Excitatory effect of propiverine hydrochloride on urethral activity in rats.
To investigate the effects of the antimuscarinic agent, propiverine, on the bladder and urethra in rats. A total of 54 female rats were given propiverine, imidafenacin (an antimuscarinic agent), or distilled water by gavage once or twice daily. After 2 weeks, bladder and urethral activity were recorded under urethane anesthesia. In the propiverine group, the changes of bladder and urethral activity before and after intravenous injection of α(1) -adrenergic antagonists (prazosin, silodosin and naftopidil) were also recorded. Furthermore, the leak point pressure after electrical stimulation of abdominal wall muscles was measured in rats with vaginal distension from the control and propiverine groups. Intravesical baseline pressure was significantly lower in the propiverine and imidafenacin groups compared with the control group, whereas the urethral baseline pressure was significantly higher in the propiverine group compared with the control or imidafenacin groups. Intravenous injection of prazosin (an α(1) -receptor antagonist) significantly decreased the urethral baseline pressure in both of the propiverine and control groups. Intravenous injection of silodosin and naftopidil (α(1A) - and α(1D) -receptor antagonists, respectively) significantly decreased the maximum contraction pressure and the urethral baseline pressure in the propiverine group. The leak point pressure of the propiverine group was significantly higher than that of the control group. An increase of catecholamines after propiverine administration might activate smooth muscle of the proximal urethra via α(1A) - and α(1D) -adrenergic receptors, as well as activating urethral and pelvic floor striated muscle via the spinal motoneurons.


The autoregulatory capability of Galen's rete cerebri and its connections.
The rete, a vascular system between the extra- and intracerebral arteries of certain animals, may have a variety of functions in different species. The calibres of the vessels of the rete and its arteries of supply have been measured under different conditions of blood pressure and PaCO2. It has been shown that the rete and its afferent arteries behave in an autoregulatory fashion down to a blood pressure of 60 mmHg. They also dilate with a rise in PaCO2. It has also been found that some parts of the system dilate even when the blood pressure drops lower than 60 mmHg. It is suggested that this autoregulatory capacity of extradural vessels limits the requirement for CSF spaces to change with blood pressure changes. A general rule has been sought which would link the known facts about cerebral autoregulation and the possession of extra- to intracranial anastomoses with the bodily shape and posture of the particular animal.


Carrying children, groceries, and water across varying terrain: Changes in gait and comfortable walking speed.
Carrying items of substantial weight and value in one's arms while traversing challenging terrain is a common task that requires considerable care. Carrying valuable (e.g., child) or variable (e.g., water) items, compared to stable ones (e.g., groceries) demands increased coordination, and is likely to lead to slower comfortable walking speed (CWS) and altered gait mechanics, especially on difficult terrain. How are gait parameters altered by carrying items of substantial weight and varying value and dynamics across more and less demanding terrain? In two experiments, participants carried their child, an equally weighted sack of groceries, or an open bucket of water in the same manner across level floor and across uneven stairs of varying heights with gaps between them. Kinematics were assessed for both terrains; kinetics were measured for one step up and one step down on stairs. Mixed models ANOVAs with repeated measures revealed that CWS on uneven stairs was approximately 65 % of CWS for level floor, regardless of the item carried. Step-to-step coefficients of variation for step length and CWS were also greater. Water was carried most slowly, with shorter steps on level floor and reduced accelerations on uneven stairs. CWS with children and groceries did not differ. Carrying items of weight and worth with varying dynamics across more and less challenging terrain illustrates the ecological complexity of walking. Terrain requiring greater flexibility, strength, and coordination reduced CWS substantially, a complexity-speed tradeoff. More variable, difficult to control items altered CWS and other gait patterns regardless of terrain difficulty, suggesting terrain and item dynamics contributed independently to gait adjustments. More valuable items were not carried more slowly than less valuable ones. Carrying tasks deserve greater attention in research and clinical assessment.


Excess of adiposity in female children and adolescents with juvenile idiopathic arthritis.
This study aims to evaluate the body composition (BC) of female children and adolescents with juvenile idiopathic arthritis (JIA). A cross-sectional, controlled study was performed to compare the BC between 42 JIA girls and 35 healthy controls, matched for age and gender. Weight and height were used to calculate body mass index (BMI), classified as a Z-score (Z-BMI). BC was evaluated by dual-energy X-ray absorptiometry (DXA; DPX-L, Lunar). The fat mass index (FMI) was calculated as the ratio between total fat mass and height squared (kilograms per square metre). The lean mass index (LMI) was calculated as the ratio between total lean mass and height squared (kilograms per square metre). In JIA patients, the median of age was 13 years (6-19) and median disease duration was 84 months (10.0-215.0). The main disease subtype was polyarticular arthritis (54.8%). We observed that 61.9% of patients had normal Z-BMI. JIA girls had higher median Z-BMI scores (0.17 vs. -0.48, p = 0.034), total body fat percentages (26.5% vs. 16.4%, p = 0.001), truncal fat (4.52 vs. 2.32, p = 0.011) and FMI (4.83 vs. 2.23, p < 0.001). For LMI, there was no difference between JIA girls and controls (13.45 vs. 12.45, p = 0.212). We did not find association between FMI and age, disease subtype, number of limited and/or active joints, months since diagnosis and use of corticosteroids or methotrexate. BC changes found in JIA girls, such as fatness and adiposity, indicate a potentially greater risk for developing hypertension, diabetes mellitus and cardiovascular diseases. These findings emphasise the importance of evaluating nutritional status and body composition to minimise the emergence of chronic diseases later in life.


Improving access to acute stroke therapies: a controlled trial of organised pre-hospital and emergency care.
To assess the effectiveness of the PAST (Pre-hospital Acute Stroke Triage) protocol in reducing pre-hospital and emergency department (ED) delays to patients receiving organised acute stroke care, thereby increasing access to thrombolytic therapy. Prospective cohort study using historical controls. Hunter Region of New South Wales, September 2005 to March 2006 (pre-intervention) and September 2006 to March 2007 (post-intervention). Consecutive patients presenting with acute stroke to a regional, tertiary referral hospital. PAST protocol, comprising a pre-hospital stroke assessment tool for ambulance officers, an ambulance protocol for hospital bypass for potentially thrombolysis-eligible patients, and pre-hospital notification of the acute stroke team. Proportion of patients who received intravenous tissue plasminogen activator (tPA), process of care time points (symptom onset to ED arrival, ED arrival to tPA treatment, and ED transit time), and clinical outcomes of patients treated with tPA. The proportion of ischaemic stroke patients treated with tPA increased from 4.7% (pre-intervention) to 21.4% (post-intervention) (P < 0.001). Time point outcomes also improved, with a reduction in median times from symptom onset to ED arrival from 150 to 90.5 min (P = 0.004) and from ED arrival to stroke unit admission from 361 to 232.5 minutes (P < 0.001). Of those treated with tPA, 43% had minimal or no disability at 3 months. Organised pre-hospital and ED acute stroke care increases patient access to tPA treatment, which is proven to reduce stroke-related disability.


Whole-genome CRISPR screen identifies RAVER1 as a key regulator of RIPK1-mediated inflammatory cell death, PANoptosis.
Transforming growth factor-β-activated kinase 1 (TAK1) is a central regulator of innate immunity, cell death, inflammation, and cellular homeostasis. Therefore, many pathogens carry TAK1 inhibitors (TAK1i). As a host strategy to counteract this, inhibition or deletion of TAK1 induces spontaneous inflammatory cell death, PANoptosis, through the RIPK1-PANoptosome complex, containing the NLRP3 inflammasome and caspase-8/FADD/RIPK3 as integral components; however, PANoptosis also promotes pathological inflammation. Therefore, understanding molecular mechanisms that regulate TAK1i-induced cell death is essential. Here, we report a genome-wide CRISPR screen in macrophages that identified TAK1i-induced cell death regulators, including polypyrimidine tract-binding (PTB) protein 1 (PTBP1), a known regulator of RIPK1, and a previously unknown regulator RAVER1. RAVER1 blocked alternative splicing of Ripk1, and its genetic depletion inhibited TAK1i-induced, RIPK1-mediated inflammasome activation and PANoptosis. Overall, our CRISPR screen identified several positive regulators of PANoptosis. Moreover, our study highlights the utility of genome-wide CRISPR-Cas9 screens in myeloid cells for comprehensive characterization of complex cell death pathways to discover therapeutic targets.


Selection of Leptospirillum ferrooxidans SRPCBL and development for enhanced ferric regeneration in stirred tank and airlift column reactor.
Presence of Leptospirillum ferrooxidans plays significant role in ferric sulphate generation during bioleaching process. Thus, an attempt was made to select L. ferrooxidans from the polymetallic concentrate leachate and further developed it for enhanced ferric iron regeneration from the leachate in shake flask, stirred tank and column reactor. When ferric to ferrous iron ratio in the shake flask reached to 20:1, L. ferrooxidans out competed Acidithiobacillus ferrooxidans and accounted for more than 99% of the total population. The isolate was confirmed by 16S rRNA genes sequence analysis and named as L. ferrooxidans SRPCBL. When the culture was exposure to UV dose and the oxidation-reduction potential of the inoculation medium was adjusted to 40 0mV by ferrous:ferric iron ratio, the IOR reached to as high as 1.2 g/L/h in shake flask, even with initial ferrous iron concentration of 200 g/L. The chalcopyrite concentrate leachate containing 12.8, 15.7, and 42.0 g/L ferrous iron, ferric iron and copper, respectively was studied for ferric iron regeneration with the developed polymetallic resistant L. ferrooxidans SRPCBL in stirred tank and a developed biofilm airlift column, the highest IOR achieved were 2.20 g/L/h and 3.1 g/L/h, respectively, with ferrous oxidation efficiency of 98%. The ferric regeneration ability of the developed isolate from the leachate proves useful for a two-stage metal extraction process.


