Unlocking the Mysteries of Chromatin Biology through Functional Epigenomics.
In the ever-evolving field of functional genomics, CRISPR-based screening technologies have become pivotal tools for elucidating gene function across various cell types. A recent study by Gilan and colleagues advances this technological frontier by introducing CRISPR-ChIP, a platform designed to investigate the complex dynamics of epigenetic regulation of chromatin. In proof-of-concept experiments, the authors demonstrate the potential of this tool to identify key molecular regulators of two major histone modifications associated with active transcription, H3 lysine 4 trimethylation (H3K4me3) and H3 lysine 79 dimethylation (H3K79me2). They further unveiled a previously unknown functional partitioning of the H3K79-specific methyltransferase DOT1L into an oncogenic complex with MLL-AF9 and a native complex with MLLT10, which cooperatively regulate Mixed Lineage Leukemia fusion protein (MLL-FP) target gene expression. This novel epigenomic approach integrates high-throughput CRISPR screening with ChIP-based direct readout of chromatin modifications in situ, offering a powerful tool to investigate the epigenetic regulatory layers across a diverse spectrum of biological processes and disease states.


Identifying genetic determinants of Streptococcus pyogenes-host interactions in a murine intact skin infection model.
Streptococcus pyogenes is an obligate human pathobiont associated with many disease states. Here, we present a model of S. pyogenes infection using intact murine epithelium. We were able to perform RNA sequencing to evaluate genetic changes undertaken by both the bacterium and host at 5 and 24 h post-infection. Analysis of these genomic data demonstrate that S. pyogenes undergoes genetic adaptation to successfully infect the murine epithelium, including changes to metabolism and activation of the Rgg2/Rgg3 quorum-sensing (QS) system. Subsequent experiments demonstrate that an intact Rgg2/Rgg3 QS cascade is necessary to establish a stable superficial skin infection. QS cascade activation results in increased murine morbidity and bacterial burden on the skin. This phenotype is associated with gross changes to the murine skin and with evidence of inflammation. These experiments offer a method to investigate S. pyogenes-epithelial interactions and demonstrate that a well-studied QS pathway is critical to a persistent infection.


Translocation (8;16) in a patient with acute myelomonocytic leukemia, occurring after treatment with fludarabine for a low-grade non-Hodgkin's lymphoma.
We describe a 65-year old woman who developed a t(8;16)(p11;p13) positive acute myeloid leukemia (AML)-M4 without a prior myelodysplasia thirty-six months after a low-grade non-Hodgkin's lymphoma treated with alkylating agents (chlorambucil and cyclophosphamide) and fludarabine, a purine analog with a significant activity in lymphoproliferative disorders. The t(8;16)(p11;p13) is present in 0.4% of AML of M4-M5 cytotype. In the present case it was identified by conventional cytogenetics; involvement of the MOZ and CBP genes was demonstrated by fluorescence in situ hybridization, but not by reverse transcription polymerase chain reaction. The patient died of sepsis after the first course of induction chemotherapy. This is the first t(8;16) AML-M4 arising after fludarabine treatment of which the leukemogenic role in our case is very difficult to ascertain. Most t(8;16) t-AML cases had received anthracyclines with or without cyclophosphamide; none was ever administered chlorambucil. Our patient was never given anthracyclines and the cumulative doses of chlorambucil and cyclophosphamide employed were low.


Titanium Dioxide (E171 grade) and the Search for Replacement Opacifiers and Colorants: Supplier Readiness Survey, Case Studies and Regulatory Perspective.
Titanium dioxide (TiO2) is used primarily as an opacifier in solid dosage forms and is present in the majority of tablet and capsule dosage forms on the market. The IQ* TiO2 Working Group has previously shown that titanium dioxide has unique properties which are necessary for its function in these formulations and noted that, as the potential replacements lack the semi-conductor properties, high refractive index and whiteness of E171, it might be hard to replicate these properties with alternative materials. In this paper we detail the results of readiness surveys and practical assessments that have been conducted with alternative materials by IQ member companies. A range of technical challenges and regulatory hurdles were identified which mean that, in the short term, it may be difficult to replace titanium dioxide with the currently available alternative materials while readily achieving the same drug product quality attributes, especially for some of the marketed formulations that titanium dioxide is currently used for. We note the higher technical complexity, due to the variability, color fading and identified scale up risk, of E171 free film coatings and the likely impact on development costs and timelines. We also highlight several regulatory hurdles that would have to be overcome if a titanium dioxide replacement was required for some markets but was not mandated by others.


Simulating Ultrasound Tissue Deformation Using Inverse Mapping.
Ultrasound guidance is used for a variety of surgical needle insertion procedures, but there is currently no standard for the teaching of ultrasound skills. Recently, computer ultrasound simulation has been introduced as an alternative teaching method to traditional manikin and cadaver training because of its ability to provide diverse scenario training, quantitative feedback, and objective assessment. Current computer ultrasound training simulation is limited in its ability to image tissue deformation caused by needle insertions, even though tissue deformation identification is a critical skill in performing an ultrasound-guided needle insertion. To fill this need for improved simulation, a novel method of simulating ultrasound tissue-needle deformation is proposed and evaluated. First, a cadaver study is conducted to obtain ultrasound video of a peripheral nerve block. Then, optical flow analysis is conducted on this video to characterize the tissue movement due to the needle insertion. Tissue movement is characterized into three zones of motion: tissue near the needle being pulled, and zones above and below the needle where the tissue rolls. The rolling zones were centered 1.34 mm above and below the needle and 4.53 mm behind the needle. Using this characterization, a vector field is generated mimicking these zones. This vector field is then applied to an ultrasound image using inverse mapping to simulate tissue movement. The resulting simulation can be processed at 3.1 frames per second. This methodology can be applied through future optimized graphical processing to allow for accurate real time needle tissue simulation.


