the legal texts regulating research, which creates difficulties for researchers implementing these experimental designs. The Ottawa Statement (Weijer et al. 2012) aims to provide detailed guidance on the ethical design, conduct and assessment of cluster trials. More broadly aims to help research stakeholders and decision-makers to make informed ethical decisions regarding the particularity of these experimental designs. It seems that this international statement, written in English, is not sufficiently accessible to all of the French professionals involved in health research. The aim of this article is to provide these professionals with a contextualized and illustrated French translation of the "Ottawa statement". . The "complex design" working group of the RECaP network (Research in Clinical Epidemiology and Public Health), carried out this work. A first version was discussed by the authors in several meetings. It was completed by contextual explanations and examples of French studies currently conducted by the authors. The final version was obtained by consensus and validated by the group. . This work reports 15 recommendations grouped into 7 key questions: How to justify cluster design? How to submit an article to an ethics committee? How to identify research participants? How and when to obtain informed consent? Who are the gatekeepers? How to assess benefits and harm? How to protect vulnerable participants? Each of these recommendations is specific to cluster trials. The recommendations are explained and detailed through concrete examples. Without interfering with current French laws, this work provides a framework for the organization, conduct and ethical assessment of cluster randomized trials in France. In the present-day context, it is essential that all concerned groups can base their decisions on recommendations in line with the elementary principles of health research ethics.


Tolerance of Fentanyl Pectin Nasal Spray for Procedural Pain in Geriatric Patients.
We aimed to assess the tolerance of fentanyl pectin nasal spray (FPNS) when used to treat procedural pain caused by wound dressing or physiotherapy in patients older than 75 years with or without opioid background treatment. This is a prospective monocentric, noncontrolled, nonrandomized study conducted from December 2014 to October 2017 in 2 geriatric wards (rehabilitation and acute medicine). Fifty-seven patients were included and 314 procedures were monitored. For each patient, 6 procedures were monitored: the first 2 without specific treatment, then fentanyl was started at 100 μg with a titration over a few procedures up to 800 μg in non-opioid-naïve patients and 400 μg in opioid-naïve. Sedation and respiratory scale were monitored during the procedures. All adverse drug events occurring from inclusion to 5 days after the intervention were collected and their imputability was assessed separately by 2 pharmacovigilance experts. Overall, 14.4% of the sessions with FPNS administration resulted in adverse drug events. Main adverse drug events were nausea and vomiting, somnolence, and confusion. Most of them were of mild to moderate severity. Four severe adverse events were due to accidental overdoses. No unexpected adverse event occurred. Tolerance was similar for opioid-naïve and non-opioid-naïve patients (P value = .93). FPNS was overall well tolerated in geriatric patients. Given its interesting pharmacokinetics, fentanyl is a promising lead for procedural pain treatment in geriatric patients, even those who are opioid naïve.


Colcemid effects on homologue pairing and crossing over during fetal mouse oogenesis.
Colcemid was administered to gestational day 13 female mice to test effects on homologue pairing, synapsis and recombination of fetal oogenesis. Pairing abnormalities were detected in pachytene oocytes by light and electron microscopy examination of bivalents and synaptonemal complexes. Reduction of total chiasmata per treated diplotene oocyte (22.74) compared to controls (31.07) was found.


Inflammation across universal definition of heart failure stages: the CASABLANCA study.
We sought to investigate the association of inflammatory biomarkers with incident heart failure (HF) events in patients at different stages of HF. Overall, 1231 study participants undergoing diagnostic coronary and/or peripheral angiography were categorized by Universal Definition of HF (UDHF) stage A (at risk), stage B (pre-HF), and stages C or D (HF, including end-stage). Twenty-four inflammatory biomarkers were collected prior to angiography and unsupervised machine learning categorized levels of inflammation into three groups (low, medium, and high). Cox proportional hazard regression was implemented to assess the associations of inflammation level with incident HF hospitalization in each UDHF stage. Using machine learning, study participants were grouped into low (n = 443), medium (n = 570) and high inflammation categories (n = 230). Significantly higher concentrations of natriuretic peptide, troponin, and soluble ST2 were observed among those with high inflammation levels (p < 0.001). During 3.7 years of follow-up, 123 (15.1%) HF hospitalizations occurred in stage A/B and 180 (41.8%) HF hospitalizations occurred in stage C/D. In multivariable model considering low inflammation level as a reference, among patients with stage A/B, the hazard ratio (HR) (95% confidence interval [CI]) of incident HF was 2.31 (1.40-3.80) for moderate inflammation level, and 4.16 (2.35-7.37) for high inflammation level. Among patients with stage C/D, the corresponding HR (95% CI) of HF hospitalization was 1.98 (1.28-3.04) for moderate inflammation level, and 2.69 (1.69-4.28) for high inflammation level. Patterns of inflammation severity may have differing prognostic meaning across UDHF stages.


Petechiae, as seen on TV.
This narrative describes how a patient facilitated a diagnosis of acute myeloid leukemia in a primary care visit because she recognized petechiae she had seen on television on her own skin.


Opportunities and risks in Philadelphia's capitation financing of public psychiatric services.
The city of Philadelphia was one of nine sites selected by the Robert Wood Johnson (RWJ) Foundation and the U.S. Department of Housing and Urban Development (HUD) to receive five-year funding to improve the delivery, quality and cost efficiency of public mental health services to its chronically mentally ill population. As part of the RWJ project, the city plans to restructure its delivery and reimbursement system, creating a not-for-profit central authority which will function as a health insurance organization (HIO) responsible for coordinating and managing psychiatric care to Medicaid clients. Operating under a model of capitation, the central authority will employ diverse funding mechanisms to finance and manage service delivery. This paper examines the benefits and risks inherent in the reorganization of Philadelphia's mental health service system under a capitation financing model. Issues considered include cost and utilization patterns, treatment outcomes, providers and their staffing patterns, service mix and the overall impact of capitation on clients.


Effect of diethylstilbestrol and related compounds on the Ca(2+)-transporting ATPase of sarcoplasmic reticulum.
Diethylstilbestrol is a potent inhibitory agent of the Ca(2+)-ATPase activity of sarcoplasmic reticulum membranes. Other structurally related molecules, such as dienestrol or hexestrol having hydroxyl groups at para positions of the two benzene rings produce similar effects. The absence or derivatization of the hydroxyl groups as occurs with trans-stilbene or diethylstilbestrol dipropionate converts the structure in an activating agent of the enzyme. The Ca2+ transport profiles in the presence of the referred drugs reproduces the same behavior observed for the hydrolytic activity. There is also a clear indication of a membrane-mediated mechanism of these drugs. Ligand binding experiments at equilibrium indicate that diethylstilbestrol decreases the affinity for Ca2+ of the high affinity Ca2+ sites. Functional studies reveal that the activation/inhibition induced by these drugs is correlated with decreased levels of phosphoenzyme at steady state, and these levels are sensitive to the Ca2+ concentration. Chase experiments of [32P]phosphoenzyme and 45Ca2+ indicate a slight activation effect of diethylstilbestrol dipropionate on Ca2+ dissociation during the enzyme turnover. The use of different anthroyloxy derivatives of stearic acid as a fluorescent probe suggest that diethylstilbestrol and other inhibitory agents could be located close to the polar region of the lipid bilayer, which interferes with the Ca(2+)-binding sites, whereas the activators trans-stilbene and diethylstilbestrol dipropionate may have a deeper position into the membrane, which accelerates the Ca2+ translocation process.


Selective interactions of trivalent cations Fe³⁺, Al³⁺ and Cr³⁺ turn on fluorescence in a naphthalimide based single molecular probe.
Synthesis and fluorescence turn-on behavior of a naphthalimide based probe is described. Selective interactions of trivalent cations Fe(3+), Al(3+) or Cr(3+) with probe 1 inhibit the PET operating in the probe, and thereby, permit the detection of these trivalent cations present in aqueous samples and live cells. Failure of other trivalent cations (Eu(3+), Gd(3+) and Nb(3+)) to inhibit the PET process in 1 demonstrates the role of chelating ring size vis-à-vis ionic radius in the selective recognition of specific metal ions.


Full screening and accurate subtyping of HLA-A*02 alleles through group-specific amplification and mono-allelic sequencing.
HLA-A*02 is the most prevalent and polymorphic major histocompatibility complex (MHC) allele family in humans. Functional differences have been revealed among subtypes, demanding further subtyping of HLA-A*02 in basic and clinical settings. However, the fast growing polymorphisms render traditional primer- or probe-based typing methods impractical and result in increasing ambiguities in direct sequence-based typing. In this study, we combined group-specific amplification and mono-allelic sequencing to design and validate a simple scheme for the complete screening and accurate subtyping of all 540 reported HLA-A*02 alleles. This scheme could be performed in routine labs to facilitate studies with an interest in HLA-A*02.


[BIOPASS hybrid navigation for endoscopic sinus surgery - an assistance system].
Previous navigation systems can determine the position of the "tracked" surgical instrument in CT images in the context of functional endoscopic sinus surgery (FESS), but do not provide any assistance directly in the video endoscopic image of the surgeon. Developing this direct assistance for intraoperative orientation and risk reduction was the goal of the BIOPASS project (Bild Ontologie und prozessgestütztes Assistenzsystem). The Project pursues the development of a novel navigation system for FESS without markers. BIOPASS describes a hybrid system that integrates various sensor data and makes it available. The goal is to abandon tracking and exclusively provide navigation information directly in the video image. This paper describes the first step of the development by collecting and structuring the surgical phases (workflows), the video endoscopic landmarks and a first clinical evaluation of the model version. The results provide the important basis and platform for the next step of the project.