Implementing a chatbot on Facebook to reach and collect data from thousands of health care providers: PharmindBot as a case.
The world is moving fast toward digital transformation as we live in the artificial intelligence (AI) era. The COVID-19 pandemic accelerates this movement. Chatbots were used successfully to help researchers collect data for research purposes. To implement a chatbot on the Facebook platform to establish connections with health care professionals who had subscribed to the chatbot, provide medical and pharmaceutical educational content, and collect data for online pharmacy research projects. Facebook was chosen because it has billions of daily active users, which offers a massive potential audience for research projects. The chatbot was successfully implemented on the Facebook platform following 3 consecutive steps. Firstly, the ChatPion script was installed on the Pharmind website to establish the chatbot system. Secondly, the PharmindBot application was developed on Facebook. Finally, the PharmindBot app was integrated with the chatbot system. The chatbot responds automatically to public comments and sends subscribers private responses using AI. The chatbot collected quantitative and qualitative data with minimal costs. The chatbot's auto-reply function was tested using a post published on a specific page on Facebook. Testers were asked to leave predefined keywords to test its functionality. The chatbot's ability to collect and save data was tested by asking testers to fill out an online survey within Facebook Messenger for quantitative data and answer predefined questions for qualitative data. The chatbot was tested on 1000 subscribers who interacted with it. Almost all testers (n = 990, 99%) obtained a successful private reply from the chatbot after sending a predefined keyword. Also, the chatbot replied privately to almost all public comments (n = 985, 98.5%) which helped to increase the organic reach and to establish a connection with the chatbot subscribers. No missing data were found when the chatbot was used to collect quantitative and qualitative data. The chatbot reached thousands of health care professionals and provided them with automated responses. At a low cost, the chatbot was able to gather both qualitative and quantitative data without relying on Facebook ads to reach the intended audience. The data collection was efficient and effective. Using chatbots by pharmacy and medical researchers will help do more feasible online studies using AI to advance health care research.


Distribution of PSA-NCAM in normal, Alzheimer's and Parkinson's disease human brain.
Polysialated neural cell adhesion molecule (PSA-NCAM) is a membrane bound glycoprotein widely expressed during nervous system development. While commonly described in the neurogenic niches of the adult human brain, there is limited evidence of its distribution in other brain regions. PSA-NCAM is an important regulator of cell-cell interactions and facilitates cell migration and plasticity. Recent evidence suggests these functions may be altered in neurodegenerative diseases such as Alzheimer's (AD) and Parkinson's disease (PD). This study provides a detailed description of the PSA-NCAM distribution throughout the human brain and quantitatively compares the staining load in cortical regions and sub-cortical structures between the control, AD and PD brain. Our results provide evidence of widespread, yet specific, PSA-NCAM expression throughout the human brain including regions devoid of PSA-NCAM in the rodent brain such as the caudate nucleus (CN) and cerebellum (CB). We also detected a significant reduction in PSA-NCAM load in the entorhinal cortex (EC) of cases that was inversely correlated with hyperphosphorylated tau load. These results demonstrate that PSA-NCAM-mediated structural plasticity may not be limited to neurogenic niches and is conserved in the aged brain. We also provide evidence that PSA-NCAM is reduced in the EC, a region severely affected by AD pathology.


Ophthalmomyiasis interna posterior.
Ophthalmomyiasis interna posterior (OIP) means infection of the posterior part of the eye with the larvae of flies. Few cases have been reported in which the larvae have been removed from the eye and the visual acuity preserved. We report four cases of OIP with living larva in the vitreous cavity. The larvae produced severe uveitis and were removed alive with vitrectomy and a procedure for removing foreign bodies. They were identified as first-stage reindeer warble fly larvae (Oedemagena tarandi). We also observed dead larva in the vitreous cavity of a patient who suffered severe uveitis in 1943, and this eye survived with normal visual acuity. Another patient had a blind eye enucleated and the remnants of a larva were found inside the eye. All patients live in Scandinavia.


A simple and inexpensive technique for the measurement of head sway.
The paper presents a relatively simple and economic system for measuring human head sway. The recording device is a downward looking 35-mm still camera which photographs a flashing infrared light emitting diode (LED) that is mounted on the top of the head. The pictures so obtained are then digitized and fed into a computer for stabilometric analysis. If desired the film can be advanced continuously at an adjustable speed to obtain a deconvoluted recording.


The analysis of three markers flanking GJB2 gene suggests a single origin of the most common 35delG mutation in the Moroccan population.
In Caucasian populations a single mutation, 35delG, accounts for the majority of GJB2 gene mediated hearing loss, with carrier frequencies estimated between 2-4%, possibly resulting from a founder effect rather than from a mutational hot spot. In Moroccan population, the 35delG mutation accounts for 90.8% of all GJB2 mutated alleles in deaf patients with a carrier frequency of 2.65%. The aim of this study was to evaluate whether the 35delG mutation has derived from a single origin in the Moroccan population. We enrolled 30 unrelated deaf patients homozygous for the 35delG mutation and 165 unrelated control individuals negative for this mutation, and genotyped three microsatellite markers flanking the GJB2 region: D13S141, D13S175 and D13S143. Data analysis revealed that the 35delG mutation is associated with particular alleles of these markers, with significant linkage disequilibrium for the 125 and 105 nucleotide long alleles of D13S141 and D13S175, and that a single specific haplotype accounts for 68% of the chromosomes carrying the 35delG mutation. The estimate age of 35delG mutation is 135 generations or approximately 2700 years old. Like in other Mediterranean populations, our results suggest that in the Moroccan population the 35delG mutation has derived from a single origin in a common founder process.


Hedgehog signaling pathway regulates autophagy in human hepatocellular carcinoma cells.
Hedgehog (Hh) signaling plays an important role in embryonic development and in the regulation of a variety of cellular functions. Aberrant activation of Hh signaling has been implicated in several human cancers including hepatocellular carcinoma (HCC). In this study we examined the pathobiological functions and molecular mechanisms of the Hh signaling pathway in HCC cells. Treatment of cultured human HCC cells (Huh7, Hep3B, and HepG2) with the Hh signaling ligand (recombinant Shh) or agonist, SAG and purmorphamine, prevented the induction of autophagy. In contrast, GANT61 (a small molecule inhibitor of Gli1 and Gli2) induced autophagy, as determined by immunoblotting for microtubule-associated protein light chain 3 (LC3) and p62, GFP-LC3 puncta, monodansylcadaverine (MDC) staining, and transmission electron microscopy. Hh inhibition-induced autophagy was associated with up-regulation of Bnip3, as determined by immunoblotting and real-time polymerase chain reaction (PCR) assay. Knockdown of Bnip3 by RNAi impaired GANT61-induced autophagy. Additionally, Hh inhibition-induced autophagy was associated with Bnip3-mediated displacement of Bcl-2 from Beclin-1, as determined by immunoblotting and immunoprecipitation assays. Furthermore, inhibition of Hh signaling increased HCC cell apoptosis and decreased cell viability, as determined by caspase and WST-1 assays. Pharmacological or genetic inhibition of autophagy by 3-methyladenine (3-MA) or Beclin-1 small interfering RNA (siRNA) partially suppressed GANT61-induced cell apoptosis and cytotoxicity. In a tumor xenograft model using SCID mice inoculated with Huh7 cells, administration of GANT61 inhibited tumor formation and decreased tumor volume; this effect was partially blocked by the autophagy inhibitor, 3-MA. These findings provide novel evidence that Hh inhibition induces autophagy through up-regulation of Bnip3 and that this mechanism contributes to apoptosis. Therefore, the status of autophagy is a key factor that determines the therapeutic response to Hh-targeted therapies.


Cell-Internalization SELEX of RNA Aptamers as a Starting Point for Prostate Cancer Research.
In the treatment of cancer, over the last decade different drugs delivery systems have been developed to increase therapeutic specificity to improve drug's efficacy, and safety by increasing bioavailability. Among these systems, small nucleic acid molecules with a three-dimensional structure, known as aptamers, have shown several advantages. Several approaches to design aptamers require modifications from starting libraries of DNA sequences. Here, we describe cell-internalization SELEX (Systematic Evolution of Ligands by Exponential Enrichment), a sophisticated technique based on RNA aptamers as a starting point, that enables design functional aptamers as drug-delivery tools. This variation of the original SELEX technique using RNA aptamers instead DNA aptamers allows to obtain aptamers that are internalized in prostate cancer cells using as a starting point an RNA aptamer library with 76 nucleotides. The major advantage of this technique is that modifications are not required in the initial library, as initial T7 transcription promoter or 2'F nucleotides before sequencing.


Discovery of a monophagous true predator, a specialist termite-eating spider (Araneae: Ammoxenidae).
True predators are characterised by capturing a number of prey items during their lifetime and by being generalists. Some true predators are facultative specialists, but very few species are stenophagous specialists that catch only a few closely related prey types. A monophagous true predator that would exploit a single prey species has not been discovered yet. Representatives of the spider family Ammoxenidae have been reported to have evolved to only catch termites. Here we tested the hypothesis that Ammoxenus amphalodes is a monophagous termite-eater capturing only Hodotermes mossambicus. We studied the trophic niche of A. amphalodes by means of molecular analysis of the gut contents using Next Generation Sequencing. We investigated their willingness to accept alternative prey and observed their specific predatory behaviour and prey capture efficiency. We found all of the 1.4 million sequences were H. mossambicus. In the laboratory A. amphalodes did not accept any other prey, including other termite species. The spiders attacked the lateral side of the thorax of termites and immobilised them within 1 min. The paralysis efficiency was independent of predator:prey size ratio. The results strongly indicate that A. amphalodes is a monophagous prey specialist, specifically adapted to feed on H. mossambicus.


Evaluation of the implementation of an internet intervention in well-baby clinics: A pilot study.
Despite promising results, internet interventions are not widely accessible or well-integrated in health services. The objective of this study was, therefore, to examine the implementation of an internet intervention ('Mamma Mia') for the prevention of perinatal depression in Norwegian well-baby clinics (i.e., primary care). Mamma Mia begins in mid-pregnancy and lasts up to 6 months after childbirth. It consists of 44 online sessions, supported by midwives and public health nurses at up to 5 contact points during this period, following principles of empathic communication. Well-baby clinics offer free, universal services to all pregnant women and children aged 0 to 5 years in Norway and were recruited via an intermediary organization for this study. Data were collected at pre- and post-training, but before the delivery of Mamma Mia in clinics, and at 3 and 6 months follow-up. Quantitative and qualitative data were used to evaluate the training in Mamma Mia, examine program implementation (i.e., number of pregnant women registered for the program), and identify barriers and enablers of implementation. Twenty-four self-selected healthcare professionals from 14 well-baby clinics were recruited, for this study. Training increased participants' knowledge about Mamma Mia and exceeded their expectations. The program review and implementation plan were necessary training components. Implementation climate was related to the number of colleagues working with Mamma Mia and overall satisfaction with implementation, while characteristics of the intervention predicted the number of registered women at 6 months. Organizational re-structuring, leadership, and competing activities were identified as barriers to implementation that need to be considered further. The dissemination and implementation of a health-service supported internet intervention appears to be promising but requires further research.