High prevalence of subclinical hypothyroidism during first trimester of pregnancy in North India.
Thyroid dysfunction is a common occurrence in pregnancy and affects both maternal and fetal outcomes. There are limited data on prevalence of hypothyroidism during pregnancy from India. Therefore, this study was designed to evaluate the prevalence of thyroid dysfunction especially hypothyroidism during first trimester in a large public hospital in North India. All the consecutive first trimester pregnant women attending Lok Nayak and Kasturba Hospitals were enrolled in the study after institutional ethics approval and consent from the study subjects. The pregnant women with diagnosed thyroid disease and on thyroid medications were excluded from the study. Morning samples of study participants were analyzed for thyroid hormone profile which included free T3, free T4, TSH, and TPO Ab. In addition, all study participants were tested for CBC, LFT, KFT, and lipid profile. A total of 1000 women were enrolled for this prospective observational study. The mean (SD) age of study subjects was 25.6 (11.1) years, and mean (SD) gestational age was 10.3 (3.4) weeks. One hundred and forty-three (14.3%) subjects had TSH values more than 4.5 mIU/L above the cutoff used for definition of hypothyroidism. Out of these, 135 had normal free T4 and therefore labeled as subclinical hypothyroidism and 7 had low free T4 suggestive of overt hypothyroidism. TPO Ab was positive in 68 (6.82%) of total, 25 (18.5%) of subclinical and 5 (71%) of overt hypothyroid patients. Hypothyroidism, especially subclinical, is common in North Indian women during first trimester. Further countrywide studies are needed to evaluate the prevalence and etiology of hypothyroidism to prevent maternal and fetal adverse effects of hypothyroidism in India.


Outcomes in Patients with SARS-CoV-2 and Clostridioides difficile Coinfection.
Coronavirus infectious disease 2019 (COVID-19) is primarily a respiratory disease. However, it may manifest with gastrointestinal symptoms that may overlap with Clostridioides difficile infection (CDI). COVID-19 appears to have higher mortality in those with comorbidities. We aimed to assess the outcomes of coinfection in these patients. A retrospective chart review was conducted to identify patients with CDI and COVID-19 from January 1st, 2020 to November 17th, 2020. Both infections were diagnosed via PCR. Clinical features, treatment for COVID-19 and CDI and outcomes including intensive care unit admission, colectomy, 30 day-mortality and long-term complications were analyzed. Overall, 21 patients (20 hospitalized) with median age 70.9 years (range 51.8-90.7 years) had CDI and COVID-19 within 4 weeks of each other. Of these, 4 patients (19%) with CDI were diagnosed with COVID-19 at the time of admission, 12 (57%) had CDI diagnosed after COVID-19, and 5 (23.9%) developed COVID-19 within 4 weeks after CDI. Fourteen patients (66.7%) were treated with medications directed against COVID-19 including remdesivir and dexamethasone (n=7), remdesivir with convalescent plasma (n= 1), remdesivir (n= 5) and dexamethasone (n=1). The most common treatment for CDI was oral vancomycin in 20 patients (95.2%), and 1 patient received intravenous metronidazole. No patient required colectomy for CDI but 2 (9.5%) required ICU admission. Four patients (19%) died likely due to COVID-19 with median age 80 years (range 61-90 years). The relationship between COVID-19 and CDI is poorly understood, and studies are required to further investigate this association. Whether coinfection results in a worsening of outcomes, including mortality and clinical course, are questions that should be answered in future research studies. Diagnosing both infections for appropriate management is vital in light of overlapping symptoms.


Novel mutant Semliki Forest virus vectors: gene expression and localization studies in neuronal cells.
Semliki Forest virus vectors (SFV) are suitable for high-level transgene expression in neuronal tissue, both in vitro and in vivo. Cortical and hippocampal primary neurons in culture are efficiently infected resulting in 75-95% of GFP-positive cells, and injection of SFV vectors into hippocampal slice cultures revealed a highly neuron-specific expression pattern with more than 90% of the infected cells being neurons. Here, we present novel SFV vector mutants and describe their infection patterns obtained in cultures of baby hamster kidney (BHK) cells, dissociated hippocampal neurons, and organotypic hippocampal slices. A less cytotoxic vector SFV(PD), carrying two point mutations in the nsP2 gene, showed much higher GFP expression levels in primary hippocampal neurons compared to the wild-type SFV vector. A triple mutant vector SFV(PDE153) demonstrated a temperature-sensitive phenotype in both BHK cells and primary neurons. In hippocampal slices cultured at 36 degrees C, SFV(PDE153) showed a remarkably higher (ca 250-fold) preference for expression in interneurons rather than in pyramidal cells as compared to wild-type SFV. The quadruple mutant SFV(PDTE) led to substantially increased and prolonged GFP expression in primary neurons. Relative to SFV(PDE153), a more pronounced temperature-sensitive phenotype was found resulting in no virus production and no GFP expression at the non-permissive temperature (36-37 degrees C) in BHK cells, in dissociated neurons, and in organotypic hippocampal slices. The described novel SFV vectors will be useful for several specific applications in neurobiology.