Are your patients taking their medicine? Validation of a new adherence scale in patients with inflammatory bowel disease and comparison with physician perception of adherence.
To date no adherence survey has been validated in IBD. The aim was to administer an improved medication adherence survey to IBD patients, to validate the scale in IBD, and to compare the results to perceived adherence by the gastroenterologists. IBD patients were given the Morisky Medication Adherence Scale (MMAS-8). To validate the scale, prescription claim information, calculated as continuous single-interval medication availability (CSA) and mean possession ratio (MPR), was correlated to the MMAS-8 scale. Nonpersistence or low adherence was defined as a CSA or MPR<0.8. Treating gastroenterologists, blinded to the instrument, then assessed adherence in these patients. Of 110 IBD patients in the study, MMAS-8 identified 54 patients as low adherers (LAs) to their IBD medication and 56 patients as medium or high adherers (MHAs). Eighty-five percent of LAs had nonpersistent fill rates, as per CSA, compared with 11% of MHAs. Physicians correctly classified 95% of patients who were MHAs but only 33% of LAs. Underestimation of adherence only occurred in 5% of patients, whereas overestimation occurred in 67% (P<0.0001). In a linear regression analysis, CSA was significantly correlated with disease activity score (P<0.001). LAs are a challenge to identify. This study demonstrates that the MMAS-8 scale is a valid instrument for assessing medication adherence in IBD. This is the first adherence scale to be validated in IBD.


Clinical aspects of the use of narcotic antagonists: the state of the art.
The clinical application of narcotic antagonists would theoretically be of value to several major groups of users. However, while it is clear that supportive services are needed, these services have not been defined by controlled studies.


Flow cytometric assays for monitoring production of recombinant HIV-1 gp160 in insect cells infected with a baculovirus expression vector.
A baculovirus expression system for the HIV-1 envelope glycoprotein gp160 has been used as a model for development of flow cytometric assays for monitoring production of cell-associated recombinant antigen. Using monoclonal antibodies to the transmembrane (gp41) or envelope (gp120) portion of gp160, gp120, but not gp41, could be reproducibly detected on the surface of insect cells 48 h after infection with the recombinant baculovirus. In contrast, fixation and permeabilization of infected cells prior to staining, to allow access of monoclonal reagents to the intracellular compartment, markedly improved the sensitivity of detection, with reactivity to both monoclonal antibodies observed at 24 h post-infection. Specificity of the intracellular immunofluorescence was verified by demonstrating that the appropriate native or recombinant HIV-1 protein blocked reactivity of monoclonal antibody with infected cells. In addition, it was observed that production of gp160 following baculovirus infection was associated with a marked increase in the 90 degrees light scatter of insect cells, as determined by flow cytometry, and that this correlated with the kinetics of cell-associated gp160 production as determined by immunofluorescence. These procedures should be of great utility for routine monitoring of recombinant proteins produced in insect cells in response to infection with recombinant baculovirus.


Effect of endoscopic variceal sclerotherapy on gas exchange and hemodynamics in humans.
Adult respiratory distress syndrome has been reported after endoscopic variceal sclerotherapy with sodium morrhuate. It has been proposed that sclerosant entering the pulmonary circulation during intravariceal injections may cause pulmonary hypertension and capillary injury. The purpose of this study was to determine whether variceal sclerotherapy with sodium morrhuate causes capillary injury or pulmonary edema in humans. We studied the effect of sclerotherapy on gas exchange and pulmonary and systemic hemodynamics in 8 patients who required endoscopic variceal sclerotherapy for treatment of variceal hemorrhage. The pulmonary vascular resistance index increased from 246 +/- 67 dyn X s X cm-5/m2 (mean +/- SEM) at baseline to a high of 303 +/- 85 dyn X s X cm-5/m2 60 min after sclerotherapy (normal range 250-500 dyn X s X cm-5/m2). Pulmonary artery pressure remained stable while cardiac index decreased by 12% over the same period. There were also small increases in systemic vascular resistance index and systemic arterial pressure after sclerotherapy. Although there was no change in arterial oxygen tension, the alveolar-arterial oxygen difference improved after sclerotherapy. These results indicate that variceal sclerotherapy with sodium morrhuate is associated with clinically insignificant changes in pulmonary and systemic hemodynamics. We did not detect evidence of acute lung injury after sclerotherapy.


Comparison of old and new TNM systems for nodal staging in adenocarcinoma of the gastro-oesophageal junction.
Adenocarcinoma of the gastro-oesophageal junction is considered a distinct clinical entity, although the current pathological tumour node metastasis (pTNM) classification does not consider this tumour specifically. A prospective study was undertaken to determine the prognostic importance of lymph node involvement in adenocarcinoma of the gastro-oesophageal junction, analysing both a number- and site-based classification, in order to develop a clinically useful nodal staging system. Two classification systems were analysed in 116 patients who underwent resection for adenocarcinoma of the gastro-oesophageal junction from January 1988 to August 2001. The Cox regression model was used to evaluate the prognostic significance of the site and number of positive nodes. The number- and site-based staging systems coincided only in 42 (56 per cent) of 75 patients; in particular, the old pN1 classification was upstaged in 13 of 41 patients and the old pN2 was downstaged in 13 of 34 patients. Lymph node involvement was the most important prognostic factor in both classifications (P < 0.001). The risk of death was significantly influenced by the site of nodal metastasis among patients with a similar number of involved nodes (relative risk with respect to pN0: 2.18 for pN1 with one to six nodes; 6.53 for pN2 with one to six nodes; 7.53 for pN1 with more than six nodes; 39.13 for pN2 with more than six nodes). Adenocarcinoma of the gastro-oesophageal junction requires a specific lymph node classification which should take into account both the number and site of nodal metastases.


Triple negative breast cancer: Pitfalls and progress.
Triple negative breast cancer (TNBC) is characterized by the lack of estrogen and progesterone receptor expression and lacks HER2 overexpression or gene amplification. It accounts for 10-15% of incident breast cancers and carries the worst prognosis. TNBC is overrepresented among Black and pre-menopausal women and is associated with significant psychological and treatment-related burdens, including financial toxicity. Like other breast cancers, TNBC is biologically heterogeneous, leading to diverse clinical and epidemiological behaviors, however, unlike the other clinical subtypes, in TNBC we still lack tumor-specific targeted therapy. Early TNBC outcomes have improved due to the intensification of therapies, including improvements in polychemotherapy and the addition of immunotherapy. Future efforts are needed to identify targetable aberrations for specific drug therapy, prevent immune evasion, and increase social-economic support. Given that the name TNBC illustrates its lack of specifically targeted and effective therapy, we look forward to being able to retire the name in favor of a group of targetable entities within what is now called "TNBC".


Maturation of functional antibody affinity in animals immunised with synthetic foot-and-mouth disease virus.
A good correlation exists between specific neutralising antibody titre and protection against challenge with foot-and-mouth disease virus (FMDV) in infected or virus-vaccinated cattle, but not in the case of animals immunised with synthetic FMDV peptides. Therefore, mechanisms other than simple neutralisation are likely to be important in vivo. Antibody affinity may influence the protective capacity of sera from immunised animals and experiments were carried out to measure the functional affinity for synthetic FMDV peptide of sera from guinea pigs and cattle given various synthetic vaccines. In guinea pigs given a single dose of synthetic vaccine, antibody affinity increased with time after immunisation. In cattle, however, administration of a second dose of peptide 21 days after the first markedly retarded the process of affinity maturation. For guinea pig sera of equivalent neutralising activity, those of higher functional affinity had higher protective indices than those of lower functional affinity. Knowledge of the importance of antibody affinity in protection against FMD is important for an improved understanding of the mechanisms of protection and for the design of novel vaccines.


Call to action: finding solutions for the drug shortage crisis in the United States.
In their article in this issue of CPT, Woodcock and Wosinska are the first to clearly outline the quality and manufacturing problems causing drug shortages of generic injectables. These authors have focused on the main issue, namely, that manufacturing problems and the lack of incentives for quality products are the primary reasons for most recent shortages of generic injectable drugs.


Methylation of hen erythrocyte DNA.
We have analysed the 5-methylcytosine content of hen erythrocyte DNA and found it to be lower than that of DNA from other chick tissues analysed. Erythrocyte DNA is also a better substrate for DNA methylase having a five-fold lower Km than DNA from white blood cells. This is probably because it contains a large number of hemimethylated sites. Thus the inverse correlation between methylation and gene expression does not apply to the chick red blood cell.


The influence of China's pollution emissions trading system on the listed companies' export products' quality.
The pollution emissions trading system (PETS) pilot policy is China's first large-scale implementation of market-based environmental regulations; whether it can reduce pollution emissions and improve the export competitiveness is crucial for China to achieve the coordinated development of environment and economy. Based on the panel data of Chinese listed companies from 2003 to 2016, this paper considers the PETS pilot policy as a natural experiment, and investigates the impact of the policy on export products' quality using the difference-in-difference (DID) model. We found that (1) the PETS pilot policy has significantly improved the quality of listed companies' export products. (2) Technological innovation plays a partial intermediary role in promoting export products' quality by the PETS pilot policy; the "Porter Hypothesis" has been verified in China. (3) When the listed companies with different characteristics face the PETS pilot policy, the quality of their export products will show a differentiated development trend. Based on the above research conclusions, we put forward corresponding recommendations for China to realize the coordinated development of environment and trade.


Rationale for 1068 nm Photobiomodulation Therapy (PBMT) as a Novel, Non-Invasive Treatment for COVID-19 and Other Coronaviruses: Roles of NO and Hsp70.
Researchers from across the world are seeking to develop effective treatments for the ongoing coronavirus disease 2019 (COVID-19) outbreak, which arose as a major public health issue in 2019, and was declared a pandemic in early 2020. The pro-inflammatory cytokine storm, acute respiratory distress syndrome (ARDS), multiple-organ failure, neurological problems, and thrombosis have all been linked to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) fatalities. The purpose of this review is to explore the rationale for using photobiomodulation therapy (PBMT) of the particular wavelength 1068 nm as a therapy for COVID-19, investigating the cellular and molecular mechanisms involved. Our findings illustrate the efficacy of PBMT 1068 nm for cytoprotection, nitric oxide (NO) release, inflammation changes, improved blood flow, and the regulation of heat shock proteins (Hsp70). We propose, therefore, that PBMT 1068 is a potentially effective and innovative approach for avoiding severe and critical illness in COVID-19 patients, although further clinical evidence is required.