Intestinal permeability assessment using lactulose and mannitol in celiac disease.
Alterations in intestinal permeability can lead to increased uptake of luminal antigens, which has been linked to several intestinal diseases, such as inflammatory bowel diseases, celiac disease, and irritable bowel syndrome, but also to extra-intestinal diseases. Promising therapies that target intestinal permeability could be developed, for instance tight junction modulators. Consequently, permeability assays are increasingly being used as treatment endpoints in clinical studies. Therefore, reliable, reproducible, and feasible methods for measuring intestinal permeability in the clinical setting are necessary. Currently, a variety of in vivo, ex vivo, and in vitro tests are available, some of which are only applicable to basic research. Despite the various options available to measure gut permeability, their use in clinical setting is still limited because of their heterogeneity. Here, we describe a clinical method to measure intestinal permeability using two non-metabolizable sugars.


Extensive ablation during pulmonary vein antrum isolation has no adverse impact on left atrial function: an echocardiography and cine computed tomography analysis.
Although pulmonary vein antrum isolation (PVAI) may cure atrial fibrillation (AF) and improve left atrial (LA) function, the effect of extensive LA ablation on LA function is not well known. To assess the impact of PVAI on LA function remotely postablation. Consecutive patients undergoing PVAI had either transthoracic (TTE) and transesophageal (TEE) echocardiography (n = 41) or cine EBCT (n = 26) performed preablation and 6 months postablation. Only patients with paroxysmal and persistent, but not permanent, AF were included. Imaging was done in sinus rhythm for all patients. LA diameter (LAD), LA systolic and diastolic areas, and left atrial fractional area change (LFAC) were assessed by TTE. Transmitral (TMF), left atrial appendage (LAA), and pulmonary venous (PVF) Doppler flows were measured by TEE. Peak A on TMF, LAA peak emptying velocity (LAAF), and peak A reversal (AR) on PVF were used as surrogates of LA contractile function. Peak S on PV flow was used as a surrogate of reservoir function. LA areas, volumes, and LA ejection fraction (LAEF) were measured from cine EBCT. Mean radiofrequency ablation time was 45 +/- 21 minutes. All four PVs were isolated for all patients; there were no cases of PV stenosis. Echocardiography revealed a significant reduction in LAD and LA areas post-PVAI. Both peak A and peak AR were also higher post, while other variables showed strong trends toward improvement. In the subset of patients with persistent AF, post-PVAI improvements were seen in LA size, peak A, and even peak S (P = 0.04). Cine EBCT showed a significant decrease in both LA areas and volumes post-PVAI. There was also a significant improvement in LAEF post-PVAI from 17 +/- 6% to 22 +/- 5% (P = 0.01). Extensive ablation during PVAI does not cause deterioration in LA function, and may cause long-term improvement, especially in patients with higher AF burden.


"Watchful waiting" for metastatic colorectal cancer, antediluvian or an option to be considered again?
The role of chemotherapy in metastatic colorectal cancer (mCRC) is firmly established and the option of watchful waiting (WW) has become an alternative rarely considered. However, there may be a group of patients who are diagnosed with low volume and asymptomatic disease and who may be suitable for a WW plan. From the South Australian Cancer Registry for mCRC we examined cancer characteristics and outcomes of patients who were suitable for chemotherapy but had their treatment delayed by more than 3 months from diagnosis of metastatic disease. Data from 417 mCRC patients who received chemotherapy as first intervention have been entered in the Registry to date and 38 (9.1%) had chemotherapy commencement delayed by more than 3 months from diagnosis. Their median age was 76.7 years (range 38-85). Overall 87% of patients had metachronous metastatic cancer with a median time to recurrence of 2.1 years (range 0.53-7.71) and 65.5% had single organ metastasis. Median delay from the diagnosis of metastatic disease to chemotherapy was 5.03 months (range 3-28). The median survival has yet to be reached. The 2-year overall survival is 65%. We found that almost 10% of all patients with mCRC had a delay in the initiation of chemotherapy, with most due to a WW approach based on case note review. Patients with a delay in chemotherapy initiation are more likely to have a single organ site of metastatic disease and are older than those who do not. Despite the treatment delay, there is no evidence of a negative impact on survival.


Characterization of the human blood plasma proteome.
We describe methods for broad characterization of the human plasma proteome. The combination of stepwise immunoglobulin G (IgG) and albumin protein depletion by affinity chromatography and ultrahigh-efficiency capillary liquid chromatography separations coupled to ion trap-tandem mass spectrometry enabled identification of 2392 proteins from a single plasma sample with an estimated confidence level of > 94%, and an additional 2198 proteins with an estimated confidence level of 80%. The relative abundances of the identified proteins span a range of over eight orders of magnitude in concentration (< 30 pg/mL to approximately 30 mg/mL), facilitated by the attomole-level sensitivity of the analysis methods. More than 80% of the observed proteins demonstrate interactions with IgG and/or albumin, and the human plasma protein loss in the affinity chromatography/strong cation exchange/reversed-phase liquid chromatography-tandem mass spectrometry methodology was investigated in detail. The results of this study provide a basis for a wide range of plasma proteomics studies, including broad quantitation of relative abundances in comparative studies of the identification of novel protein disease markers, as well as further studies of protein-protein interactions.


Importance of continuous chest compressions during cardiopulmonary resuscitation: improved outcome during a simulated single lay-rescuer scenario.
Interruptions to chest compression-generated blood flow during cardiopulmonary resuscitation (CPR) are detrimental. Data show that such interruptions for mouth-to-mouth ventilation require a period of "rebuilding" of coronary perfusion pressure to obtain the level achieved before the interruption. Whether such hemodynamic compromise from pausing to ventilate is enough to affect outcome is unknown. Thirty swine (weight 35 +/- 2 kg) underwent 3 minutes of untreated ventricular fibrillation before 12 minutes of basic life support CPR. Animals were randomized to receive either standard airway (A), breathing (B), and compression (C) CPR with expired-gas ventilation in a 15:2 compression-to-ventilation ratio or continuous chest compression CPR. Those randomized to the standard 15:2 group had no chest compressions for a period of 16 seconds each time the 2 ventilations were delivered. Defibrillation was attempted at 15 minutes of cardiac arrest. All resuscitated animals were supported in an intensive care environment for 1 hour, then in a maintenance facility for 24 hours. The primary end point of neurologically normal 24-hour survival was significantly better in the experimental group receiving continuous chest compression CPR (12 of 15 versus 2 of 15; P<0.0001). Mouth-to-mouth ventilation performed by single layperson rescuers produces substantial interruptions in chest compression-supported circulation. Continuous chest compression CPR produces greater neurologically normal 24-hour survival than standard ABC CPR when performed in a clinically realistic fashion. Any technique that minimizes lengthy interruptions of chest compressions during the first 10 to 15 minutes of basic life support should be given serious consideration in future efforts to improve outcome results from cardiac arrest.


Biological early warning system based on the responses of aquatic organisms to disturbances: a review.
Aquatic ecosystems are subject to a number of anthropogenic disturbances, including environmental toxicants. The efficient monitoring of water resources is fundamental for effective management of water quality and aquatic ecosystems. Spot sampling and continuous water quality monitoring based on physicochemical factors are conducted to assess water quality. However, not all contaminants or synergistic and antagonistic toxic effects can be determined by solely analyzing the physicochemical factors. Thus, various biotests have been developed using long-term and automatic observation studies based on the ability of the aquatic organisms to continuously sense a wide range of pollutants. In addition, a biological early warning system (BEWS) has been developed based on the response behaviors of organisms to continuously detect a wide range of pollutants for effective water quality monitoring and management. However, large amounts of data exhibiting non-linearity and individual behavioral variation are continuously accumulated over long-term and continuous behavioral monitoring studies. Thus, appropriate mathematical and computational data analyses are necessary to manage and interpret such large datasets. Here, we review the development and application of BEWS by using various groups of organisms and the computational methods used to process the behavioral monitoring data.


Risk of breast cancer two years after a benign biopsy depends on the mammographic feature prompting recall.
We aimed to explore whether the type of mammographic feature prompting a false-positive recall (FPR) during mammography screening influences the risk and timing of breast cancer diagnosis, particularly if assessed with invasive procedures. We included information on women screened and recalled for further assessment in Spain between 1994 and 2015, with follow-up until 2017, categorizing FPRs by the assessment (noninvasive or invasive) and mammographic feature prompting the recall. Breast cancer rates in the first two years after FPR (first period) and after two years (second period). The study included 99,825 women with FPRs. In both periods, the breast cancer rate was higher in the invasive assessment group than in the noninvasive group (first period 12 ‰ vs 1.9 ‰, p < 0.001; second period 4.4‰ vs 3.1‰, p < 0.001). During the first period, the invasive assessment group showed diverse breast cancer rates for each type of mammographic feature, with a higher rate for asymmetric density (31.9‰). When the second period was compared with the first, the breast cancer rate decreased in the invasive assessment group (from 12‰ to 4.4‰, p < 0.001) and increased in the noninvasive assessment group (from 1.9‰ to 3.1‰, p < 0.001). In the context of mammography screening, the risk of breast cancer diagnosis during the first two years after FPR was particularly high for women undergoing invasive assessment; importantly, the risk was modified by type of mammographic feature prompting the recall. This information could help to individualize follow-up after exclusion of malignancy.