The use of hyperventilation in the treatment of plateau waves in two patients with severe traumatic brain injury: contrasting effects on cerebral oxygenation.
We present the case reports of two patients with severe traumatic brain injury who, in the absence of external stimuli, developed episodes of acute elevation of intracranial pressure (plateau waves) associated with jugular bulb oxyhemoglobin (SjO2) desaturation, severe reduction of cerebral tissue PO2 (PbrO2), and deterioration of neurological status. In all of these episodes hyperventilation was successful in extinguishing plateau waves, but in one patient it was associated with an improvement of both the global (increased SjO2) and local (increased PbrO2) cerebral perfusion, while in the other patient it was associated with a reduction of both SjO2 and PbrO2. In both patients the effects of hyperventilation (and other pharmacological treatments) were short-lived; plateau waves reappeared and the patients had to be submitted to decompressive craniotomy (first patient) and cerebrospinal fluid (CSF) drainage (second patient). We conclude that hyperventilation can be useful as a temporary measure to treat plateau waves, but cerebral oxygenation should always be monitored to avoid iatrogenic cerebral ischemia.


[Detection and identification of the influenza virus in nasopharyngeal washings by solid-phase radioimmunological analysis].
In the period of epidemic rise of the morbidity level in 1983-1984, 207 specimens of nasopharyngeal washings from patients with influenza were analysed by solid-phase radioimmunoassay. Test sera containing a wide range of antihemagglutinating antibodies to different drift variants of influenza type A and type B viruses were used as diagnostic ones. The results indicate the predominance of influenza B infection (18.4%). Influenza A accounted for 14.5%, 9.2% of it being subtype H1N1. Noteworthy is a considerable portion (23.2%) of mixed influenza A and B infection. The results of this study are compared with analysis of paired sera from the same patients by the HI test.


Long noncoding RNA AB073614 promotes the malignance of glioma by activating Wnt/β-catenin signaling through downregulating SOX7.
Long noncoding RNA (lncRNA) AB073614 has recently shown to be aberrantly increased and identified as a poor prognostic biomarker in human glioma. However, the potential mechanisms remain unknown. This study demonstrated that AB073614 expression was significantly upregulated in both glioma tissues and cell lines, and glioma patients with high AB073614 expression had lower overall survival rates. Importantly, silencing AB073614 expression remarkably inhibited U251 cell proliferation, migration, and invasion in vitro, as well as suppressed tumor formation in vivo. The level of AB073614 was found to correlate inversely with sex-determining region Y-box 7 (SOX7) expression but correlate positively with Wnt/β-catenin signaling activity. Of note, the data showed that the inhibition of SOX7 could reverse the tumor-suppressive effect of the silencing AB073614 on glioma in vitro and in vivo. Furthermore, the results indicated that AB073614 induced Wnt/β-catenin signaling activity by repressing SOX7 expression. In conclusion, the findings demonstrated that AB073614 promoted the progression of glioma by targeting SOX7 to activate the Wnt/β-catenin signaling pathway, suggesting that the inhibition of AB073614 might be a potential target for therapeutic intervention in glioma patients.


Clinical and analytical problems of sodium azide poisonings as exemplified by a case of fatal suicidal poisoning.
To present clinical and analytical aspects associated with sodium azide poisoning. The problems were verified on the basis of a case of sodium azide poisoning which was unique due to its circumstances and the development of an analytical method applied for medico-legal practice. The object of the study was a toxicological analysis of biological specimens collected from a woman who ingested two doses of sodium azide purchased over the Internet, in a suicide attempt. After the ingestion of the first dose, the clinical management in the form of symptomatic treatment indicated a possibility of recovery. However, the ingestion of a second dose of the xenobiotic, already in the hospital, caused death. Toxicological findings were obtained with the dedicated technique of gas chromatography-mass spectrometry (GC-EI-MS-MS) after extraction combined with derivatization using pentafluorobenzyl bromide (PFBBr). Post-mortem toxicological studies demonstrated sodium azide in the blood (0.18 mg/l) and urine (6.50 mg/l) samples collected from the woman. Cases of sodium azide poisoning are rare and difficult to treat, but a review of the literature over a longer interval of time shows that they continue to occur. Therefore, case studies of sodium azide poisoning, together with descriptions of research methodology, can be useful both in clinical terms and in the preparation of toxicological expert opinions for medico-legal purposes.


MRI quantification techniques in fatty liver: the diagnostic performance of hepatic T1, T2, and stiffness measurements in relation to the proton density fat fraction.
Nonalcoholic fatty liver disease (NAFLD) can progress to liver cirrhosis and is predicted to become the most frequent indication for liver transplantation in the near future. Noninvasive assessment of NAFLD is important for diagnosis and patient management. This study aims to prospectively determine the liver stiffness and T1 and T2 values in patients with NAFLD and to compare the diagnostic performance of magnetic resonance elastography (MRE) and mapping techniques in relation to the proton density fat fraction (PDFF). Eighty-three patients with NAFLD and 26 participants with normal livers were imaged with a 1.5 T scanner. PDFF measurements obtained from the multiecho Dixon technique were used to quantify the liver fat. MRE, native T1 mapping (modified Look-Locker inversion recovery [MOLLI] schemes 5(3)3, 3(3)3(3)5, and 3(2)3(2)5 and the B1-corrected variable flip angle [VFA] method), and T2 mapping values were correlated with PDFF. The diagnostic performance of MRE and the mapping techniques were analyzed and compared. T1 values measured with the MOLLI schemes and the B1-corrected VFA (P < 0.001), and the stiffness values from MRE (P = 0.047) were significantly higher in the NAFLD group. No significant difference was found between the groups in terms of T2 values (P = 0.127). In differentiation of the NAFLD and control groups, the B1-corrected VFA technique had slightly higher accuracy and area under the curve (AUC) than the MOLLI schemes. In the NAFLD group, there was a good correlation between the PDFF, MOLLI 3(3)3(3)5 and 3(2)3(2)5, and VFA T1 measurements (r=0.732; r=0.735; r=0.716, P < 0.001, respectively). Liver T1 mapping techniques have the potential to distinguish steatotic from nonsteatotic livers, and T1 values seem to have a strong correlation with the liver fat content.