The role of intraoperative angiography in salvaging bovine grafts for hemodialysis.
Bovine grafts used in hemodialysis frequently need declotting. Success of the declotting procedure usually is dependent upon relieving outflow obstruction. Intraoperative angiography was done during 22 declotting procedures and outflow obstructions were detected in 14 grafts. Of these 5 grafts had clinically unsuspected clots, residual to the initial declotting attempt. Four grafts had stenotic areas at the site of the venous anastomosis, which were corrected subsequently by patch grafts. Two grafts had stenotic areas in the graft owing to an infolding of the intima covered with an organized blood clot. In 2 grafts the veins draining the grafts were stenotic for a considerable length and needed revision. In 1 graft there was stenotic change at the site of the arterial anastomosis, which required revision. Of the 14 grafts 11 have remained functioning for an additional 6 to 18 months after relief of obstruction.


Focal and segmental glomerulosclerosis: analogies to atherosclerosis.
In summary, both the developing atherosclerotic and FSGS lesions seem to share certain postulated pathophysiologic mechanisms, including endothelial cell injury, macrophage infiltration, hyperlipoproteinemia, and hypertension. As depicted in Figure 1, any initial glomerular injury results in flux of macromolecular substances into the glomerular mesangium. As an adjunct to increased glomerular barrier dysfunction, hyperlipoproteinemia is believed to secondarily develop from the dramatic losses of albumin, stimulating increased hepatic lipoprotein synthesis and the loss of lipoprotein lipase-activating substance into the urine which would effectively produce a reduction in circulating chylomicra and triglyceride catabolism. Certain elevated circulating lipoproteins could, theoretically, pass through the damaged glomerular filter into the mesangium, thereby enhancing the flux of macromolecules. Also associated with certain experimental glomerular disorders is the development of glomerular hypertension, as manifested by an elevated glomerular capillary hydrostatic pressure (PGC), which can further augment macromolecular flux into the mesangium. Overloading of the glomerular mesangium by the above mechanisms is believed to be an injurious stimulus for MC to both proliferate and produce excess mesangial matrix substance. Both of these events are thought to be pathologic harbingers of glomerulosclerosis. Glomerular hypertension is also capable of damaging endothelial cells within the glomerular microcirculation, and this purportedly can activate platelets and result in glomerular thrombosis. At present, it is unclear how glomerular thrombosis produces increased mesangial cell injury; however, this process is believed to cause both systemic and glomerular hypertension which may serve as intermediary mechanisms producing the untoward effects of mesangial cell proliferation and matrix overproduction.


Ultrastructural identification of synaptic terminals from cortical axons and from collateral axons of geniculo-cortical relay cells in the perigeniculate nucleus of the cat.
Electron microscopic analysis of sections of the perigeniculate nucleus (PGN) of the cat processed with horseradish peroxidase (HRP) histochemistry after massive injections of this enzyme in the visual cortex showed two types of synaptic terminals labeled with HRP reaction products. One type (RLD terminals) is characterized by round synaptic vesicles, large size, dark mitochondria and asymmetrical synaptic contacts with somata and dendrites. The second type (RSD terminals) is characterized by round synaptic vesicles, small size, dark mitochondria and asymmetrical synaptic contacts with dendrites. The HRP+ RSD terminals, which were also found in the dorsal lateral geniculate nucleus (LGN), are interpreted as terminals of cortical origin both in the PGN and LGN, since previous studies have identified cortical terminals as being of RSD type in the LGN and in other thalamic nuclei. The HRP+ RLD terminals are interpreted as synaptic terminals of collaterals axons of geniculocortical relay cells in the PGN labeled by retrograde transport of HRP from the cortex. In addition, in semithin and ultrathin sections somata in the PGN were never found labeled with HRP products indicating the absence of a PGN projection to the visual cortex.


Physical activity and long COVID: findings from the Prospective Study About Mental and Physical Health in Adults cohort.
The study investigated the longitudinal association between physical activity and the risk of long COVID in patients who recovered from COVID-19 infection. We analyzed longitudinal data of the Prospective Study About Mental and Physical Health cohort, a prospective cohort study with adults living in Southern Brazil. Participants responded to an online, self-administered questionnaire in June 2020 (wave 1) and June 2022 (wave 4). Only participants who self-reported a positive test for COVID-19 were included. Physical activity was assessed before (wave 1, retrospectively) and during the pandemic (wave 1). Long COVID was assessed in wave 4 and defined as any post-COVID-19 symptoms that persisted for at least 3 months after infection. A total of 237 participants (75.1% women; mean age [standard deviation]: 37.1 [12.3]) were included in this study. The prevalence of physical inactivity in baseline was 71.7%, whereas 76.4% were classified with long COVID in wave 4. In the multivariate analysis, physical activity during the pandemic was associated with a reduced likelihood of long COVID (prevalence ratio [PR]: 0.83; 95% confidence interval [CI]: 0.69-0.99) and a reduced duration of long COVID symptoms (odds ratio: 0.44; 95% CI: 0.26-0.75). Participants who remained physically active from before to during the pandemic were less likely to report long COVID (PR: 0.74; 95% CI: 0.58-0.95), fatigue (PR: 0.49; 95% CI: 0.32-0.76), neurological complications (PR: 0.47; 95% CI: 0.27-0.80), cough (PR: 0.40; 95% CI: 0.22-0.71), and loss of sense of smell or taste (PR: 0.43; 95% CI: 0.21-0.87) as symptom-specific long COVID. Physical activity practice was associated with reduced risk of long COVID in adults.


Progress in Kdo-glycoside chemistry.
Glycosylation chemistry of 3-deoxy-D-manno-oct-2-ulosonic acid units has been considerably developed within the last decade. This review covers major achievements with respect to improved yields and anomeric selectivity as well as suppression of the elimination side reaction via selection of dedicated protecting groups and appropriate activation of the anomeric center.


Activation of CRHR2 exerts an inhibitory effect on the expression of collapsin response mediator protein 3 in hippocampal neurons.
Corticotropin-releasing hormone (CRH) family peptides as well as their receptors have been shown to exhibit various functions in hippocampus. However, effects of CRH receptors activation on collapsin response mediator protein 3 (CRMP3), the key protein for dendrite outgrowth and cell apoptosis, remain unclear. In the present study, we determined the effects of CRHR1 and CRHR2 on CRMP3 expression in cultured hippocampal neurons. CRH and urocortin II (UCNII) dose-dependently suppressed CRMP3 mRNA and protein expression. The inhibitory effect on CRMP3 expression was completely reversed by CRHR2 antagonist but not by CRHR1 antagonist. Investigations on the signaling pathways of UCNII showed that CRHR2 mediated UCNII-induced increase in phosphorylated phospholipase C (PLC)-β3 expression. Blocking PLC activity with U73122 and PKC with Gö6976 completely prevented UCNII-inhibited CRMP3 expression. Our results suggest that CRHR2 activation decrease CRMP3 expression in hippocampal neurons via a mechanism that is dependent on PLC/PKC signaling pathways.


Cognitive behavioral therapy for persons living with HIV in China: A randomized pilot trial.
Chinese persons living with HIV (PLWH) suffer from prevalent mental health issues. We aimed to develop a tailored cognitive behavioral therapy (CBT), test its feasibility, acceptability, and preliminary effects (depression, anxiety, and medication adherence) for Chinese PLWH. Twenty PLWH were assigned randomly. Intervention participants learned skills in CBT and relaxation training in a tailored group-based weekly 10-session project. Each session lasted for two hours and was delivered by nurses and volunteers. Control participants only received laboratory tests and free antiretroviral therapy (ART) medication. Feasibility and acceptability were descriptively summarized. Depression, anxiety, and ART medication adherence data were collected at the baseline (T0), after the intervention (T1) and after 6 months of follow-up (T2). The average CBT attendance rate for all sessions was 60%. No participants in the intervention group dropped out of the study. All participants in the intervention group agreed that they could benefit from the CBT. Participants in the intervention group showed a greater improvement in anxiety and self-reported ART medication adherence than those in the control group at T1. However, no preliminary intervention effect was found at T2. The small sample size leads to a lack of representativeness in the study sample. We excluded participants with severe comorbidities, which may lead to an underestimate of the intervention effect of CBT among Chinese PLWH. CBT is feasible and acceptable, demonstrating promising preliminary effects on anxiety and ART medication adherence among Chinese PLWH. Additional research is needed to test the effectiveness of this approach.


A new technique to in vivo study the corneocyte features at the surface of the skin.
To design, develop and validate a new device allowing the features of corneocytes at the surface of the skin to be visualized in vivo and objectively characterized. Monochromatic light is focused at the proximal end of a coherent bundle of optical fibres. Fluorescence of skin, stained with fluorescein, is then captured by the same fibre bundle and displayed, through a dichroic mirror, by a CCD camera. Fluorescence images are analysed using dedicated software to measure the projected area of cells. The new device allows the mean projected area of corneocytes to be routinely studied and quantified on most of the skin areas of the human body. Measurements carried out on two age groups of women confirm that corneocyte size on the forearm is smaller in young women than in older women. The new non-invasive device is easy to use and appear quite appropriate for cutaneous investigations carried out in clinical research.