A quest for meaning: A qualitative exploration among children with advanced cancer and their parents.
Meaning-making may assist individuals in adaptation to stressful life events, particularly bereavement. However, few studies have examined meaning-making among pediatric populations with advanced illness to understand how this process unfolds before the child's death. This study explores meaning-making pre-bereavement among children with advanced cancer and their parents. As part of a larger study examining shared decision-making near the end of life, 24 children with advanced cancer and/or high-risk cancer, 26 mothers, and 11 fathers participated in individual, semi-structured interviews. Analyses focused on questions regarding meaning-making. Four coders analyzed the data via directed content analysis. Three major meaning-making themes emerged: (1) sense-making (i.e., unknown, no sense/meaning, religious/spiritual explanations, scientific explanations), (2) benefit-finding, and (3) purpose/legacy. Some stated they were unable to make sense of the diagnosis, because there was no reason, they were not there yet, or they were dealing with the situation and moving forward. Others reported finding meaning through spiritual and scientific explanations. Many identified benefits related to the child's illness, such as personal growth and stronger relationships. Some parents expressed their purpose in life was to live for their children, while others shared their child's legacy as a way to find meaning. Our findings highlight the struggle children and parents often face when attempting to make sense of the child's advanced or high-risk illness. Clinicians might consider if meaning-centered interventions designed for use in adults at the end of life and bereaved parents may be helpful for children with advanced or high-risk cancer and their parents.


[Training simulation during the announcement of fetal malformation discovered on screening ultrasound: Results of a pilot study].
Breaking bad news (BBN) to a pregnant woman with fetal abnormalities (FA) on ultrasound (US) examination is a challenge. Announcement technique influences patient reaction. Physicians receive little training in BBN. The simulation and using a BBN protocol as the English SPIKES protocol which guides the announcement consultation according to 6 steps (Setting Up, Perception, Invitation, Knowledge, Emotions and Empathy, Strategy and Summary) can be used for this teaching. The objective was to assess feasibility simulation scenarii of BBN for FA discovered during US and to evaluate the usefulness of SPIKES protocol in this situation. Two scenarios have been created combining US simulator (US Mentor, Symbionix®) with simulated patient (SP). Scenarii objectives were to diagnose FA and break it to SP. Checklist derived from SPIKES was fulfilled by two investigators thanks to video recording, the SP and every participant (residents, physicians, fetal medicine specialists [FMS]). Participants filled out survey about the usefulness of this exercise too. Nine physicians (3 residents, 4 physicians, 2 FMS) produced 18 scenarii. Seventy-eight percent of physicians thought simulation was like real situation of BBN during US examination. Majority of participant (88%) found that this simulation training could help them to increase their ability to BBN and that it can be used to teach residents (89%) or physicians (100%). FMS had better SPIKES checklist than physicians (P<0,05). Simulation scenario of BBN for FA discovered during US is feasible by combining US simulator and SP. SPIKES protocol can be useful but a validated checklist should be created.


[Epithelial-mesenchymal transition and tumor drug resistance].
Resistance to antineoplastic drugs is a common problem in cancer treatments. Epithelial-mesenchymal transition (EMT), which plays an important role in the process of drug resistance, may provide opportunity to solve this problem. This article reviews the characteristics of EMT, relationship between EMT and drug resistance, mechanism of EMT in tumor drug resistance in details.


Eosinophilic alveolitis in immunologic interstitial lung disorders.
To analyze the role of eosinophils in alveolitis due to immunological interstitial lung disorders, 568 bronchoalveolar lavage (BAL) from 537 patients affected by 13 types of interstitial lung disease involving immunologic mechanisms were considered. An arbitrary cut-off of 4% of eosinophils in BAL was assumed. In five (idiopathic pulmonary fibrosis (IPF), allergic bronchopulmonary aspergillosis (ABPA), amiodarone-induced pneumonitis (AIP), chronic eosinophilic pneumonia (CEP), Churg-Strauss syndrome (CSS)) out of the thirteen groups we took into consideration, the level of eosinophils was greater than 4%. In CEP and CSS in particular, the arbitrary cut-off of 4% was greatly exceeded (28.9% +/- 27.4, p less than 0.01 and 33.6% +/- 14.5, p less than 0.01, respectively). In the same two groups the increase of eosinophils in BAL was isolated with a direct correlation to the number of eosinophils in blood. By contrast, the increase of eosinophils in BAL of IPF, AIP and ABPA was of lesser extent (4.7% +/- 5.7 p less than 0.01, 5.0% +/- 3.0 p less than 0.01 and 6.1% +/- 10.4 p less than 0.01, respectively) and was accompanied by an increase of neutrophils in IPF, of lymphocytes in AIP and both in ABPA. These patterns are generally defined as "mixed alveolitis." On the basis of these data we conclude that the term "eosinophilic alveolitis" should be reserved for CEP and CSS.


Neurofeedback and neuroplasticity of visual self-processing in depressed and healthy adolescents: A preliminary study.
Adolescence is a neuroplastic period for self-processing and emotion regulation transformations, that if derailed, are linked to persistent depression. Neural mechanisms of adolescent self-processing and emotion regulation ought to be targeted via new treatments, given moderate effectiveness of current interventions. Thus, we implemented a novel neurofeedback protocol in adolescents to test the engagement of circuits sub-serving self-processing and emotion regulation. Depressed (n = 34) and healthy (n = 19) adolescents underwent neurofeedback training using a novel task. They saw their happy face as a cue to recall positive memories and increased displayed amygdala and hippocampus activity. The control condition was counting-backwards while viewing another happy face. A self vs. other face recognition task was administered before and after neurofeedback training. Adolescents showed higher frontotemporal activity during neurofeedback and higher amygdala and hippocampus and hippocampi activity in time series and region of interest analyses respectively. Before neurofeedback there was higher saliency network engagement for self-face recognition, but that network engagement was lower after neurofeedback. Depressed youth exhibited higher fusiform, inferior parietal lobule and cuneus activity during neurofeedback, but controls appeared to increase amygdala and hippocampus activity faster compared to depressed adolescents. Neurofeedback recruited frontotemporal cortices that support social cognition and emotion regulation. Amygdala and hippocampus engagement via neurofeedback appears to change limbic-frontotemporal networks during self-face recognition. A placebo group or condition and contrasting amygdala and hippocampus, hippocampi or right amygdala versus frontal loci of neurofeedback, e.g. dorsal anterior cingulate cortex, with longer duration of neurofeedback training will elucidate dosage and loci of neurofeedback in adolescents.


Challenges and Opportunities for Quantitative Clinical Pharmacology in Cancer Immunotherapy: Something Old, Something New, Something Borrowed, and Something Blue.
Cancer immunotherapy (CIT) initiates or enhances the host immune response against cancer. Following decades of development, patients with previously few therapeutic options may now benefit from CIT. Although the quantitative clinical pharmacology (qCP) of previous classes of anticancer drugs has matured during this time, application to CIT may not be straightforward since CIT acts via the immune system. Here we discuss where qCP approaches might best borrow or start anew for CIT.


Region-specific and state-dependent action of striatal GABAergic interneurons.
Striatum processes a wide range of functions including goal-directed behavior and habit formation, respectively encoded by the dorsomedial striatum (DMS) and dorsolateral striatum (DLS). GABAergic feedforward inhibition is known to control the integration of cortical information by striatal projection neurons (SPNs). Here we questioned whether this control is specific between distinct striatal functional territories. Using opto-activation and opto-inhibition of identified GABAergic interneurons, we found that different circuits are engaged in DLS and DMS, both ex vivo and in vivo: while parvalbumin interneurons efficiently control SPNs in DLS, somatostatin interneurons control SPNs in DMS. Moreover, both parvalbumin and somatostatin interneurons use a dual hyperpolarizing/depolarizing effect to control cortical input integration depending on SPN activity state: GABAergic interneurons potently inhibit spiking SPNs while in resting SPNs, they favor cortical activity summation via a depolarizing effect. Our findings establish that striatal GABAergic interneurons exert efficient territory-specific and state-dependent control of SPN activity and functional output.


Acute Peritoneal Dialysis During the COVID-19 Pandemic at Bellevue Hospital in New York City.
The COVID-19 pandemic strained hospital resources in New York City, including those for providing dialysis. New York University Medical Center and affiliations, including New York City Health and Hospitals/Bellevue, developed a plan to offset the increased needs for KRT. We established acute peritoneal dialysis (PD) capability, as usual dialysis modalities were overwhelmed by COVID-19 AKI. Observational study of patients requiring KRT admitted to Bellevue Hospital during the COVID surge. Bellevue Hospital is one of the largest public hospitals in the United States, providing medical care to an underserved population. There were substantial staff, supplies, and equipment shortages. Adult patients admitted with AKI who required KRT were considered for PD. We rapidly established an acute PD program. A surgery team placed catheters at the bedside in the intensive care unit; a nephrology team delivered treatment. We provided an alternative to hemodialysis and continuous venovenous hemofiltration for treating patients in the intensive-care unit, demonstrating efficacy with outcomes comparable to standard care. From April 8, 2020 to May 8, 2020, 39 catheters were placed into ten women and 29 men. By June 10, 39% of the patients started on PD recovered kidney function (average ages 56 years for men and 59.5 years for women); men and women who expired were an average 71.8 and 66.2 years old. No episodes of peritonitis were observed; there were nine incidents of minor leaking. Some patients were treated while ventilated in the prone position. Demand compelled us to utilize acute PD during the COVID-19 pandemic. Our experience is one of the largest recently reported in the United States of which we are aware. Acute PD provided lifesaving care to acutely ill patients when expanding current resources was impossible. Our experience may help other programs to avoid rationing dialysis treatments in health crises.


Association of PLT specificity of alloreactive lymphocyte clones with HLA-DR, MB and MT determinants.
The HLA-D region encodes for several serologically defined systems, including DR, MB, and MT. The antigens of MB and MT are strongly associated with two or more DR specificities. The purpose of this study was to determine the role of MB and MT antigens in lymphocyte alloactivation. A soft agar colony assay was used to generate alloreactive lymphocyte clones primed in mixed leukocyte culture against a stimulator who typed as HLA-DR4,-;MB3,-;MT3,-. In secondary primed lymphocyte typing (PLT) assays, several clones were identified with PLT specificities strongly associated with DR4, MB3, or MT3. The data suggest that HLA-D controls different lymphocyte-activating determinants associated with the serologically defined DR, MB, or MT antigens.


A lethal neonatal dwarfing condition with short ribs, polysyndactyly, cranial synostosis, cleft palate cardiovascular and urogenital anomalies and severe ossification defect.
A case of severe lethal neonatal dwarfism is reported. It appears to be a new variety of short rib-polydactyly dwarfism. It is characterized by severe lack of ossification of all bones except the clavicle and the presence of cleft palate, as well as genitourinary, central nervous system and cardiovascular anomalies. Electronmicroscopy revealed accumulations of granular material in the chondrocytes.