The impact factors of social media users' forwarding behavior of COVID-19 vaccine topic: Based on empirical analysis of Chinese Weibo users.
Social media, an essential source of public access to information regarding the COVID-19 vaccines, has a significant effect on the transmission of information regarding the COVID-19 vaccines and helps the public gain correct insights into the effectiveness and safety of the COVID-19 vaccines. The forwarding behavior of social media users on posts concerned with COVID-19 vaccine topics can rapidly disseminate vaccine information in a short period, which has a significant effect on transmission and helps the public access relevant information. However, the factors of social media users' forwarding posts are still uncertain thus far. In this paper, we investigated the factors of the forwarding COVID-19 vaccines Weibo posts on Chinese social media and verified the correlation between social network characteristics, Weibo textual sentiment characteristics, and post forwarding. This paper used data mining, machine learning, sentiment analysis, social network analysis, and regression analysis. Using " (COVID-19 vaccine)" as the keyword, we used data mining to crawl 121,834 Weibo posts on Sina Weibo from 1 January 2021 to 31 May 2021. Weibo posts not closely correlated with the topic of the COVID-19 vaccines were filtered out using machine learning. In the end, 3,158 posts were used for data analysis. The proportions of positive sentiment and negative sentiment in the textual of Weibo posts were calculated through sentiment analysis. On that basis, the sentiment characteristics of Weibo posts were determined. The social network characteristics of information transmission on the COVID-19 vaccine topic were determined through social network analysis. The correlation between social network characteristics, sentiment characteristics of the text, and the forwarding volume of posts was verified through regression analysis. The results suggest that there was a significant positive correlation between the degree of posting users in the social network structure and the amount of forwarding. The relationship between the closeness centrality and the forwarding volume was significantly positive. The betweenness centrality was significantly positively correlated with the forwarding volume. There was no significant relationship between the number of posts containing more positive sentiments and the forwarding volume of posts. There was a significant positive correlation between the number of Weibo posts containing more negative sentiments and the forwarding volume. According to the characteristics of users, COVID-19 vaccine posts from opinion leaders, "gatekeepers," and users with high-closeness centrality are more likely to be reposted. Users with these characteristics should be valued for their important role in disseminating information about COVID-19 vaccines. In addition, the sentiment contained in the Weibo post is an important factor influencing the public to forward vaccine posts. Special attention should be paid to the negative sentimental tendency contained in this post on Weibo to mitigate the negative impact of the information epidemic and improve the transmission effect of COVID-19 vaccine information.


Biofabricated soft network composites for cartilage tissue engineering.
Articular cartilage from a material science point of view is a soft network composite that plays a critical role in load-bearing joints during dynamic loading. Its composite structure, consisting of a collagen fiber network and a hydrated proteoglycan matrix, gives rise to the complex mechanical properties of the tissue including viscoelasticity and stress relaxation. Melt electrospinning writing allows the design and fabrication of medical grade polycaprolactone (mPCL) fibrous networks for the reinforcement of soft hydrogel matrices for cartilage tissue engineering. However, these fiber-reinforced constructs underperformed under dynamic and prolonged loading conditions, suggesting that more targeted design approaches and material selection are required to fully exploit the potential of fibers as reinforcing agents for cartilage tissue engineering. In the present study, we emulated the proteoglycan matrix of articular cartilage by using highly negatively charged star-shaped poly(ethylene glycol)/heparin hydrogel (sPEG/Hep) as the soft matrix. These soft hydrogels combined with mPCL melt electrospun fibrous networks exhibited mechanical anisotropy, nonlinearity, viscoelasticity and morphology analogous to those of their native counterpart, and provided a suitable microenvironment for in vitro human chondrocyte culture and neocartilage formation. In addition, a numerical model using the p-version of the finite element method (p-FEM) was developed in order to gain further insights into the deformation mechanisms of the constructs in silico, as well as to predict compressive moduli. To our knowledge, this is the first study presenting cartilage tissue-engineered constructs that capture the overall transient, equilibrium and dynamic biomechanical properties of human articular cartilage.