Dipeptidyl peptidase-3 is associated with severity of liver disease and circulatory complications in patients with cirrhosis.
Patients with cirrhosis suffer from a complex multiorgan disturbance and their prognosis is influenced by the development of portal hypertension and systemic circulatory dysfunction. Although non-invasive techniques such as transient elastography aid in early detection, there is an unmet need for reliable markers of these clinically significant complications. We conducted an exploratory single-center study investigating dipeptidyl peptidase-3 (DPP3) concentrations in various vascular beds in a cohort of 48 patients with cirrhosis and 16 healthy controls. Liver vein catheterisation with sampling from femoral artery and femoral, renal and hepatic veins as well as measurement of hepatic pressure and liver function via indocyanine green and galactose elimination tests were performed. DPP3 concentrations were higher in cirrhotic patients compared to controls (12.6 vs. 7.4 ng/mL, p = 0.006) and increased according to the severity of cirrhosis. DPP3 associated with MELD-Na score, Child class, indocyanine green clearance, increased DPP3 with the increased hepatic venous pressure gradient (p = 0.015) as well as increased heart rate and reduced systemic vascular resistance. DPP3 concentrations predicted the presence of clinically significant portal hypertension in cirrhotic patients (AUROC 0.78, 95% CI 0.65-0.9). DPP3 is a promising marker for portal hypertension and systemic hemodynamic changes in cirrhosis.


Optimal production of polyhydroxyalkanoates (PHA) in activated sludge fed by volatile fatty acids (VFAs) generated from alkaline excess sludge fermentation.
To reduce the production cost of polyhydroxyalkanoates (PHA) and disposal amount of excess sludge simultaneously, the feasibility of using fermentative volatile fatty acids (VFAs) as carbon sources to synthesize PHA by activated sludge was examined. At pH 11.0, 60 degrees C and fermentative time of 7d, the VFAs yield was 258.65 mgTOC/gVSS. To restrain cell growth during PHA production, the released phosphorus and residual ammonium in the fermentative VFAs was recovered by the formation of struvite precipitation. Acetic acid was the predominant composition of the fermentative VFAs. PHA accumulation in excess sludge occurred feeding by fermentative VFAs with aerobic dynamic feeding process. The maximum PHA content accounted for 56.5% of the dry cell. It can be concluded from this study that the VFAs generated from excess sludge fermentation were a suitable carbon source for PHA production by activated sludge.


Assessment of vanadium and nickel enrichment in Lower Athabasca River floodplain lake sediment within the Athabasca Oil Sands Region (Canada).
Sediment quality monitoring is commonly used to assess for river pollution by industrial activities, but requires knowledge of pre-disturbance conditions. This has long been a critical knowledge gap for assessing pollution of the Lower Athabasca River within the Athabasca Oil Sands Region (AOSR) because sediment quality monitoring started 30 years after mining operations began in 1967. Here, we analyze oil-sands pollution indicator metals vanadium (V) and nickel (Ni) in sediment cores from five Athabasca River floodplain lakes spanning from 17 km upstream to 58 km downstream of central oil sands operations. These data are used to define pre-development baseline (i.e., reference) concentrations and assess for enrichment in sediment deposited after 1967. Measurements of organic and inorganic matter content were used to differentiate periods of strong and weaker Athabasca River influence in the sediment records, as needed to discern pathways of metal deposition. Numerical analyses reveal that post-1967 V and Ni enrichment factors have remained below the 1.5 threshold for 'minimal enrichment' (sensu Birch, 2017) in stratigraphic intervals of strong river influence in the floodplain lakes. Thus, concentrations of V and Ni carried by Athabasca River sediment have not become measurably enriched since onset of oil sands development, as demonstrated by our before-after study design with >99.99% power to detect a 10% increase above pre-development baselines. At the closest lake (<1 km) to oil sands operations, however, enrichment factors for V and Ni increased to 2.1 and 1.5, respectively, in the mid-1980s and have remained at this level when river influence was weaker, indicating contamination via atmospheric transport. Localized enrichment within the oil sands region via atmospheric pathways is a greater concern for ecosystems and society than local and far-field transport by fluvial pathways.


Cutis laxa: a review.
Cutis laxa is a rare disorder of elastic tissue resulting in loose, redundant, hypoelastic skin. Both acquired and inherited forms exist, some of which have significant systemic manifestations. Here, we review the various forms of cutis laxa, with focus on the inherited forms. Recent molecular studies have provided many new insights into the causes of cutis laxa and revealed greater genetic heterogeneity than previously appreciated.


Is there a role for the use of aviation assessment instruments in surgical training preparation? A feasibility study.
Selection for surgical residency programmes could potentially be improved through pretraining preparation, after assessment of surgical candidates' sensorimotor skills and personality traits. Existing aviation pilot selection instruments are available to test sensorimotor skills and personality traits. This study examined selected instruments to assess medical trainees' sensorimotor skills and personality traits. Aviation's validated computer-based Computerized Pilot Aptitude and Screening System (COMPASS) and Checklist Professional Profile (CPP) were applied to 166 final year medical students during a surgical clerkship between 2013 and 2015. All trainees completed COMPASS and CPP within the prescribed 2 hours. Compared with an age-matched and gender-matched cohort of 165 pilot candidates, medical trainees scored significantly higher on eye-hand coordination (p<0.001), need for variation (p<0.001), empathy (p=0.006), helpfulness (p<0.001) and autonomy (p<0.001). Pilot candidates scored higher on eye-hand-foot coordination (p<0.001), spatial orientation (p<0.001), persuasiveness (p<0.001), stress tolerance (p<0.001), dominance (p<0.001), ambition (p<0.001) and resilience (p<0.001). Final year medical trainees from one medical school were able to complete aviation's sensorimotor skills and personality traits selection instruments within the set time frame. They scored differently from aviation trainees on selected skills and personality traits. The applicability and utility of aviation instruments to presurgical training preparation remains to be tested.


Evaluation of rotary drum composting for the management of invasive weed Mikania micrantha Kunth and its toxicity assessment.
Mikania micrantha Kunth is an abhorrent weed that destroys agricultural output. It contains toxic compounds that are detrimental to the natural ecosystem and have negative impacts on the economic and aesthetic aspects of the environment. This study depicts the treatment and management of this plant by in-vessel composting using a 550 L rotary drum composter. Six different mix proportions of biomass, cow dung, and sawdust were used for the study. Rotary drum (RD2) with 2.71% has the highest Total Kjeldahl Nitrogen (TKN). Total Organic Carbon (TOC) decreased to 19.72% at the end of the 20th day. Final C/N ratio falls between 7 and 14 in all the reactors. The phytotoxicity test of Mikania was evaluated using Vigna radiata and Allium cepa. The findings of the study suggest that Mikania can be efficiently utilised to produce mature and stable compost that might be recommended for field application as the process can reduce toxicity.


Total or partial percutaneous renal ablation in the treatment of renovascular hypertension: radiological and clinical aspects.
In 15 patients with renovascular hypertension, considered unsuitable for angioplasty or surgery, percutaneous renal ablation was performed by injection of ethanol into the renal vasculature. Partial or complete renal ablation was confirmed by follow-up intravenous pyelography or arteriography. Patients were followed-up for a mean of 24.8 months after therapy and blood pressure was improved in all patients with five being cured. This study shows that percutaneous renal ablation is a useful and successful method of therapy for renal hypertension, and that it should be considered in patients unsuitable for surgery or angioplasty.


Comparative effects of BRL 38227, nitrendipine and isoprenaline on carbachol- and histamine-stimulated phosphoinositide metabolism in airway smooth muscle.
1. The ability of BRL 38227 and nitrendipine to affect muscarinic agonist and histamine-stimulated [3H]-inositol phosphate accumulation in slices of bovine tracheal smooth muscle has been studied and compared with the established inhibitory effects of isoprenaline on this pathway. 2. Pre-addition of BRL 38227 (5 microM), nitrendipine (1 microM) or isoprenaline (10 microM) significantly inhibited the subsequent inositol phosphate response to histamine at all concentrations studied (10- 1000 microM). BRL 38227 and nitrendipine also significantly inhibited the [3H]-inositol phosphate response to low (1 microM), but not high (100 microM) concentrations of carbachol. Isoprenaline had no effect at any concentration of carbachol studied. 3. Nitrendipine (IC50 = 95 nM) and BRL 38227 (IC50 = 322 nM) caused concentration-related inhibitions of the inositol phosphate response to histamine (100 microM). Similar maximal inhibitions were caused by each agent (55-58%). Inhibitory effect of BRL 38227 was reduced in potency (IC50 = 5.5 microM), but not magnitude, in the presence of glibenclamide (0.5 microM). 4. Time-course studies comparing the effects of BRL 38227 addition 15 min before, and 10 min after histamine challenge showed that for pre-addition a distinct (less than 2 min) lag occurred following histamine addition before the inhibitory effect of BRL 38227 was manifest. In contrast, when BRL 38227 was added 10 min after histamine, an inhibitory effect was immediately apparent. 5. Further evidence for an initial, 'protected' phase of inositol phosphate accumulation was provided by the finding that BRL 38227 pre-addition had no effect on the early (0-300 s) time-course of inositol 1,4,5-trisphosphate mass accumulation. 6. The inhibitory effect of BRL 38227, but not that of nitrendipine or isoprenaline, on histaminestimulated [3H]-inositol phosphate accumulation was completely prevented in the presence of an elevated extracellular K+ (65 mM) concentration. 7. The results demonstrate that membrane hyperpolarization, and/or blockade of voltage-operated Ca2"-channels can regulate agonist-stimulated phosphoinositide metabolism in airway smooth muscle. The possible contribution of this regulatory mechanism to the relaxant properties of these agents is discussed.


Neighborhood interactions in a natural population of the perennial bunchgrassBouteloua gracilis.
We analyzed neighborhood interactions in a natural population of the perennial bunchgrass blue grama (Bouteloua gracilis). Space occupation by individual plants was characterized in terms of neighborhood size. Neighborhood size was defined as the area potentially 'available' to an individual, which included the basal area of the plant and the bare area closer to the edges of the plant than to any others. Geographic Information Systems (GIS) were used to describe space partitioning. Growing season performance was evaluated as a function of neighborhood area and neighbor size, controlling for focal plant size. The area of the neighborhood was significant in explaining the remaining variation of allometric relationships between basal area and current vegetative and reproductive performance. In contrast, current performance of focal individuals was not related to the average basal area or the sum of basal areas of adjacent neighbors. Growing season performance was apparently affected by plant spacing, suggesting that competition for spatially distributed resources occurs. The presence of relatively small plants in neighborhoods with a high proportion of bare soil is consistent with the view of a community composed of patches undergoing their own successional dynamics. Competition and disturbances seem to play an important role in this semiarid grassland.