Different isoforms of the C. elegans FGF receptor are required for attraction and repulsion of the migrating sex myoblasts.
The Caenorhabditis elegans FGF receptor, EGL-15, is alternatively-spliced to yield two major isoforms that differ in their extracellular domains. The EGL-15(5A) isoform is necessary for the gonadal chemoattraction of the migrating sex myoblasts (SMs), while the EGL-15(5B) isoform is required for viability. Here we show that 5A is predominantly expressed in the M lineage, which gives rise to the migrating SMs and their sex muscle descendants, while 5B is predominantly expressed in the hypodermis. Tissue-specific expression, however, explains only part of the functional differences between these two receptor isoforms. 5A can carry out the reciprocal essential function of 5B when expressed in the hypodermis, but 5B is incapable of carrying out SM chemoattraction. Our data, therefore, indicate that the structural differences in these two isoforms contribute to their functional differences. Two lines of evidence indicate that the 5B isoform also plays a role in SM migration, implicating it in the repulsion that is observed when the chemoattraction is compromised. Thus, structural differences in the extracellular domains of these two isoforms can specify either attraction to or repulsion from the gonad.


The Development Impacts of COVID-19 at Home and Abroad: Politics and Implications of Government Action.
What is COVID-19's impact on development? What lessons can be drawn from development studies regarding the effects of and recovery from COVID-19? The unprecedented scale and scope of government interventions carry implications at all levels: global, national, and local. In this introduction, our team of Editors underline the importance of systematic substantive study to further knowledge acquisition, and rigorous global-, national-, or context-specific evaluation to inform evidence-based policymaking. The 12 articles summarised here capture these values and sense of "high quality". In particular, despite early considerations in the first year of the pandemic, they illuminate the need for diverse responses beyond business-as-usual, attention to the multiplicity of impact of policies formulated, and progressive strategies to counteract the impacts of this disaster around the world. The path of future research is clear: studies need to consider and give voice to marginalised groups to counteract the short- and long-term impacts of the pandemic.


Impact of preoperative laboratory frailty index on mortality and clinical outcomes in older surgical patients with cancer.
Frailty in older patients is associated with poor postoperative outcomes. The use of uncomplicated frailty measurement tools is preferred in busy clinical settings. Therefore, we validated the frailty index using routine laboratory data and the surgical outcomes of older patients with cancer who underwent cancer resection. We retrospectively analyzed 9015 patients aged 65 years and older who underwent cancer resection at a single tertiary hospital. Based on electronic-medical-record data regarding preoperative blood test results and vital signs, Laboratory Frailty Index (FI-Lab) scores were generated to measure preoperative frailty. The associations of FI-Lab with postoperative length of stay (LOS), readmission within 30 days, intensive care unit (ICU) admission within 30 days, and mortality were evaluated. The mean FI-Lab score of the 9015 patients was 0.20 ± 0.10. Increased FI-Lab scores (0.25-0.4; > 0.4) were associated with longer LOS, increased readmission within 30 days of surgery, ICU admission, and increased mortality, compared with FI-Lab scores < 0.25. The FI-Lab score, as a frailty indicator, was able to predict the risk of poor postoperative outcomes. Therefore, the FI-Lab is a potentially useful tool for assessing preoperative frailty in older patients with cancer in acute clinical setting.


Clinical Features of Genetic Cardiac Diseases Related to Potassium Channelopathies.
Genetic cardiac diseases related to potassium channelopathies are a group of relatively rare syndromes that includes long QT syndrome, short QT syndrome, Brugada syndrome, and early repolarization syndrome. Patients with these syndromes share a propensity for the development of life-threatening ventricular arrhythmias in the absence of significant cardiac structural abnormalities. Familial atrial fibrillation has also been associated with potassium channel dysfunction but differs from the other syndromes by being a rare cause of a common condition. This article focuses on the clinical features, diagnosis, and management of these syndromes.


Viscoelastic clot strength predicts coagulation-related mortality within 15 minutes.
Predicting refractory coagulopathy early in resuscitation of injured patients may decrease a leading cause of preventable death. We hypothesized that clot strength (G) measured by point-of-care rapid thrombelastography (r-TEG) on arrival in the emergency department can predict massive transfusion (MT) and coagulation-related mortality (MT-death). Trauma alerts/activations from May 2008 to September 2010 were reviewed. The variables included the following: age, sex, injury severity score (ISS), systolic blood pressure (SBP), base deficit (BD), traditional coagulation tests (international normalized ratio ([INR], partial thromboplastin time [PTT]), TEG-derived G, and blood products transfused within the first 6 hours. Independent predictors of 2 outcomes (MT [≥10 packed red blood cells units/6 h] and MT-related death) were identified using logistic regression. The individual predictive values of BD, INR, PTT, and G were assessed comparing the areas under the receiver operating characteristic curves (AUC ROC), while adjusting for age, ISS, and SBP. Among the 80 study patients, 48% required MT, and 21% died of MT-related complications. INR, ISS, and G were independent predictors of MT, whereas age, ISS, SBP, and G were independently associated with MT-death. The predictive power for outcome MT did not differ among INR (adjusted AUC ROC = 0.92), PTT (AUC ROC = 0.90, P = .41), or G (AUC ROC = 0.89, P = .39). For outcome MT-death, G had the greatest adjusted AUC ROC (0.93) compared with the AUC ROC for BD (0.87, P = .05), INR (0.88, P = .11), and PTT (0.89; P = .19). These data suggest that the point-of-care TEG parameter clot strength (G) provides consistent, independent prediction of MT and MT-death early in the resuscitation of injured patients.


Predominant type-2 response in infants with respiratory syncytial virus (RSV) infection demonstrated by cytokine flow cytometry.
Acute RSV infection in infancy may produce some asthma-like symptoms and may be followed by a recurrent wheeze later in childhood. It has been proposed that RSV infection stimulates type-2 cytokine responses, resembling those found in atopy and asthma. Peripheral blood cells were obtained from RSV-infected infants (n = 30) and healthy controls (n = 10). After in vitro restimulation of the cells, intracellular IL-4 and interferon-gamma (IFN-gamma) were measured by flow cytometry. The cells from RSV-infected infants produced more IL-4 and less IFN-gamma than those from healthy controls. IL-4 production was more frequent in CD8 than in CD4 cells, and the bias toward IL-4 production was greatest in infants with mild infections, whereas IFN-gamma production increased with disease severity. Our conclusions are that RSV infection is associated with IL-4 production in peripheral T cells, and that peripheral blood in infants with severe disease may be depleted of cytokine-producing cells.


Mitochondrial interference by anti-HIV drugs: mechanisms beyond Pol-γ inhibition.
The combined pharmacological approach to the treatment of HIV infection, known as highly active antiretroviral therapy (HAART), has dramatically reduced AIDS-related morbidity and mortality. However, its use has been associated with serious adverse reactions, of which those resulting from mitochondrial dysfunction are particularly widespread. Nucleos(t)ide-reverse transcriptase inhibitors (NRTIs) have long been considered the main source of HAART-related mitochondrial toxicity due to their ability to inhibit Pol-γ, the DNA polymerase responsible for the synthesis of mitochondrial DNA. Nevertheless, accumulating evidence points to a more complex relationship between these organelles and NRTIs. Also, alternative pathways by which other groups of anti-HIV drugs (non-nucleoside reverse transcriptase inhibitors and protease inhibitors) interfere with mitochondria have been suggested, although their implications, both pharmacological and clinical, are open to debate. This review aims to provide a comprehensive overview of the mechanisms and factors which influence the mitochondrial involvement in the toxicity of all three major classes of anti-HIV drugs.


Standardization of heparins by means of high performance liquid chromatography equipped with a low angle laser light scattering detector.
This study shows that HPLC-LALLS (high performance liquid chromatography with a light-scattering detector) is a convenient and reliable method for the characterization of standard heparin samples, provided that polyelectrolyte artefacts are suppressed by a suitable dialysis procedure. The method has been successfully applied to the assessment of calibrated relations like the Mark-Houwink relation and the calibration curve of gel permeation chromatography. Furthermore, this study confirms that gel permeation chromatography for heparins cannot be calibrated with dextranes or polyethyleneglycols, but in addition to this well known fact it is shown that even the universal (hydrodynamic volume) calibration procedure does not work. Moreover, in addition to the familiar conclusion that heparins should be calibrated with heparins, it is shown that calibrated relations are valid only when the calibration has been made with heparin samples of the same origin (i.e. same tissue source, same animal source, and same purification scheme).


Thrombocytopaenia in antiphospholipid syndrome: a free radical perspective.
Thrombosis associated with thrombocytopaenia is an apparent paradox that is present across a wide spectrum of disorders. While thrombocytopaenia has been a controversial clinical classification criterion for APS, as initial reports failed to demonstrate a relation between low platelet count with other clinical or laboratory manifestations of the syndrome, recent data highlight the association between mild-moderate thrombocytopaenia and the risk of thrombosis. Although aPL antibodies may induce platelet activation in vitro, additional stimuli may contribute to their activation in vivo, among which are reactive oxygen and nitrogen species and lipid peroxidation products, which are elevated in patients with APS; an excess of the same stimuli may induce megakaryocyte and platelet apoptosis that leads to decreased platelet production and increased destruction, resulting ultimately in thrombocytopaenia. Herein we provide a novel plausible framework involving free radicals that could add to the understanding of the thrombocytopaenia-thrombosis paradox in APS.


Cannabinoid Hyperemesis Syndrome in a 17-Year-Old Adolescent.
Cannabis is the most widely used illicit drug in the world. In Canada, cannabis use has been decreasing among youth since 2008. However, it is still two times more prevalent than among adults. A distinct syndrome, characterized by recurrent vomiting associated with abdominal pain and compulsive bathing, has been increasingly recognized in chronic adult users. The cannabinoid hyperemesis syndrome (CHS) is still underdiagnosed among adults and even more among adolescents. The authors describe the case of a 17-year-old adolescent, who sought emergency care five times over a year for uncontrolled nausea, profuse vomiting, and weight loss. The patient's symptoms were ameliorated by repetitive hot showering and by avoiding cannabis use. Cannabinoid hyperemesis syndrome is a clinical diagnosis and should be consider in every case of cyclical vomiting. A review of the clinical aspects and the treatment is presented here.