Idiopathic inflammatory-demyelinating diseases of the central nervous system.
Idiopathic inflammatory-demyelinating diseases (IIDDs) include a broad spectrum of central nervous system disorders that can usually be differentiated on the basis of clinical, imaging, laboratory and pathological findings. However, there can be a considerable overlap between at least some of these disorders, leading to misdiagnoses or diagnostic uncertainty. The relapsing-remitting and secondary progressive forms of multiple sclerosis (MS) are the most common IIDDs. Other MS phenotypes include those with a progressive course from onset (primary progressive and progressive relapsing) or with a benign course continuing for years after onset (benign MS). Uncommon forms of IIDDs can be classified clinically into: (1) fulminant or acute IIDDs, such as the Marburg variant of MS, Baló's concentric sclerosis, Schilder's disease, and acute disseminated encephalomyelitis; (2) monosymptomatic IIDDs, such as those involving the spinal cord (transverse myelitis), optic nerve (optic neuritis) or brainstem and cerebellum; and (3) IIDDs with a restricted topographical distribution, including Devic's neuromyelitis optica, recurrent optic neuritis and relapsing transverse myelitis. Other forms of IIDD, which are classified clinically and radiologically as pseudotumoral, can have different forms of presentation and clinical courses. Although some of these uncommon IIDDs are variants of MS, others probably correspond to different entities. MR imaging of the brain and spine is the imaging technique of choice for diagnosing these disorders, and together with the clinical and laboratory findings can accurately classify them. Precise classification of these disorders may have relevant prognostic and treatment implications, and might be helpful in distinguishing them from tumoral or infectious lesions, avoiding unnecessary aggressive diagnostic or therapeutic procedures.


ChemSpaceAL: An Efficient Active Learning Methodology Applied to Protein-Specific Molecular Generation.
The incredible capabilities of generative artificial intelligence models have inevitably led to their application in the domain of drug discovery. Within this domain, the vastness of chemical space motivates the development of more efficient methods for identifying regions with molecules that exhibit desired characteristics. In this work, we present a computationally efficient active learning methodology that requires evaluation of only a subset of the generated data in the constructed sample space to successfully align a generative model with respect to a specified objective. We demonstrate the applicability of this methodology to targeted molecular generation by fine-tuning a GPT-based molecular generator toward a protein with FDA-approved small-molecule inhibitors, c-Abl kinase. Remarkably, the model learns to generate molecules similar to the inhibitors without prior knowledge of their existence, and even reproduces two of them exactly. We also show that the methodology is effective for a protein without any commercially available small-molecule inhibitors, the HNH domain of the CRISPR-associated protein 9 (Cas9) enzyme. We believe that the inherent generality of this method ensures that it will remain applicable as the exciting field of in silico molecular generation evolves. To facilitate implementation and reproducibility, we have made all of our software available through the open-source ChemSpaceAL Python package.


Is there a role for humidified heated high-flow nasal cannula therapy in paediatric emergency departments?
Humidified heated high-flow nasal cannula (HFNC) therapy is a potentially useful form of non-invasive respiratory support for children with moderate respiratory distress and/or hypoxaemia. No prospective data support its use in the paediatric emergency department (ED). We introduced HFNC therapy into a paediatric ED and evaluated its use and failure rates. Prospective observational study of all patients presenting to the Royal Children's Hospital, Australia, who received HFNC therapy between April 2013 and September 2013 (one southern hemisphere winter season). We assessed demographics, indications, failure rate, predictors of failure and adverse events. 71 patients commenced HFNC therapy in ED over the study period. The median age was 9 months. The most common indication was bronchiolitis (49/71; 69%). Five (7%) of the patients failed HFNC and were escalated to other forms of respiratory support in ED, four to nasal continuous positive airway pressure and one required intubation. A further 21 (32%) failed HFNC therapy after intensive care unit (ICU) admission, giving a total failure of 28 (39%). There were no serious adverse events in ED, and one child with asthma developed air leak syndrome after transfer to the ICU. HFNC therapy may have a role in the paediatric ED as an easily administered and well tolerated form of non-invasive respiratory support, but about one-third of patients required escalation to a higher level of respiratory support. Further studies should assess the safety profile of HFNC in larger series, and define the role of HFNC in key respiratory conditions compared with other possible interventions.


Baroreflex activation therapy: a new approach to the management of advanced heart failure with reduced ejection fraction.
: Chronic heart failure is a common clinical condition characterized by persistent excessive sympathetic nervous system activation. The derangement of the sympathetic activity has relevant implications for disease progression and patient survival. Aiming to positively impact patient outcome, autonomic nervous system modulatory therapies have been developed and tested in animal and clinical studies. As a general gross assumption, direct vagal stimulation and baroreflex activation are considered equivalent. This assumption does not take into account the fact that direct cervical vagal nerve stimulation involves activation of both afferent and efferent fibers innervating not only the heart, but the entire visceral system, leading to undesired responses to and from this compartment. The different action of baroreflex activation is based on generating a centrally mediated reduction of sympathetic outflow and increasing parasympathetic activity to the heart via a physiological reflex pathway. Thus, baroreflex activation rebalances the unbalanced autonomic nervous system via a specific path. Independent and complementary investigations have shown that sympathetic nerve activity can be rebalanced via control of the arterial baroreflex in heart failure patients.Results from recent pioneering research studies support the hypothesis that baroreflex activation can add significant therapeutic benefit on top of guideline-directed medical therapy in patients with advanced heart failure. In the present review, baroreflex activation therapy results are discussed, focusing on critical aspects like patient selection rationale to support clinician orientation in opting for baroreflex activation therapy when, on top of current guideline-directed medical treatment, other therapies are to be considered.