Shifting the healthcare paradigm: the case manager's opportunity and responsibility.
Recent shifts in the healthcare system reflect a shift in thinking from sickness to wellness. This article reviews the paradigm shift, incentive system, and issues related to cost and quality. The role of case management in facilitating this transition is discussed. The article concludes with a discussion of the challenge to use nursing's unique disciplinary perspective that is focused on health to develop new approaches and strategies and the opportunities for case management to expand its scope of practice.


Pirimicarb resistance and associated mechanisms in field-collected and selected populations of Neoseiulus californicus.
The predatory mite Neoseiulus californicus McGregor (Acari: Phytoseiidae) is an important natural enemy of phytophagous mites, and naturally established populations are often found in apple orchards. However, insecticide applications to control pests cause side effects to non-target organisms such as N. californicus. Pirimicarb, a widely used carbamate insecticide in apple orchards, is generally considered a selective aphidicide, however, toxicity to beneficial insects and predatory mites has been reported. Furthermore, the molecular basis for this selectivity, if present in N. californicus, is still largely unknown. In this study, 8 field-collected N. californicus populations were investigated and showed up to 27-fold resistance compared to a susceptible laboratory population. Selection in the laboratory for 5 consecutive generations resulted in a 69-fold pirimicarb resistance. Although there were no significant difference in terms of the acetlycholinesterase (AChE) activity between susceptible and field-collected populations, the selected population exhibited a significantly higher AChE activity. In addition, gene copy number variation of acetylcholinesterase (ace) gene among populations was detected and ranged from 1.6 to 2.1-fold relative to the susceptible population. All field-collected populations, but not the selected population, had a significantly higher ace copy number compared to the susceptible population (t-test, p < 0.05). Molecular analysis of the target-site (AChE) revealed, for the first time, a phenylalanine to tryptophan substition at position 331 in AChE (Torpedo californica numbering), both in field-collected and the selected population, but not in the susceptible population. Last, the selected F5 population consumed significantly more Tetranychusurticae adults than the parental population. Together, the results of this study shed light on the molecular determinants of acaricide selectivity in predatory mites, and will contribute to a better design of an integrated mite management program, including the use of pesticide resistant N. californicus in apple orchards.


[Benefits of statin therapy based on plasma carbohydrate antigen 125 values following an admission for acute heart failure].
The prognostic benefit of statins in patients with heart failure is a topic of controversy. Under the hypothesis that statins may provide greater benefit in a subgroup of patients with heightened inflammatory activity, we sought to explore whether statins are associated with a decreased risk of long-term mortality in patients with acute heart failure based on elevated levels of carbohydrate antigen 125, a biomarker related to systemic congestion and proinflammatory status. We analysed 1222 consecutive patients admitted with acute heart failure in a single teaching center during a median follow-up of 20 months. carbohydrate antigen 125 was measured during index hospitalization and dichotomized according to the established reference cut-off (>35 U/mL). Increased levels of carbohydrate antigen 125 (>35 U/mL) were observed in 793 (64.9%) and prescription of statins registered in 455 (37.2%) patients. In patients with carbohydrate antigen 125 >35 U/mL, mortality was lower in statin-treated patients (1.89 vs 2.80 per 10 patient-years of follow-up, P <.001). Conversely, in those with carbohydrate antigen 125 in normal range, mortality did not differ (1.76 vs 1.63 per 10 patient-years of follow-up, P = .862). After covariate adjustment, this differential effect persisted (P for interaction = .024) and statin use was associated with a significant mortality reduction in patients with elevated values of carbohydrate antigen 125 (hazard ratio=0.65, 95% confidence interval: 0.51-0.82; P <.001), but not in those with values equal to or below 35 U/mL (hazard ratio=1.02, 95% confidence interval: 0.74-1.41; P = .907). Elevation of carbohydrate antigen 125 (>35 U/mL) identified a subset of patients with acute heart failure who could benefit from statin treatment in regard to total mortality.


Bronchial carcinoid with fibrillary inclusions related to cytokeratins: an immunohistochemical and ultrastructural study with subsequent investigation of 12 foregut APUDomas.
A bronchial P cell carcinoid, which was negative for all hormones immunocyto chemically tested, showed a globular intracytoplasmic inclusion in almost every cell. The inclusions were not clearly distinguishable using the haematoxylin- eosin- safran procedure; they were best demonstrated with the Masson trichrome stain and the Grimelius technique and were easily detected in 1 micron thick Epon sections as target-like structures. On electron microscopy, they were found to be composed of filamentous aggregates entrapping a few endosecretory granules, which showed degenerative changes. The filaments, 8-10 nm in diameter, lacked any periodicity; they were randomly dispersed in the central area and arranged in broken concentric swirls at the periphery of the inclusions. The globules lacked the tinctorial properties of amyloid, but showed a strong immunostaining for keratin-like proteins. A systematic investigation of 12 APUDomas of bronchial or duodenopancreatic origin, using both light and electron microscopy, identified a few filamentous bodies in one case, a somatostatin cell tumour of ampulla of Vater. In both cases, the structures appeared similar to those previously reported in growth hormone cell pituitary adenomas as well as in a few bronchial or gut carcinoids. Whatever their nature, morphological data suggest that they are related to abnormalities in the secretory function, involving the Golgi apparatus, the endosecretory granules and the microtubular microfilamentous system.


Schedule-dependent synergistic interaction between docetaxel and gefitinib in NSCLC cell lines regardless of the mutation status of EGFR and KRAS and its molecular mechanisms.
Tyrosine-kinase inhibitors (TKIs) and chemotherapy had different pharmacological mechanisms and therefore combined administration of TKIs and chemotherapy agents may have synergy. Our research aimed at exploring the cytotoxic interactions between gefitinib and docetaxel with different concentrations for non-small-cell lung cancer cell lines, and furthermore, the mechanisms underlying the cytotoxic synergism. NCI-H1650 [epidermal growth factor receptor (EGFR) mutation and KRAS wild-type], NCI-H292 (EGFR wild-type and KRAS wild-type) and A549 (EGFR wild-type and KRAS mutation) cell lines were treated with docetaxel and/or gefitinib. Cytotoxic interactions, cell cycle distribution and cell signal pathway were analyzed, respectively. Cytotoxic interactions between docetaxel and gefitinib were dose-dependent and sequence-dependent in all these three cell lines. Docetaxel followed by gefitinib treatment was optimum regimen regardless of the mutation status of EGFR and KRAS. KRAS mutation and EGFR wild-type predicted insensitive to gefitinib and docetaxel combined treatment as well as gefitinib alone. G1 arrest was inconsistently associated with combination index (CI). However, apoptosis induction was schedule-dependent and can explain the synergism completely. Mitogen-activated protein kinase (MAPK) phosphorylation ratio was also schedule-dependent and positively correlated with CI. Cytotoxic interactions between docetaxel and gefitinib were sequence-dependent regardless of the mutation status of EGFR and KRAS. Cell characteristic, apoptosis induction and MAPK phosphorylation but not cell cycle change may explain the molecular mechanisms of synergism.


Associations between body mass index, waist circumference and body shape index with resting blood pressure in Portuguese adolescents.
Elevated blood pressure (BP) in childhood and adolescence is associated with overweight and obesity. Recently a body shape index (ABSI) has been suggested as superior to body mass index (BMI, kg/m(2)) and waist circumference (WC) as a measure of disease risk. To examine the association between ABSI, BMI, WC and BP in Portuguese adolescents and to consider the role of ABSI, BMI and WC when examining this issue in adolescents. Height, body mass, WC and resting blood pressure were assessed in 445 Portuguese adolescents (252 girls and 193 boys) aged 10-17 years. ABSI, BMI and WC were all significantly related to both SBP and DBP (all p = 0.001 or better). ABSI, BMI and WC were all significant predictors of SBP and DBP for the whole sample and when analysed in separate gender groups (p = 0.001 or better in all cases). However, in all cases ABSI was a better predictor of BP than BMI or WC. Although BMI and WC significantly predict resting BP in adolescents, the use of ABSI explained a greater amount of the variance in BP in this population. When examining the effect of weight status on BP, researchers should consider use of ABSI alongside BMI.


Overexpression of PD-L1 causes germ cells to slough from mouse seminiferous tubules via the PD-L1/PD-L1 interaction.
Spermatogenesis is a cyclical process in which different generations of spermatids undergo a series of developmental steps at a fixed time and finally produce spermatids. Here, we report that overexpression of PD-L1 (B7 homolog1) in the testis causes sperm developmental disorders and infertility in male mice, with severe malformation and sloughing during spermatid development, characterized by disorganized and collapsed seminiferous epithelium structure. PD-L1 needs to be simultaneously expressed on Sertoli cells and spermatogonia to cause spermatogenesis failure. After that, we excluded the influence of factors such as the PD-L1 receptor and humoral regulation, confirming that PD-L1 has an intrinsic function to interact with PD-L1. Studies have shown that PD-L1 not only serves as a ligand but also plays a receptor-like role in signal transduction. PD-L1 interacts with PD-L1 to affect the adhesive function of germ cells, causing malformation and spermatid sloughing. Taken together, these results indicate that PD-L1 can interact with PD-L1 to cause germ cell detachment and male infertility.


Caffey disease with raised immunoglobulin levels and thrombocytosis.
Infantile cortical hyperostosis (Caffey disease) is characterized by radiological evidence of cortical hyperostosis, soft tissue swellings, fever and irritability. We report a case of Caffey disease highlighting its presentation with thrombocytosis and high serum immunoglobulin level to alert physicians to use steroids cautiously in view of the known thrombocythemic effect of the drug. Raised Immunoglobulin also suggests that this syndrome could be infectious in origin.