Anterior distal femoral hemiepiphysiodesis with and without patellar tendon shortening for fixed knee flexion contractures in children with cerebral palsy.
Surgery is often required for fixed knee flexion contractures in patients with neuromuscular conditions. Anterior distal femoral hemiepiphysiodesis (ADFH) is an alternative to distal femoral extension osteotomy (DFEO) in skeletally immature patients. ADFH is typically not accompanied by patellar tendon shortening surgery (PTS). Our purpose was to compare ADFH alone versus ADFH with PTS for treatment of fixed knee flexion contractures and crouched gait in children with cerebral palsy (CP). Retrospective review of pre- and postoperative gait analysis data for children with CP who underwent ADFH alone, or ADFH with PTS. Data were analysed using linear mixed models to control for covariates. In total, 25 participants (42 limbs) were included, 17 male and eight female, mean age at surgery 12.9 (sd 1.9) years. Both groups experienced significant improvement in popliteal angle, knee extension range of motion (ROM) and knee extension in stance phase. Greater improvement was seen for all variables in the ADFH/PTS group, mainly due to greater popliteal angle and knee flexion during gait preoperatively in that group (p ≤ 0.02) rather than the procedure performed (p ≥ 0.19). There was no difference between groups postoperatively. Rate of contracture resolution was 0.5° to 1.0° per month, faster in larger contractures (p = 0.02). ADFH with and without PTS is effective in improving knee extension in skeletally immature patients with CP, correcting contractures at a rate of 0.5° to 1.0° per month. Combined ADFH and PTS surgery may be preferable in patients with larger contractures of up to 30° to 35°. III.


Influence of assembly procedure and material combination on the strength of the taper connection at the head-neck junction of modular hip endoprostheses.
A stable fixation between femoral head and endoprosthesis taper is necessary to prevent relative motions and corrosion at the taper junction. Although the importance of the component assembly has been recognised, no definitive instructions are available. The purpose of this study was to assess the influence of assembly force, assembly tool and number of hammer strokes on the taper junction strength of various material combinations. Co-Cr29-Mo (n=10) and Ti-6Al-4V (n=10) neck tapers were assembled with Co-Cr and Al(2)O(3) ceramic heads either by push-on or by impaction with single or multiple hammer blows. The strength of the taper-head connection was evaluated by measuring the head pull-off forces according to ISO 7206-10 and the turn-off moment capacity. The taper strength linearly increased with assembly forces (P<0.001). Co-Cr heads combined with Co-Cr tapers showed significantly lower pull-off forces and turn-off moments than the combination with Ti tapers (0.001<P<0.025). Multiple impaction did not increase taper strength (0.063 <P<0.995). Ceramic and Co-Cr heads showed similar fixation patterns on Ti tapers. Turn-off moments varied between 6 Nm and 19 Nm, dependent on material combination and assembly force. It is suggested that sufficient head-taper junction strength in all bearing conditions is achieved by impaction forces of at least 4 kN. A single impact is sufficient to achieve fixation. Special attention should be paid to the assembly of Co-Cr heads on Co-Cr tapers.


Relationship between gallamine plasma concentration and neuromuscular paralysis in surgical patients.
The pharmacodynamics of the neuromuscular blocking drug gallamine were investigated in 10 surgical patients using a constant-rate infusion regimen, and results are compared to those for d-tubocurarine (dTc). Gallamine effect (paralysis)-time data gathered during and following the infusion were fitted to a pharmacodynamic effect model, while paralysis-plasma concentration data gathered during (onset) and following (offset) the infusion were fitted separately to a nonlinear form of the Hill equation. The effect model was most appropriate in characterizing the combined (on and off infusion) effect data. While there was also an excellent characterization of onset and offset data with the Hill equation, the two effect-concentration curves were not superimposable. The mean (+/- S.D.) plasma concentration of gallamine at 50 per cent paralysis during onset of action (Cp50(onset) 8.0 +/- 1.8 micrograms/ml) or that predicted to exist at steady state using the effect model (Cp50(ss) 5.4 +/- 1.4 micrograms/ml). Cp50(offset) and Cp50(ss) did not differ significantly, and there was no significant difference in the power factor (lambda) estimates for the various model fits. Comparison of the pharmacodynamic parameters for gallamine and dTc using the effect model revealed no significant differences in keo, t1/2(keo), and lambda estimates. However, Cp50(ss) for gallamine (5.4 +/- 1.4 micrograms/ml) was nine times higher than that for dTc (0.61 +/- 0.15 micrograms/ml) in absolute terms and seven times higher when compared on a molar basis.


Rotation of the terminal ileum in laparoscopic right hemicolectomy.
This case report describes rotation of the terminal ileum in a patient who had a laparoscopic right hemicolectomy. To prevent this complication, the terminal ileum should be inspected laparoscopically for rotation before exteriorization of the terminal ileum and, in addition, after completion of the anastomosis.


The actions of two monoamines on spinal motoneurons from stimulation of the locus coeruleus in the cat.
The present study investigates the role of the two putative amine transmitters (norepinephrine and serotonin) in mediating the facilitatory action following locus coeruleus (LC) stimulation on hindlimb flexor and extensor monosynaptic reflexes (MSRs) in unanesthetized, decerebrate cats. When administered sequentially, in either order, methysergide (a serotonergic blocker) and prazosin (an alpha 1-adrenergic blocker) were observed to cause subtotal, decremental changes in the potentiation of gastrocnemius-soleus and common peroneal MSRs by stimuli applied in the LC. These changes were determined to be independent of the blood pressure changes induced by the aminergic blockers. These results support the hypothesis that the facilitation of the group Ia reflex transmission in cat spinal cord by stimulation of LC is mediated in part by alpha 1-noradrenergic and serotonergic mechanisms.


Versorgung geriatrischer Krankheitsbilder unter ausgewählten ambulanten Facharztgruppen: Kombination von Befragungs- und GKV-Routinedaten zur Abbildung des Leistungsgeschehens.
In light of an aging population, the German health system faces the challenge of adapting regional health care structures to the changing care needs of geriatric patients. Since geriatric care is interprofessional, a structural analysis of the service providers involved is required. Therefore, the aim of this study is to determine the primary and joint care responsibilities for geriatric patients with specific characteristics, to estimate the associated effort for selected outpatient medical service providers and to identify resulting care concentrations. The analysis includes six selected specialist disciplines in the outpatient sector and is based on two databases: 1) A representative survey among outpatient physicians related to geriatric care (n = 400) to examine both the primary geriatric care needs that professionals treat regularly and aggravating geriatric morbidity. 2) A claims data analysis determines services and efforts for approximately 300,000 geriatric patients for every year from 2014 to 2018. For the specialists included in the analysis, care concentration was determined by association analysis comparing the care efforts of outpatient physicians for patients with different geriatric characteristics. General practitioners, in particular, serve as primary care providers for all geriatric characteristics; there is no concentration of care on specific patient groups. Concentrations associated with care efforts and joint care responsibilities for patients with certain geriatric characteristics are found among the more specialized physician groups. Across all professions, the physicians surveyed believe that geriatric-specific immobility, depression, anxiety disorders and cognitive deficits make the provision of care more difficult. The results contribute to the understanding of primary and interdisciplinary care responsibilities of outpatient physicians related to the treatment of geriatric conditions and can thus represent an important basis for the structural planning of geriatric care. Nevertheless, it should be noted that within the scope of the analysis presented, only general practitioners and five specialist disciplines could be taken into account. Therefore, the considerations primarily allow initial conclusions about the care responsibility of outpatient physicians with regard to geriatric morbidity. To enable comprehensive structural planning, however, the analyses would have to be expanded to include all specialists involved in geriatric care. The joint care responsibility of outpatient physicians for specific geriatric patients underlines the relevance for interdisciplinary care models and the need for expansion of geriatric expertise in the outpatient sector. In view of the ageing population and an increase in morbidity, the planning of care structures should be based on the needs of geriatric patients and the associated expenses incurred by the various health care providers.


The simulation of condensation removal of a heavy metal from exhaust gases onto sorbent particles.
A numerical model BAEROSOL for solving the general dynamic equation (GDE) of aerosols is presented. The goal was to model the capture of volatilized metals by sorbents under incinerator-like conditions. The model is based on algorithms presented by Jacobson and Turco [Aerosol Science and Technology 22 (1995) 73]. A hybrid size bin was used to model growth and formation of particles from the continuum phase and the coagulation of existing particles. Condensation and evaporation growth were calculated in a moving size bin approach, where coagulation and nucleation was modeled in the fixed size bin model of the hybrid grid. To account for the thermodynamic equilibrium in the gas phase, a thermodynamic equilibrium code CET89 was implemented. The particle size distribution (PSD) calculated with the model was then compared to analytical solutions provided for growth, coagulation and both combined. Finally, experimental findings by Rodriguez and Hall [Waste Management 21 (2001) 589-607] were compared to the PSD predicted by the developed model and the applicability of the model under incineration conditions is discussed.


Early Post-Percutaneous Coronary Intervention Chest Pain: A Nationwide Survey on Interventional Cardiologists' Perspective.
Early post-percutaneous coronary intervention chest pain (EPPCP) appears to be a common clinical phenomenon. EPPCP has not been fully explained or studied in the literature despite the abundance of clinical trials on percutaneous coronary intervention (PCI). The objective of this questionnaire-based survey is to assess the current perception of EPPCP among practicing interventional cardiologists nationwide. A survey questionnaire was designed utilizing the Survey Monkey tool to address the perceptions and current practices regarding key aspects of EPPCP among interventional cardiologists. The survey was sent to the interventional cardiologists via email. The survey questionnaire regarding EPPCP was provided to 2615 practicing interventional cardiologists and resulted in 623 total survey responses, with 503 of those respondents completing all eight survey questions. A total of 50.2% of the interventional cardiologists perceive that the incidence of EPPCP is 5-10%, and 57.5% consider that repeat angiography or PCI is rarely needed (1 in 1000 cases). A total of 47.1% of the participants think that EPPCP is due to transient microvascular dysfunction, while 39% perceive it as a different entity requiring a different approach. When asked about developing a standardized labeling for the phenomenon of EPPCP, 34.8% of responders indicated that they believe EPPCP should be labeled as a benign form of chest pain/angina, and 28% preferred to describe EPPCP in non-standardized terms. Among interventional cardiologists, 80% thought that the treatment of this entity is a combination of reassurance and vasodilators and, without ischemic ECG changes, medical management is appropriate. A total of 72% of interventional cardiologists in our survey preferred to label EPPCP as standard nomenclature to facilitate communication between healthcare providers, patients and families in a consistent way. There is a diversity of opinion regarding EPPCP, no standard nomenclature, and no guideline to standardize practice. Further large-scale prospective studies are needed to better understand the pathophysiological mechanisms, optimal management strategies, prognostic implications, and clinical reporting of EPPCP.