[A new method for measuring spinal kyphosis using CT images and a study of its relationship with reflux esophagitis].
[Purpose] This study aimed to examine the validity and reproducibility of a new quantitative method for measuring spinal kyphosis using computed tomography (CT), and to investigate its relationship with reflux esophagitis. [Method] Using a new method to measure the index of kyphosis in CT images (IKCT), 10 examiners evaluated 10 cases of spinal kyphosis. One examiner measured 47 cases twice and 20 cases were examined to assess the validity with the kyphosis index. A case-control study was conducted on 303 cases of reflux esophagitis, of which 241 were mild and 62 severe. [Results] Regarding IKCT reproducibility, the inter-rater intraclass correlation coefficient was 0.977. The intra-rater intraclass correlation coefficient was 0.974. The correlation index with the kyphosis index was 0.731. A greater IKCT value, not contracting serious atrophic gastritis, and severe hiatal hernia were identified as risk factors for severe reflux esophagitis. [Conclusion] IKCT is a simple and useful method for measuring kyphosis. The prevention of kyphosis can help suppress severe reflux esophagitis.


A technical review of optical mapping of intracellular calcium within myocardial tissue.
Optical mapping of Ca(2+)-sensitive fluorescence probes has become an extremely useful approach and adopted by many cardiovascular research laboratories to study a spectrum of myocardial physiology and disease conditions. Optical mapping data are often displayed as detailed pseudocolor images, providing unique insight for interpreting mechanisms of ectopic activity, action potential and Ca(2+) transient alternans, tachycardia, and fibrillation. Ca(2+)-sensitive fluorescent probes and optical mapping systems continue to evolve in the ongoing effort to improve therapies that ease the growing worldwide burden of cardiovascular disease. In this technical review we provide an updated overview of conventional approaches for optical mapping of Cai (2+) within intact myocardium. In doing so, a brief history of Cai (2+) probes is provided, and nonratiometric and ratiometric Ca(2+) probes are discussed, including probes for imaging sarcoplasmic reticulum Ca(2+) and probes compatible with potentiometric dyes for dual optical mapping. Typical measurements derived from optical Cai (2+) signals are explained, and the analytics used to compute them are presented. Last, recent studies using Cai (2+) optical mapping to study arrhythmias, heart failure, and metabolic perturbations are summarized.


Balanced botox chemodenervation of the upper face: symmetry in motion.
Cosmetic botulinum toxin type A (Botox, Allergan, Inc., Irvine, CA) has revolutionized minimally invasive treatment of the upper face. Increasingly sophisticated outcomes result in facial symmetry in motion. The face is a three-dimensional moving unit, not an isolated photograph. This is why the advanced injector must hone an astute ability to observe casual microexpressions. Consideration is then given to the patient's age, facial anatomy, facial asymmetry, and dynamic rhytids. The ratio of dosing to agonist and antagonist muscles that allows unopposed action is determined. Nuance in placement and dose combined with adjunct therapy results in natural and appropriate facial emotion and avoids unnatural or bizarre patterns of movement. Asymmetrical scenarios are presented to exemplify this process of analysis and treatment. Many authors have detailed the mechanism of action, history of Botox development, and specific muscle group treatment in the periorbital region. In this discussion, I leave behind rigorous academic analysis and wish to offer my approach, which has evolved through 15 years experience treating the aesthetic patient with Botox. The clinician can read about recommended patterns of injection, and the procedure is quite simple. It is only through skilled observation and understanding of expressive nuance and anatomy that the advanced injector will meet the goal of a natural communicative result with chemodenervation. Experience is accumulated through critical analysis of patient results over time. This discussion first directs attention to why it is important to learn how to look at the face in motion as well as at facial rhytids. A plan is developed for treatment including drug preparation, dosing decisions, precise three-dimensional delivery, and adjunct therapy. Perils may generally be avoided by choosing appropriate dosing and placement. The asymmetrical patient scenario is used to demonstrate nuance in evaluation and treatment.


Antibiofilm Efficacy of Peptide 1018 against Listeria monocytogenes and Shiga Toxigenic Escherichia coli on Equipment Surfaces.
Listeria monocytogenes and Shiga toxigenic Escherichia coli (STEC) are important foodborne bacterial pathogens that can form biofilms on equipment surfaces at food processing facilities. Pathogens in biofilms are resistant to conventional antimicrobials and require higher antimicrobial concentrations to be inactivated. In this study, the efficacy of a synthetic innate defense regulator peptide 1018 (peptide 1018) for inactivating L. monocytogenes and STEC (O26, O111, O145, O157) biofilms on stainless steel and polycarbonate surfaces was investigated. Stainless steel and polycarbonate coupons (12 mm in diameter) were used in a Centers for Disease Control and Prevention biofilm reactor containing 400 mL of 10% tryptic soy broth (TSB) that had been inoculated with an individual strain of L. monocytogenes or STEC to obtain 6 log CFU/mL populations. The reactor was set with a constant flow rate at 50 mL/h of 10% TSB for 48 h. After 48 h, coupons were treated with peptide 1018 at 0, 10, 20, or 50 μg/mL in phosphate buffer saline (PBS) for 24 h. Surviving bacterial populations were determined by scraping off the coupons and spiral plating on selective media. Significantly higher levels of pathogens in biofilms formed by certain bacterial strains, including L. monocytogenes F6854, E. coli O157:H7 RM4407 and NADC5713, and non-O157 E. coli NADC3629, were recovered on polycarbonate surfaces than on stainless steel. Antibiofilm efficacy of peptide 1018 against pathogens was concentration-dependent and varied with the type of pathogen and material surfaces. Peptide 1018 at 50 μg/mL significantly inactivated all tested bacterial biofilms on both surfaces compared with the PBS control (P < 0.05). L. monocytogenes was the bacterium most sensitive to peptide 1018; on stainless steel surfaces treated with 50 μg/mL peptide 1018, there was a 3.7- to 4.6-log CFU/cm2 reduction in Listeria populations compared with a 1.0- to 3.5-log CFU/cm2 reduction of STEC. Results suggest that peptide 1018 may be used to inactivate L. monocytogenes and STEC biofilms on equipment surfaces.