Four nucleophilic additions to alkenynedioic acid derivatives in tandem; efficient one-pot synthesis of bicyclo[4.2.0]octenols.
When alkenynedioic acid derivatives were treated with a Grignard reagent, tandem cyclization and the incorporation of two molecules of the Grignard reagent occurred to give stereodefined bicyclo[4.2.0]octenols via four nucleophilic additions.


Supracondylar osteotomy for cubitus varus. The value of the straight arm position.
Supracondylar osteotomy for traumatic cubitus varus is usually considered to be difficult, and to have a significant incidence of complications. Most difficulty is in maintaining correction after operation. We report 20 osteotomies performed by a modification of French's technique and managed postoperatively with the elbow extended. When a plaster splint was used only three of seven cases had good or satisfactory results, two requiring revision. Postoperative management by straight arm traction maintained correction and achieved a good or satisfactory result in all 13 cases. This new technique is recommended.


In vitro degradation of mouse, rabbit and dog antibodies to Vibrio cholerae by succus entericus.
Purified antibodies to Vibrio cholerae from mouse, rabbit and dog were digested in vitro by homologous intestinal secretions. When assessed with regard to their complement-dependent vibriocidal activity, IgG antibodies were generally more susceptible to degradation than IgM antibodies, High levels of tryptic inhibitors were required to inhibit this digestion. Rabbit IgG was unusual in being quite resistant to digestion. Gel filtration studies demonstrated that secretory IgA, isolated from mouse intestinal secretions, was resistant to proteolysis. Similar studies on dog IgG and mouse IgM demonstrated production of F(ab') 2-like fragments. Digestss of these antibodies, while devoid of Fc-mediated vibriocidal activity, retained significant protective activity for baby mice.


Optimizing development time in a seasonal environment: The 'ups and downs' of clinal variation.
This paper explores the problem of adapting development time to changes in the length of time conditions are favourable for growth and reproduction ('season length'). It is shown that systematic changes in season length along some gradient such as latitude can generate either simple clines in development time or 'saw-tooth' clines. The relationship between development time and body size gives rise to a corresponding variation in body size. The generation of a 'saw-tooth' cline does not require sharp environmental changes. Both types of clinal variation are observed in insects.


Serum caspase-3 levels during the first week of traumatic brain injury.
Confluence between the intrinsic and extrinsic apoptosis pathways is reached at the point of caspase-3 activation, which induces death cell. Higher serum caspase-3 levels have been recorded on day 1 of traumatic brain injury (TBI) in 30-day non-survivors compared to survivors. The objectives of this study therefore were to determine whether serum caspase-3 levels are persistently higher in non-survivors than in survivors, and whether these levels may be used to predict 30-day mortality. A prospective observational study was carried out. Six Spanish Intensive Care Units. Patients with severe isolated TBI (defined as Glasgow Coma Scale <9 points and non-cranial Injury Severity Score <10 points). Serum caspase-3 concentrations were measured on days 1, 4 and 8 of TBI. Thirty-day mortality was considered as the study endpoint. In comparison with non-survivors (n=34), 30-day survivors (n=90) showed lower serum caspase-3 levels on days 1 (p=0.001), 4 (p<0.001) and 8 (p<0.001) of TBI. Analysis of the ROC curves showed serum caspase-3 concentrations on days 1, 4 and 8 of TBI to have an AUC (95% CI) in predicting 30-day mortality of 0.70 (0.61-0.78; p=0.001), 0.83 (0.74-0.89; p<0.001) and 0.87 (0.79-0.93; p<0.001), respectively. The novel findings of our study were that serum caspase-3 levels during the first week of TBI were lower in survivors and could predict 30-day mortality.


Wnt and Vitamin D at the Crossroads in Solid Cancer.
Abnormal activation of the Wnt/β-catenin pathway is common in many types of solid cancers. Likewise, a large proportion of cancer patients have vitamin D deficiency. In line with these observations, Wnt/β-catenin signaling and 1α,25-dihydroxyvitamin D3 (1,25(OH)2D3), the active vitamin D metabolite, usually have opposite effects on cancer cell proliferation and phenotype. In recent years, an increasing number of studies performed in a variety of cancer types have revealed a complex crosstalk between Wnt/β-catenin signaling and 1,25(OH)2D3. Here we review the mechanisms by which 1,25(OH)2D3 inhibits Wnt/β-catenin signaling and, conversely, how the activated Wnt/β-catenin pathway may abrogate vitamin D action. The available data suggest that interaction between Wnt/β-catenin signaling and the vitamin D system is at the crossroads in solid cancers and may have therapeutic applications.


Observation of head trauma patients at home: a prospective study of compliance in the rural south.
A prospective study was conducted to test the reliability of at-home observation of head trauma victims in the rural South among a population of low educational level. During a four-month period, 99 patients entered and 90 patients finished the study. In all cases, an individual was identified as willing to accept the responsibility of observing the patient. The observer received written and verbal instructions to stay with the patient for 24 hours and to wake the patient every four hours during that time. Patients then were contacted seven to nine days after their injury and questioned as to their present symptoms and observer compliance. For patients under 15 years of age (n = 34), the observer was questioned. Thirteen percent of the observers did not remain with the patient for 24 hours, 16% passed the responsibility of observation to another individual, and 71% awoke the patient as instructed. Observers who were not the patient's mother were significantly more likely to abandon the patient during the first 24-hour period. Observer compliance for patient awakening significantly decreased with the increase in patient age. When spouses and live-in friends were combined as a group of observers and compared with parents, the parents awoke the patient significantly more often. The authors conclude that in this population, at-home observation of head trauma patients, particularly those more than 25 years old, may not be reliable. Special attention should be directed toward the care of these patients.


Towards a midwifery profession in Bangladesh--a systems approach for a complex world.
The midwifery profession is crucial for a functioning health system aiming at improved maternal and child health outcomes. Complex Adaptive Systems (CAS) can be used as a tool to understand actors' interactions in the system around midwifery profession for improved maternal and child health. The purpose of this study is to explore how actors connect to promote the Bangladesh's midwifery profession. An explorative study based on the framework of CAS was performed. Data were collected through semi-structured interviews with 16 key persons representing nine different organisations promoting the establishment of the midwifery profession. Qualitative analysis was used. Findings show that the actors were intertwined and driving towards a common goal; to save lives through education and deployment of 3000 midwives. The unique knowledge contributions of everyone involved were giving the system strength and power to perform. Collaboration was seen as more could be achieved compared to what an individual organisation could do. Significant results of this were that two midwifery curricula and faculty development had been produced. Although collaboration was mostly seen as something positive to move the system forward, the approach to reach the set goal varied with different interests, priorities and concerns, both on individual organisational level as well as at system level. Frequent struggles of individual philosophies versus organisational mandates were seen as competing interests for advancing the national priorities. It would appear that newcomers with innovative ideas were denied access on the same terms as other actors. This study illustrates that CAS thinking can be used as a metaphor to understand how to adapt more emergent ways of working instead of the traditional planned approaches to change and develop in order to deal better with a more complex world. Through examining how actors connect for establishing a midwifery profession, offers insights of shared interests towards stepping up efforts for a competent midwifery profession in Bangladesh and elsewhere. Good relationships, where everyone's expertise and innovations, are used to the full, are crucial for establishing a strong midwifery profession and thus improved maternal and child health.


L -Carnitine and the recovery from exhaustive endurance exercise: a randomised, double-blind, placebo-controlled trial.
We hypothesised that L: -carnitine could accelerate recovery from exhaustive exercise since increased blood L: -carnitine concentrations elicit a vasodilation in isolated animal vessels as well as in patients with peripheral vascular or coronary artery disease during exercise. Twelve subjects received either 2 g L: -carnitine or a placebo in a study which was double-blind and crossover in design. Two hours after administration, the subjects performed a constant-load exercise test (CET(1)) cycling at their individual anaerobic threshold to exhaustion. Three hours later this test was repeated (CET(2)). After 4-14 days, each subject performed the same cycling tests after having taken the other substance. Exercise times of the 12 subjects were identical with L: -carnitine (CET(1): 21.3+/-5.7 min; CET(2): 21.4+/-5.3 min) and placebo (CET(1): 21.9+/-6.2 min; CET(2): 20.4+/-4.8 min). Also, heart rate, oxygen consumption, respiratory exchange ratio, and blood lactate concentration were identical. In conclusion, 2 g of L-carnitine taken 2 h before a first of two constant-load exercise tests had no influence on the second tests performed 3 h after the first test compared with placebo.


Persistent and transient distal renal tubular acidosis with bicarbonate wasting.
Bicarbonate titration studies were performed on two patients with bicarbonate wasting distal renal tubular acidosis (RTA; patients 1 and 2) and on three patients (3,4, and 5) with classic distal RTA. Daily requirements of alkali were 4.5 mEq/kg body wt in patient 1, a 3-year-old boy, and 16 mEq/kg in patient 2, a 5-month-old male infant. In contrast, only 1.5-2 mEq/kg/24 hr alkali were required in the three patients with classic distal RTA (age 8 1/2- 22 years). Patient 1 had glucose-6-phosphate dehydrogenase deficiency and patient 3 had inner ear deafness as an associated anomaly. In patient 2, the acidification defect was transient. Mean fractional excretion of bicarbonate (ChCO3-/Cin) times 100 at a plasma concentration of HCO3 below 20 mmol/liter was 5.1% in patient 1, 11.6% in patient 2, and 1.7% in patients 3-5. Minimal urine pH during the study was 7.38 in patient 1, 7.66 in patient 2, and 6.78-6.97 in the other patients. Values of net acid excretion at plasma HCO3 = 16 mmol/liter were strongly negative in patients 1 and 2 (-75 and -195 mumol/100 ml glomerular filtrate (GF), respectively) but slightly positive in the three patients with classic RTA (+3 to +20 mumol/100 ml GF). The two patients with bicarbonate wasting distal RTA were thus clearly separated from the group of patients with classic distal RTA.