Cathepsin B secretion by rabbit articular chondrocytes: modulation by cycloheximide and glycosaminoglycans.
Rabbit articular chondrocytes in monolayer culture are modulated away from their differentiated state and undergo morphological and biochemical changes. One of the characteristics of the modulated state is an abnormally high production of the cysteine endopeptidase cathepsin B. Addition to chondrocyte cultures of the protein biosynthesis inhibitor, cycloheximide, resulted in a concentration-dependent reduction of cathepsin B secretion, which was fully restored after removal of cycloheximide. Glycosaminoglycans added to the culture medium of modulated chondrocytes partially reduced the rate of secretion of cathepsin B, this effect being dependent on their structure, the degree of sulfation, and concentration. The age of the chondrocytes and the duration of the treatment also influenced this response. The switching off of cathepsin B release was apparently best favored by a high concentration of negatively charged sulfate groups attached to a polymeric glycosaminoglycan chain; this simulates the natural environment of the chondrocytes in articular cartilage.


Jumping to conclusions bias, psychosis and impulsivity in early stages of Parkinson's disease.
The aim was to explore the correlations between Jumping to Conclusions (JtC) tendency and neuropsychiatric features in patients with early Parkinson's disease (PD). According to few reports, PD patients with impulsive-compulsive behaviors (ICBs) are prone to working memory difficulties including JtC bias. The correlation of psychotic features and JtC tendency remains still unclear. Healthy controls and patients within 3 years of PD onset were recruited. Participants were examined for psychotic symptoms using a 10 question PD-specific psychosis severity scale. JtC was measured by a probalistic reasoning scenario (beads task). In PD group, medication use, motor and non-motor symptoms were documented. Impulsivity was evaluated using the Questionnaire for Impulsive-Compulsive Disorders in PD (QUIP). The prevalence of JtC bias was 9% (6/70) in healthy individuals, compared to 32% (22/68) of PD group [p = 0.001]. No association was detected between the presence of JtC tendency and PD-associated psychosis (p = 0.216). Patients with JtC had shorter duration of PD, more tremor-dominant PD subtype and higher QUIP scores, regardless of the dopaminergic therapy (p = 0.043, p = 0.015, p = 0.007, respectively). A trend towards attention and inhibition control deficit was noticed in JtC patients. We found a high prevalence of JtC bias in early, cognitively intact PD population and a potential link between subthreshold ICBs and poor performance on beads task. Additional studies are needed to confirm our results and elaborate on the mechanisms that correlate impulsivity with JtC tendency, which are likely to be different from those mediating psychotic features in early PD.


Resolving the Tension Between Exploration and Confirmation in Preclinical Biomedical Research.
Confirmation through competent replication is a founding principle of modern science. However, biomedical researchers are rewarded for innovation, and not for confirmation, and confirmatory research is often stigmatized as unoriginal and as a consequence faces barriers to publication. As a result, the current biomedical literature is dominated by exploration, which to complicate matters further is often disguised as confirmation. Only recently scientists and the public have begun to realize that high-profile research results in biomedicine can often not be replicated. Consequently, confirmation has become central stage in the quest to safeguard the robustness of research findings. Research which is pushing the boundaries of or challenges what is currently known must necessarily result in a plethora of false positive results. Thus, since discovery, the driving force of scientific progress, is unavoidably linked to high false positive rates and cannot support confirmatory inference, dedicated confirmatory investigation is needed for pivotal results. In this chapter I will argue that the tension between the two modes of research, exploration and confirmation, can be resolved if we conceptually and practically separate them. I will discuss the idiosyncrasies of exploratory and confirmatory studies, with a focus on the specific features of their design, analysis, and interpretation.


[Traumatic lesions of the supra-hepaticocaval veins or lessons from failure. Apropos of 5 cases].
Strategic therapeutic principles in 5 cases of injury to supra-hepaticocaval veins were based on vascular exclusion of liver prior to any approach to the lesion. An approach to the intrapericardial inferior vena cava by sternotomy is proposed together with the use of an endocaval shunt introduced through the atrium.


Prognostic significance of perioperative chemotherapy on resectable colorectal mucinous adenocarcinoma liver metastasis.
Mucinous adenocarcinoma (MAC) is an uncommon subtype of colorectal cancer (CRC). For colorectal cancer liver metastasis (CRLM), perioperative chemotherapy (PCT) has been developed to improve the rate of resection and reduce the rate of early recurrence; however, its impact on long-term outcomes in MAC is unclear. From 1999 to 2016, 442 patients with CRLM were retrospectively reviewed, all of whom underwent CRC resection and liver metastasis resection. Among them, 34 were MAC, and the others were non-MAC. A total of 102 non-MAC patients with CRLM who underwent surgery at the same period were matched with 34 MAC patients in a ratio of 3:1 by using a random number table for analysis. Clinicopathologic characteristics for the MAC group (n=34) and non-MAC group (n=102) had no statistical difference. Both recurrence free survival (RFS) and overall survival (OS) did not significantly differ between the two groups. Nevertheless, in the non-MAC group, OS was fundamentally prolonged in patients with PCT compared to those who didn't have PCT (P=0.031). In this study, PCT had a survival benefit on non-MAC patients with CRLM while MAC patients with resectable CRLM do not benefit from PCT. When developing treatment like PCT or surgery alone for CRLM, mucinous histology should be considered as an important influence factor.


[Not Available].
Growing consumption of beer in present diet may lead to higher risk of piling up of ochratoxin A. In our studies we evaluated malt and beer from the local Pomeranian brewery which offers its products at the market in the lowest price. The evaluation had been conducted for 3 months during winter time and the content of fungi, OTA and ergosterol had been analyzed.High concentration of ergosterol was found in all the malt samples, whereas ochratoxin A was present in one delivery of the product only. In contrast, in 70% beer samples low concentration of OTA was found.


Student life - A challenging transition.
After leaving school, I had no idea what I wanted to do until I became a healthcare assistant (HCA) on a paediatric cardiac ward in Bristol.


Molecular cloning of fragments of bacteriophage T4 DNA.
Non-glucosylated T4 DNA was digested with R.EcoRI and the resulting fragments covalently joined to lambda vectors. The genetic content of each lambda-T4 hybrid was determined by marker-rescue tests. The isolation of many recombinants containing partial-digestion products of T4 DNA provided the overlapping sequences necessary to order fragments within the T4 genome. The present analyses include parts of the "early" region between genes 42 and 46, and much of the "late" region between genes 50 and 29. T4 cytosine-DNA digested to completion by R.EcoRI was used to identify the fragments of DNA within the lambda-T4 recombinants. The T4 cytosine-DNA was also sensitive to R.HindIII and R.Xho but not to R.BamH1.


Identifying indices of happiness and unhappiness among adults with autism: potential targets for behavioral assessment and intervention.
Research is increasingly demonstrating the importance of monitoring indices of happiness as part of behavioral programs for individuals who have severe intellectual disabilities. We evaluated a practitioner-oriented process for identifying and validating individualized indices of this private event among three adults with autism who were nonvocal or minimally vocal. Caregiver surveys were administered to obtain agreement regarding behavior displayed when the individuals were happy and unhappy, as well as situations in which they were likely to experience happiness and unhappiness. Observations corroborated caregiver opinion in that participants displayed more happiness indices in situations reported to be accompanied by happiness, and for the most part, more unhappiness indices in reported unhappiness situations. Subsequent choices by each participant supported the validity of the individualized indices. Results are discussed regarding how identifying happiness indices can be a useful component of behavioral applications, as well as guidelines and cautions regarding use of the indices in routine practice.


Second-look arthroscopy of cartilage changes of the patellofemoral joint, especially the patella, following acute and recurrent patellar dislocation.
The purpose of this study was to clarify some pathogenesis of the cartilage changes of the patellofemoral joint in patellar dislocation knees. A first arthroscopy was performed in a total of 60 knees, including 30 knees of acute patellar dislocation (APD) and 30 knees of recurrent patellar dislocation (RPD). At the time of the first arthroscopy, 58 knees sustained open medial patellofemoral ligament repair/reconstruction, and 2 knees had only arthroscopy examination. In APD knees, the second-look arthroscopy was performed 16.7 months after the first arthroscopy, and in RPD knees, 25.2 months after the first arthroscopy. In most APD knees, cracking primarily on the central dome of the patella did not have a remarkable change but in several knees that had a high number of cracking or interlaced cracking, cracking became worse with fibrillation. Osteochondral defect site primarily on the medial facet showed fibrillation and/or ulceration (erosion). In most RPD knees, fissuring primarily on the central dome did not have a remarkable change, and fibrillation and/or erosion mainly on the medial facet also did not have a remarkable change. However, in four knees with the continuation of patellar dislocation, the patellar cartilage changes had definitely worsened. On the other hand, in the first and second-look arthroscopy, most APD and RPD knees had no remarkable cartilage lesions or cartilage changes of the femoro-trochlear aspect. One of the pathogenesis of fissuring in RPD knees seems to be cracking occurring at the time of APD. Two of the pathogenesis of fibrillation may result from the reparative reaction of the cartilage in osteochondral defect site and the cartilage change due to a high degree of cracking damage mainly on the central dome in APD injury. The continuation of patellar dislocation definitely makes the patellar cartilage lesions worse.