A systematic review of the effects of non-conscious regulatory processes in physical activity.
Physical activity theories have almost exclusively focused on conscious regulatory processes such as plans, beliefs, and expected value. The aim of this review was to aggregate the burgeoning evidence showing that physical activity is also partially determined by non-conscious processes (e.g., habits, automatic associations, priming effects). A systematic search was conducted and study characteristics, design, measures, effect size of the principle summary measures, and main conclusions of 52 studies were extracted by two independent coders. The findings support that habitual regulatory processes measured via self-report are directly associated with physical activity beyond conscious processes, and that there is likely interdependency between habit strength and intentions. Response latency measures of automatic associations with physical activity were widely disparate, precluding conclusions about specific effects. A small body of evidence demonstrated a variety of priming effects on physical activity. Overall, it is evident that physical activity is partially regulated by non-conscious processes, but there remain many unanswered questions for this area of research. Future research should refine the conceptualisation and measurement of non-conscious regulatory processes and determine how to harness them to promote physical activity.


Association of ADAMTS13 polymorphism with cerebral malaria.
Cerebral malaria is one of the most severe manifestations of Plasmodium falciparum malaria. The sequestration of parasitized red blood cells (PRBCs) to brain microvascular endothelium has been shown to contribute to the pathophysiology of cerebral malaria. Recent studies reported increased levels of von Willebrand factor (VWF) and reduced activity of VWF-cleaving protease, ADAMTS13 (a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13), in patients with cerebral malaria. Association of six single nucleotide polymorphisms (SNPs) of the ADAMTS13 gene with cerebral malaria was examined in 708 Thai patients with P. falciparum malaria. Among six SNPs, the derived allele of a SNP located in intron 28, rs4962153-A, was significantly associated with protection against cerebral malaria when 115 cerebral malaria patients were compared with 367 mild malaria patients (Fisher's exact P-value = 0.0057; OR = 0.27; 95% CI = 0.096-0.76). Significant association was also detected between 115 cerebral malaria and 593 non-cerebral malaria (226 non-cerebral severe malaria and 367 mild malaria) patients (Fisher's exact P-value = 0.012; OR = 0.30; 95% CI = 0.11-0.83). Excessive adhesion of PRBCs to the platelet-decorated ultra-large VWF (ULVWF) appears to enhance the sequestration of PRBCs to cerebral microvascular endothelium. The genetic association observed in the present study implies that the regulation of platelet-decorated ULVWF strings by ADAMTS13 may play a role in the development of cerebral malaria.


Personalized glucose forecasting for type 2 diabetes using data assimilation.
Type 2 diabetes leads to premature death and reduced quality of life for 8% of Americans. Nutrition management is critical to maintaining glycemic control, yet it is difficult to achieve due to the high individual differences in glycemic response to nutrition. Anticipating glycemic impact of different meals can be challenging not only for individuals with diabetes, but also for expert diabetes educators. Personalized computational models that can accurately forecast an impact of a given meal on an individual's blood glucose levels can serve as the engine for a new generation of decision support tools for individuals with diabetes. However, to be useful in practice, these computational engines need to generate accurate forecasts based on limited datasets consistent with typical self-monitoring practices of individuals with type 2 diabetes. This paper uses three forecasting machines: (i) data assimilation, a technique borrowed from atmospheric physics and engineering that uses Bayesian modeling to infuse data with human knowledge represented in a mechanistic model, to generate real-time, personalized, adaptable glucose forecasts; (ii) model averaging of data assimilation output; and (iii) dynamical Gaussian process model regression. The proposed data assimilation machine, the primary focus of the paper, uses a modified dual unscented Kalman filter to estimate states and parameters, personalizing the mechanistic models. Model selection is used to make a personalized model selection for the individual and their measurement characteristics. The data assimilation forecasts are empirically evaluated against actual postprandial glucose measurements captured by individuals with type 2 diabetes, and against predictions generated by experienced diabetes educators after reviewing a set of historical nutritional records and glucose measurements for the same individual. The evaluation suggests that the data assimilation forecasts compare well with specific glucose measurements and match or exceed in accuracy expert forecasts. We conclude by examining ways to present predictions as forecast-derived range quantities and evaluate the comparative advantages of these ranges.


[Experience in organizing the work of forensic medical experts with mass human victims after an earthquake (Neftegorsk, May-June 1995)].
The authors analyze the activities of a group of forensic medical experts of the Khabarovsk Bureau of Forensic Medical Expert Evaluation working in the team for liquidation of the consequences of the catastrophe in the town of Neftegorsk. The principles of work organization in the field were demonstrated under conditions of the minimal financing and material supply. General recommendations on the preparation and equipment of forensic medics for work in far-away regions in a focus of disaster involving numerous victims are offered.