A method for the detection of amyloid in human tissue embedded in epon using a combination of polarizing light microscopy and electron microscopy.
This paper describes a method for demonstrating amyloid in human tissue embedded in epon using a combination of congo red staining and polarizing microscopy. The method involves the removal of the embedding medium from semi-thin sections prior to staining with congo red and examination in the polarizing microscope. Typical apple green birefringence was detected in areas of amyloid deposition; these areas were mapped for selective trimming and ultra-thin sections taken serially were examined in the electron microscope. The method was found to be reliable, easy to use and particularly of value as a sampling procedure prior to investigation in the electron microscope.


Single-cell dissection of the human brain vasculature.
Despite the importance of the cerebrovasculature in maintaining normal brain physiology and in understanding neurodegeneration and drug delivery to the central nervous system1, human cerebrovascular cells remain poorly characterized owing to their sparsity and dispersion. Here we perform single-cell characterization of the human cerebrovasculature using both ex vivo fresh tissue experimental enrichment and post mortem in silico sorting of human cortical tissue samples. We capture 16,681 cerebrovascular nuclei across 11 subtypes, including endothelial cells, mural cells and three distinct subtypes of perivascular fibroblast along the vasculature. We uncover human-specific expression patterns along the arteriovenous axis and determine previously uncharacterized cell-type-specific markers. We use these human-specific signatures to study changes in 3,945 cerebrovascular cells from patients with Huntington's disease, which reveal activation of innate immune signalling in vascular and glial cell types and a concomitant reduction in the levels of proteins critical for maintenance of blood-brain barrier integrity. Finally, our study provides a comprehensive molecular atlas of the human cerebrovasculature to guide future biological and therapeutic studies.


Collie Eye Anomaly in Australian Kelpie dogs in Poland.
To report the occurrence of choroidal hypoplasia in the Australian Kelpie breed in Poland, the affected dogs testing positive for the Collie Eye Anomaly NHEJ1 gene mutation. Choroidal hypoplasia (CH) was initially diagnosed in a young female Australian Kelpie presented for routine ophthalmological examination prior to breeding. Indirect ophthalmoscopy revealed tigroid fundi bilaterally with areas of abnormally arranged choroidal vasculature temporal to the optic disc. These lesions had the appearance of the choroidal hypoplasia diagnostic for Collie Eye Anomaly, a genetically determined disease seen most commonly in Collie types. The DNA based test for the NHEJ1 gene mutation that is confirmatory for Collie Eye Anomaly proved the dog to be homozygous for this mutation. Twenty one other related dogs were subsequently examined genetically, the dam proving to be affected and eight others were shown to be carriers. This report demonstrates that Collie Eye Anomaly is present in a Polish bred Australian Kelpie line and as such breeders in this country and those importing dogs or semen internationally should be aware of other possible cases.


Implementation of a circular supply chain model using reusable components in multiple product generations.
The paper deals with a version of Economic Order Quantity (EOQ) and Economic Production Quantity (EPQ) models that considers the reusability of raw materials and components in multiple product generations. With the scarcity of available raw materials and disruptions in supply chains, production companies need to find novel solutions to meet demand. Additionally, waste management of used products is becoming an increasing problem for the environment. Our study presents available solutions for managing end-of-life products and aims to present a cost minimization EOQ/EPQ model. The model considers the use of components extracted from the previous product generation and new components during the production of the new product generation. The study aims to answer the following research questions (i) what is the optimal strategy for the company for the number of cycles of extracted and new components during the production? (ii) Which variables affects the optimal strategy of the company? The presented model allows companies to use the value created for a longer period, and reduces the amount of raw material extracted and waste generated.


Response to lithium of a cell surface ECTO-NOX protein with time-keeping characteristics.
Lithium has been used widely both as a clinical agent to treat manic depressive disorders and as a substance targeted to the regulation of the circadian cycle. In this study, we show that lithium at physiological concentrations of less than 1microM uniquely induces an ECTO-NOX activity previously inactive from plant (soybean), murine (3T3 cells) and human (HUVEC and HeLa cells) sources and resets the period of the constitutive CNOX. The average period length of the new oscillation set induced by the presence of lithium of 23.5min was slightly less than the period length in the absence of lithium (24min). The constitutive period was retained in the presence of lithium but the period length was increased on an average by 4% to about 25min. Targeting circadian rhythm abnormalities may be a particularly useful strategy in management of bipolar disorder and related illnesses since circadian cycles appear to be an inherent function conserved through evolution in all organisms and consistently implicated in the pathophysiology of bipolar disorder.


Use of sequence analysis for classifying individual antidepressant trajectories to monitor population mental health.
Over the past decade, antidepressant prescriptions have increased in European countries and the United States, partly due to an increase in the number of new cases of mental illness. This paper demonstrates an innovative approach to the classification of population level change in mental health status, using administrative data for a large sample of the Scottish population. We aimed to identify groups of individuals with similar patterns of change in pattern of prescribing, validate these groups by comparison with other indicators of mental illness, and characterise the population most at risk of increasing mental ill health. National Health Service (NHS) prescription data were linked to the Scottish Longitudinal Study (SLS), a 5.3% sample of the Scottish population (N = 151,418). Antidepressant prescription status over the previous 6 months was recorded for every month for which data were available (January 2009-December 2014), and sequence dissimilarity was computed by optimal matching. Hierarchical clustering was used to create groups of participants who had similar patterns of change, with multi-level logistic regression used to understand group membership. Five distinct prescription pattern groups were observed, indicating: no prescriptions (76%), occasional prescriptions (10%), continuation of prior use of prescriptions (8%), a new course of prescriptions started (4%) or ceased taking prescriptions (3%). Young, white, female participants, of low social grade, residing in socially deprived neighbourhoods, living alone, being separated/divorced or out of the labour force, were more likely to be in the group that started a new course of antidepressant prescriptions. The use of sequence analysis for classifying individual antidepressant trajectories offers a novel approach for capturing population-level changes in mental health risk. By classifying individuals into groups based on their anti-depressant medication use we can better identify how over time, mental health is associated with individual risk factors and contextual factors at the local level and the macro political and economic scale.


Expression of basic fibroblast growth factor and receptor: immunolocalization studies in developing rat fetal lung.
To study the role of basic fibroblast growth factor (bFGF) in fetal lung development, the distribution of bFGF peptide and FGF receptor (FGF-R) was examined by immunohistochemistry in embryonic and fetal rat lung [d 12 to term (term = 22 d)]. Throughout development bFGF was localized to airway epithelial cells, their basement membranes, and their extracellular matrix. FGF-R was also detected in airway epithelial cells, especially in the branching areas, and in interstitial cells as early as d 13. The number of FGF-R immunoreactive cells increased during the embryonic and pseudoglandular stages of lung development, followed by fluctuations in reactivity during the canalicular stage. No FGF-R was detected in tissue from the saccular stage of lung development. The presence of bFGF and FGF-R in developing airway epithelium and mesenchyme is compatible with a role for this growth factor during fetal lung development. In the developing lung, bFGF seems to be sequestered and stored in the extracellular matrix, and may be released at times of need. Furthermore, FGF-R up- and down-regulation offers another mechanism by which the growth of specific cell populations may be controlled during fetal lung development.


Glucocorticoid receptors: ATP-dependent cycling and hormone-dependent hyperphosphorylation.
The dependence of hormone binding to glucocorticoid receptors (GRs) on cellular ATP levels led us to propose that GRs normally traverse an ATP-dependent cycle, possibly involving receptor phosphorylation, and that without ATP they accumulate in a form that cannot bind hormone. We identified such a form, the null receptor, in ATP-depleted cells. GRs are basally phosphorylated, and become hyperphosphorylated after treatment with hormone (but not RU486). In mouse receptors we have identified 7 phosphorylated sites, all in the N-terminal domain. Most are on serines and lie within a transactivation region. The time-course of hormone-induced hyperphosphorylation indicates that the primary substrates for hyperphosphorylation are the activated receptors; unliganded and hormone-liganded nonactivated receptors become hyperphosphorylated more slowly. After dissociation of substrates for hyperphosphorylation are the activated receptors; unliganded and hormone-liganded nonactivated receptors become hyperphosphorylated more slowly. After dissociation of hormone, most receptors appear to be recycled and reutilized in hyperphosphorylated form. From these and related observations, we have concluded that the postulated ATP-dependent cycle can be accounted for by hormone-induced or spontaneous dissociation of receptor-Hsp90 complexes, followed by reassociation of unliganded receptors with Hsp90 via an ATP-dependent reaction like that demonstrated in cell-free systems. Other steroid hormone receptors might traverse a similar cycle. Four of the 7 phosphorylated sites in the N-terminal domain are in consensus sequences for p34cdc2 kinases important in cell cycle regulation. This observation, along with the known cell cycle-dependence of sensitivity to glucocorticoids and other evidence, point to a role for receptor phosphorylation in controlling responses to glucocorticoids through the cell cycle.