Vascular dementia: a diagnosis running out of time.
The concept of vascular dementia has a long history but its usefulness as a diagnostic category has been called into question. To evaluate vascular disease as a risk factor for dementia and the interface between cerebrovascular pathology and Alzheimer's disease. The literature on this topic was selectively reviewed and synthesised. Risk factors for cerebrovascular disease are also risk factors for dementia. However, the course of dementia, once it has developed, appears to be frequently determined by Alzheimer's disease. As a public health measure, modification of vascular risk represents a potentially powerful means to prevent dementia through delaying its onset. However, an effect on progression of dementia, once it has developed, has yet to be established. The traditional view of vascular dementia and Alzheimer's disease as distinguishable conditions is becoming steadily less tenable.


A stretch of "late" SV40 viral DNA about 400 bp long which includes the origin of replication is specifically exposed in SV40 minichromosomes.
Examination of DNA fragments produced from either formaldehyde-fixed or unfixed SV40 minichromosomes by multiple-cut restriction endonucleases has led to the following major results: Exhaustive digestion of unfixed minichromosomes with Hae III generated all ten major limit-digest DNA fragments as well as partial cleavage products. In striking contrast to this result, Hae III acted on formaldehyde-fixed minichromosomes to yield only one of the limit-digest fragments, F, which is located in the immediate vicinity of the origin of replication, spanning nucleotides 5169 and 250 on the DNA sequence map of Reddy et al. (1978). This 300 base pair (bp) fragment was released as naked DNA from formaldehyde-fixed, Hae III-digested minichromosomes following treatment either by pronase-SDS or by SDS alone. In the latter case, the remainder of the minichromosome retained its compact configuration as assayed by both sedimentational and electrophoretic methods. In minichromosomes, the F fragment is therefore not only accessible to Hae III at its ends, but is also neither formaldehyde cross-linked into any SDS-resistant nucleoprotein structure nor topologically "locked" within the compact minichromosomal particle. This same fragment was preferentially produced during the early stages of digestion of unfixed minichromosomes with Hae III, and its final yield in the exhaustive Hae III digest was significantly higher than that of other limit-digest fragments. Similar results were obtained upon digestion of either unfixed or formaldehyde-fixed minichromosomes with Alu I. In particular, of approximately twenty major limit-digest DNA fragments, only two fragments (F and P, encompassing nucleotides 5146 to 190, and 190 to 325, respectively) were produced by Alu I from the formaldehyde-fixed minichromosomes. All other restriction endonucleases tested (Mbo I, Mbo II, Hind III, Hin II+III and Hinf I), for which there are no closely spaced recognition sequences in the above mentioned regions of the SV40 genome, did not produce any significant amount of limit-digest DNA fragments from formaldehyde-fixed minichromosomes. These findings, taken together with our earlier data on the preferential exposure of the origin of replication in SV40 minichromosomes (Varshavsky, Sundin and Bohn, 1978), strongly suggest that a specific region of the "late" SV40 DNA approximately 400 bp long is uniquely exposed in the compact minichromosome. It is of interest that, in addition to the origin of replication, this region contains binding sites for T antigen (Tjian, 1977), specific tandem repeated sequences and apparently also the promoters for synthesis of late SV40 mRNAs (Fiers et al., 1978; Reddy et al., 1978).


[Neuroethics of pharmaceutical cognitive enhancement: the first ten years: current problems and practical guiding principles].
An evaluating survey of the development of the neuroethics of pharmaceutical cognitive enhancement (PCE) during the last decade, focussing on the situation in Germany, has been undertaken. This article presents the most important conceptual problems, current substances and central ethical and legal issues. Very first guidelines and recommendations for policy-makers are formulated at the end of the text.


Purification of two Leishmania donovani membrane proteins recognized by sera from patients with visceral leishmaniasis.
Two Leishmania donovani membrane proteins recognized by sera from patients with visceral leishmaniasis were purified using species-specific monoclonal antibodies and characterized. The molecular weights of the proteins, as determined by sodium dodecyl sulfate-polyacrylamide gel electrophoresis, were approximately 70,000 and approximately 72,000, respectively. The 70 kDa protein, which appears as a diffuse band on silver staining, was resolved into a doublet by Western blotting with monoclonal antibody. Though of similar molecular weight and amino acid composition, the two proteins were shown to be distinct by peptide mapping and Western blotting of the purified material. The two proteins are recognized specifically by human visceral leishmaniasis serum and not by serum from cutaneous leishmaniasis or Chagas' disease. These proteins will be useful in developing a direct serodiagnostic assay for visceral leishmaniasis.


Subacute exposure to lead promotes disruption in the thyroid gland function in male and female rats.
Exposure to heavy metals, such as lead, is a global public health problem. Lead has a long historic relation to several adverse health conditions and was recently classified as an endocrine disruptor. The aim of this study was to investigate the effects of subacute exposure to lead on the thyroid gland function. Adult male and female Wistar rats received a lead acetate solution containing 10 or 25 mg/kg, by gavage, three times a week, for 14 days. One week later, behavioral testing showed no alterations in anxiety and motor-exploratory parameters, as evaluated by Open-Field and Plus-Maze Tests, but impairment in learning and memory was found in the male 25 mg/kg lead-treated group and in both female lead-treated groups, as evaluated by the Inhibitory Avoidance Test. After one week, serum levels of tT3 were reduced in the 25 mg/kg female group and in the 10 mg∕ kg male group. However, tT4 levels were increased in the 25 mg/kg male group and in both female treated groups. TSH levels did not change and lead serum levels were undetectable. Morphologic alterations were observed in the thyroid gland, including abnormal thyroid parenchyma follicles of different sizes, epithelial stratification and vacuolization of follicular cells, decrease in colloid eosinophilia and vascular congestion, accompanied by morphometric alterations. An increase in collagen deposition was also observed. No differences were observed in TPO activity or protein expression, H2O2 generation by NADPH oxidases or hepatic D1 mRNA expression. However, thyroid NIS protein expression was considerably decreased in the male and female lead-treated groups, while TSHr expression was decreased in the 25 mg/kg female lead-treated group. These findings demonstrated that subacute exposure to lead acetate disrupts thyroid gland function in both sexes, leading to morphophysiological impairment and to changes in learning and memory abilities.


Loneliness and associated factors among older adults during COVID-19 lockdown in Spain.
Considering the health outcomes of loneliness, it is important to understand the effects of the COVID-19 pandemic for older adults to facilitate detection and intervention. The aim of this study was to examine loneliness among Spanish older adults during the first wave lockdown and associated factors, in comparison to younger adults. An online survey was completed by 3508 adults (401 aged 60 or above). Older adults felt higher social loneliness than younger adults, but lower emotional loneliness. Living alone, poor mental health, and poor healthy habits were related to higher loneliness for both age groups. The results suggest that loneliness should be an important factor in primary care, and prevention efforts should be taken, e.g., by generating open and safe community spaces and contexts for social interaction and promoting the access and ability to use technologies that maintain social connections.


A fast chemical reprogramming system promotes cell identity transition through a diapause-like state.
Cellular reprogramming by only small molecules holds enormous potentials for regenerative medicine. However, chemical reprogramming remains a slow process and labour intensive, hindering its broad applications and the investigation of underlying molecular mechanisms. Here, through screening of over 21,000 conditions, we develop a fast chemical reprogramming (FCR) system, which significantly improves the kinetics of cell identity rewiring. We find that FCR rapidly goes through an interesting route for pluripotent reprogramming, uniquely transitioning through a developmentally diapause-like state. Furthermore, FCR critically enables comprehensive characterizations using multi-omics technologies, and has revealed unexpected important features including key regulatory factors and epigenetic dynamics. Particularly, activation of pluripotency-related endogenous retroviruses via inhibition of heterochromatin significantly enhances reprogramming. Our studies provide critical insights into how only environmental cues are sufficient to rapidly reinstate pluripotency in somatic cells, and make notable technical and conceptual advances for solving the puzzle of regeneration.


Long-term alterations to dendritic morphology and spine density associated with prenatal exposure to nicotine.
Prenatal exposure to nicotine has been associated with many long-term cognitive and behavioral abnormalities. Based upon these observable outcomes, we hypothesized that prenatal nicotine exposure would induce lasting changes in dendritic morphology and synaptic connectivity throughout the cortex. Pregnant Long-Evans rats were administered nicotine or saline for the duration of pregnancy and offspring were sacrificed at P100 for Golgi-Cox analysis (dendritic length, dendritic branching, and spine density) of the prefrontal cortex (AID and Cg3), parietal cortex, and nucleus accumbens. In male offspring dendritic branching increased in AID and NAc, but decreased in the apical field of Cg3; spine density increased everywhere except NAc where it decreased; and dendritic length was increased in Cg3(basilar) and NAc but reduced in PAR(basilar). In female offspring, dendritic branching increased in NAc but decreased in AID; spine density increased in AID and PAR but decreased in Cg3 and NAc, and dendritic length was reduced in Cg3, PAR, and NAc. As changes were identified at P100, prenatal exposure to nicotine dramatically reorganized neuroanatomy in a persistent manner, likely altering the brain's response to normal and abnormal experiences.


Dentinal tubule infection as the cause of recurrent disease and late endodontic treatment failure: a case report.
This article describes a case of recurrent post-treatment apical periodontitis and late failure after endodontic retreatment performed in a single visit. The patient presented with a tooth exhibiting inadequate endodontic treatment and a large periradicular lesion that extended laterally to the root. Retreatment was performed in a single visit and involved chemomechanical preparation using 5.25% NaOCl as the irrigant and root canal obturation by Schilder's vertical compaction technique. A large lateral canal was radiographically revealed after obturation. After 2 years, the lesion was no longer radiographically discernible, a condition that was confirmed 9 years after retreatment procedures. Nonetheless, after 12 years, radiographs revealed recurrent disease. Apical surgery was performed, and the root apex, including the area of the large lateral canal, was resected with care to maintain the lesion attached to it. The biopsy specimen was subjected to histopathologic and histobacteriologic analyses. Longitudinal sections of the apical root specimen revealed a heavy dentinal tubule infection surrounding the area of the lateral canal. Bacteria were not found in any other area of the specimen. No other possible reason for the inflammatory periradicular lesion, such as root fracture, coronal leakage, or foreign-body reaction, was evident. A persistent intraradicular infection caused by bacteria located within dentinal tubules is the most reasonable explanation for resurgence of the apical periodontitis lesion. This case report stresses the importance of attaining proper disinfection of the root canal system for a predictable long-term outcome of the treatment.