Effects of N-acetylcysteine on CG8005 gene-mediated proliferation and apoptosis of Drosophila S2 embryonic cells.
To investigate the effect of the antioxidant N-acetylcysteine (NAC) on the proliferation and apoptosis in CG8005 gene-interfering Drosophila S2 embryonic cells by scavenging intracellular reactive oxygen species (ROS). The interfering efficiency of CG8005 gene in Drosophila S2 embryonic cells was verified by real-time quantitative PCR (qRT-PCR). Different concentrations of NAC and phosphate buffered saline (PBS) were used to affect the Drosophila S2 embryonic cells. The growth state of Drosophila S2 embryonic cells was observed by light microscope. Two probes dihydroethidium (DHE) and 2,7-dichlorodihydrofluorescein-acetoacetate (DCFH-DA) were used to observe the ROS production in each group after immunofluorescence staining. TUNEL staining and flow cytometry were used to investigate the apoptosis level of Drosophila S2 embryos, and CCK-8 (Cell Counting Kit-8) was used to detect the cell viability of Drosophila S2 embryos. The knockdown efficiency of siCG8005-2 fragment was high and stable, which was verified by interference efficiency (P < 0.05). There was no significant change in the growth of Drosophila S2 embryonic cells after the treatment of NAC as compared to PBS group. Moreover, knockdowning CG8005 gene resulted in an increase in ROS and apoptosis in Drosophila S2 embryonic cells (P < 0.05) and a decrease in proliferation activity (P < 0.05). In addition, the pretreatment of antioxidant NAC could inhibit ROS production in Drosophila S2 embryonic cells (P < 0.05), reduce cell apoptosis (P < 0.05), and improve cell survival (P < 0.05). The CG8005 gene in Drosophila S2 embryonic cells could regulate the proliferation and apoptosis of S2 embryonic cells by disrupting the redox homeostasis, and antioxidant NAC could inhibit cell apoptosis and promotes cell proliferation by scavenging ROS in Drosophila S2 embryonic cells, which is expected to provide novel insights for the pathogenesis of male infertility and spermatogenesis.


Management of low-grade squamous intraepithelial lesions of the uterine cervix.
Strategies of management for low-grade squamous intraepithelial lesion (SIL) vary even on a national level. We evaluated the diversity of management algorithms. This should serve as a source to find a common basis for the management of low-grade SIL. A total of 38 representatives and specialists for colposcopy and cervical pathology were contacted to provide national guidelines, recommendations or consensus for the management of patients diagnosed with the cytologic diagnosis of low-grade SIL. In all, 23 addressees (60%) responded. The algorithms provided varied considerably. Three variants of algorithms could be defined. Variant 1 was proposed in 14 countries and recommended colposcopy immediately after cytologic diagnosis of low-grade SIL or at the same time the smear is taken. If available, HPV testing was recommended as a triage option in some countries. Variant 2 is used in three countries and colposcopy is only performed after a repeated abnormal cytologic result within a 6-month interval or after an optional test positive for high-risk HPV. Variant 3, as proposed in six countries, takes into account the socio-economic status of the patient: In patients with poor compliance, 'see and treat' management is recommended; in patients where compliance can be assured, follow-up is carried out by cytology and colposcopy. Global policy of management of patients with low-grade SIL can be summarised in three algorithms. Quality standards and outcome parameters must be defined in order to improve the management of women with low-grade SIL.


Hyperplastic gingivitis during diltiazem therapy.
This report concerns a patient with ischemic heart disease, who developed hyperplastic gingivitis with verapamil. The gingivitis resolved completely when the drug was discontinued, but recurred when another calcium antagonist, diltiazem, was administered. It is suggested that it is the mechanism of action of calcium antagonists which is responsible for the gingival changes.


The cerebral ventricles as the avenue for the dipsogenic action of intracranial angiotensin.
Using low doses of angiotensin II (1-128 ng), a mapping study was carried out to redefine the region within the brain from which the dipsogenic response can be elicited. The most sensitive sites were either close to the anterior cerebral ventricles or were at the tips of cannulae that traversed a ventricular space en route to the tissue site. Conversely, insensitive sites were remote from the ventricles and were not reached by cannulae with a ventricular trajectory. Therefore, a thorough assessment of the role of the ventricular system in the angiotensin thirst phenomenon was demanded. Further studies revealed that direct intraventricular injections were as effective as those made into any tissue site tested. Also, regardless of the similarity in the sites of their termination, cannulae which passed through a ventricular space en route to that site yielded highly sensitive preparations whereas those which did not were insensitive to the hormone. Autoradiographic and radioassay studies showed that tritiated angiotensin II injected into anterior diencephalic tissue through cannulae which traversed the ventricles was rapidly distributed throughout the ventricular system. Thus, efflux of the injected material up the cannula shaft and its entry into the ventricular system is essential for a dipsogenic response to low doses of the hormone. These results support the hypothesis of a periventricular receptor site for angiotensin. It is suggested that systemically generated angiotensin and angiotensin endogenous to the brain may use the ventricular route as a means of access to the sensitive periventricular site.


Self-reported coping behavior of wives of alcoholics and its association with drinking outcome.
The frequency of the use of coping behavior by wives of alcoholics was found to be related to their husband's drinking outcome. In general, a high frequency of coping behavior was associated with a poor outcome, but some components of coping behavior were more likely than others to be linked with a poor prognosis.


Selection of DNA binding sites by regulatory proteins: the LexA protein and the arginine repressor use different strategies for functional specificity.
The DNA sequences in the operator sites of the arginine regulon and of the SOS regulon have been subject to a statistical analysis. A quantitative correlation is found between the statistics of sequence choice and the activity at individual operator sites in both systems, as expected from theoretical considerations [Berg & von Hippel, J.Mol.Biol. (1987) 193, 723-750]. Based on these correlations it is possible to predict the effect of various sequence mutations. There is a significant difference in the slopes of the correlation lines between sequence and activity for the two systems. From this difference it can be expected that individual point mutations in the ARG boxes will have a much smaller effect on activity than similar changes in the SOS boxes. This difference may be related to a strong cooperative activity at tandem ARG boxes while the binding at SOS boxes appears to be mostly noncooperative.


JQ1-Loaded Polydopamine Nanoplatform Inhibits c-MYC/Programmed Cell Death Ligand 1 to Enhance Photothermal Therapy for Triple-Negative Breast Cancer.
Programmed cell death ligand 1 (PD-L1) blockade has achieved great success in cancer immunotherapy; however, the response of triple-negative breast cancer (TNBC) to PD-L1 antibodies is limited. To address this challenge, we use the bromodomain and extra-terminal inhibitor JQ1 to down-regulate the expression of PD-L1 and thus elicit the immune response to TNBC instead of using antibodies to block PD-L1. JQ1 also inhibits the growth of TNBC as a targeted therapeutic agent by inhibiting the BRD4-c-MYC axis. The polydopamine nanoparticles (PDMNs) are introduced as a biodegradable and adaptable platform to load JQ1 and induce photothermal therapy (PTT) as another synergistic therapeutic modality. Because the JQ1-loaded PDMNs (PDMN-JQ1) are self-degradable and release JQ1 continuously, this synergistic treatment can lead to remarkable activation of cytotoxic T lymphocytes and induce a strong immune-memory effect to protect mice from tumor re-challenge. Taken together, our study demonstrates a compact and simple nanoplatform for triple therapy, including targeted therapy, PTT, and immunotherapy, for TNBC treatment.


Semagacestat Is a Pseudo-Inhibitor of γ-Secretase.
γ-secretase inhibitors (GSI) are drugs developed to decrease amyloid-β peptide (Aβ) production by inhibiting intramembranous cleavage of β-amyloid protein precursor (βAPP). However, a large phase 3 trial of semagacestat, a potential non-transition state analog (non-TSA) GSI, in patients with Alzheimer's disease (AD) was terminated due to unexpected aggravation of cognitive deficits and side effects. Here, we show that some semagacestat effects are clearly different from a phenotype caused by a loss of function of presenilins, core proteins in the γ-secretase complex. Semagacestat increases intracellular byproduct peptides, produced along with Aβ through serial γ-cleavage of βAPP, as well as intracellular long Aβ species, in cell-based and in vivo studies of AD model mice. Other potential non-TSA GSIs, but not L685,458, a TSA GSI, have similar effects. Furthermore, semagacestat inhibits release of de novo intramembranous γ-byproducts to the soluble space. Thus, semagacestat is a pseudo-GSI, and therefore, the semagacestat clinical trial did not truly test the Aβ hypothesis.


Surgical management of intraductal papillary mucinous neoplasm (IPMN) of the pancreas.
Intraductal papillary mucinous neoplasm (IPMN) of the pancreas is characterized by papillary growths within the pancreatic ductal system that are at risk for undergoing malignant transformation. Main duct IPMN carries a significant risk of malignancy, and operation is recommended regardless of the presence of symptoms. The risk of malignancy is much lower for side branch IPMN, and current evidence suggests that, in the absence of symptoms, mural nodules, positive cytology, or cyst size less than 3 cm, observation is warranted. When operation is indicated, targeted pancreatic resection with frozen-section analysis of margins is recommended. Pancreatoduodenectomy or distal pacreatectomy is appropriate for the majority. Only in about 10% of patients is the disease so diffuse at presentation that total pancreatectomy is necessary. Survival following pancreatic resection for noninvasive IPMN is excellent. The risk of recurrence following pancreatic resection for invasive IPMN is significant. Surveillance is warranted both for patients subjected to pancreatic resection and for those under observation with side branch IPMN. Much is yet to be learned regarding this neoplasm, and surgical management remains in evolution.


Causal thinking and causal language in epidemiology: it's in the details.
Although epidemiology is necessarily involved with elucidating causal processes, we argue that there is little practical need, having described an epidemiological result, to then explicitly label it as causal (or not). Doing so is a convention which obscures the valuable core work of epidemiology as an important constituent of public health practice. We discuss another approach which emphasizes the public health "use value" of research findings in regard to prediction and intervention independent from explicit metaphysical causal claims. Examples are drawn from smoking and lung cancer, with particular focus on the original 1964 Surgeon General's report on smoking and the new version released in 2004. The intent is to help the epidemiologist focus on the pertinent implications of research, which, from a public health point of view, in large part entails the ability to predict and to intervene. Further discussion will center on the importance of differentiating between technical/practical uses of causal language, as might be used in structural equations or marginal structural modeling, and more foundational notions of cause. We show that statistical/epidemiological results, such as "smoking two packs a day increases risk of lung cancer by 10 times" are in themselves a kind of causal argument that are not in need of additional support from relatively ambiguous language such as "smoking causes lung cancer." We will show that the confusion stemming from the use of this latter statement is more than mere semantics. Our goal is to allow researchers to feel more confident in the power of their research to tell a convincing story without resorting to metaphysical/unsupportable notions of cause.