Lung cancer following bronchoscopic lung volume reduction for severe emphysema: a case and its management.
Bronchoscopic lung volume reduction using endobronchial valves has been suggested as a potentially safer alternative to surgery in selected cases. Complications of this technique include pneumothoraces, pneumonia, COPD exacerbations, hemoptysis, and valve migrations. We report the case of a male patient who developed a parenchymal mass in the treated lobe after valve insertion. Due to severe emphysema, transthoracic needle aspiration was not feasible. Removal of the valves was mandatory to perform transbronchialbiopsies which revealed a non-small cell primary lung cancer. This first description illustrates the potential risk of lung cancer development following bronchoscopic lung volume reduction and highlights the different approach to diagnosis and management of indeterminate peripheral lung lesions needed in this context.


Counting White Blood Cells from a Blood Smear Using Fourier Ptychographic Microscopy.
White blood cell (WBC) count is a valuable metric for assisting with diagnosis or prognosis of various diseases such as coronary heart disease, type 2 diabetes, or infection. Counting WBCs can be done either manually or automatically. Automatic methods are capable of counting a large number of cells to give a statistically more accurate reading of the WBC count of a sample, but the specialized equipment tends to be expensive. Manual methods are inexpensive since they only involve a conventional light microscope setup. However, it is more laborious and error-prone because the small field-of-view (FOV) of the microscope necessitates mechanical scanning of a specimen for counting an adequate number of WBCs. Here, we investigate the use of Fourier ptychographic microscopy (FPM) to bypass these issues of the manual methods. With a 2x objective, FPM can provide a FOV of 120 mm2 with enhanced resolution comparable to that of a 20x objective, which is adequate for non-differentially counting WBCs in just one FOV. A specialist was able to count the WBCs in FPM images with 100% accuracy compared to the count as determined from conventional microscope images. An automatic counting algorithm was also developed to identify WBCs from FPM's captured images with 95% accuracy, paving the way for a cost-effective WBC counting setup with the advantages of both the automatic and manual counting methods.


Asynchronous terrestrial and marine signals of climate change during Heinrich events.
Tropical regions have been reported to play a key role in climate dynamics. To date, however, there are uncertainties in the timing and the amplitude of the response of tropical ecosystems to millennial-scale climate change. We present evidence of an asynchrony between terrestrial and marine signals of climate change during Heinrich events preserved in marine sediment cores from the Brazilian continental margin. The inferred time lag of about 1000 to 2000 years is much larger than the ecological response to recent climate change and appears to be related to the nature of hydrological changes.


Fatigue in women receiving adjuvant chemotherapy for breast cancer: characteristics, course, and correlates.
This study investigated the characteristics, course, and correlates of fatigue in women receiving adjuvant chemotherapy for breast cancer. Fifty-four patients were assessed before the start of chemotherapy and during the first three treatment cycles. An age-matched sample of women with no cancer history was assessed at similar time intervals for comparison purposes. Results indicated that breast cancer patients experienced worse fatigue than women with no cancer history. These differences were evident before and after patients started chemotherapy. In addition, fatigue worsened among patients after treatment started. More severe fatigue before treatment was associated with poorer performance status and the presence of fatigue-related symptoms (e.g., sleep problems and muscle weakness). Increases in fatigue after chemotherapy started were associated with continued fatigue-related symptoms and the development of chemotherapy side effects (e.g., nausea and mouth sores). These findings demonstrate the clinical significance of fatigue in breast cancer patients before and during adjuvant chemotherapy treatment. Results also suggest that aggressive management of common side effects, such as nausea and pain, may be useful in relieving chemotherapy-related fatigue.


Evaluating Medical Students' Views of the Complexity of Sexual Minority Patients and Implications for Care.
Purpose: Sexual and gender minority (SGM) people experience many health care disparities. We aimed to determine if medical students viewed sexual minority patients (lesbian, gay, or bisexual [LGB] men/women) as more complex than heterosexual patients, even when presenting with the same symptoms, and whether this perceived complexity affected confidence caring for LGB patients. Methods: A fictional patient with an upper respiratory infection was presented with systematic variation of the patient's sexual orientation across six experimental conditions in an online, vignette-based experimental study. Participants rated their perception of the medical, therapeutic, and social complexity of the patient, and completed a measure of stigma toward SGM people. Finally, participants indicated their confidence caring for the presented patient. Results: Overall, 665 students participated. Participants viewed the LGB patients as more complex across all domains, relative to heterosexual patients. Perceived medical and social complexity predicted lower confidence caring for the patient. Participants reported lower confidence caring for gay male patients with indirect effects of medical and social complexity. LGB identity was broadly and indirectly associated with lower confidence through social complexity. Conclusion: Our results suggest students view LGB patients as more complex compared with heterosexual patients. Medical education programs must provide training about the effects of social biases on clinical judgments and care for LGB patients, as well as build skills to ensure confidence caring for LGB patients.


Attitudes of successful contact lens wearers toward refractive surgery.
Traditionally, spectacle wearers and contact lens failures have been the patient population targeted for refractive surgery. We surveyed successful contact lens wearers to determine their attitudes toward refractive surgery. One hundred thirty-three consecutive successful myopic contact lens wearers older than 21 years were requested to read information regarding both radial keratotomy and excimer photorefractive keratectomy and complete a questionnaire. We report on the relationship between interest in undergoing radial keratotomy or photorefractive keratectomy and various patient parameters. More than 75% of those surveyed indicated that they would consider either procedure at any time in the future. The only statistically significant correlation found was that patients younger than 40 more frequently expressed an interest in undergoing radial keratotomy than patients older than 40. Nearly 70% of those surveyed would not spend more than $ 500 per eye for either procedure, and most patients grossly underestimated the costs associated with contact lens wear. In addition to spectacle wearers and contact lens failures, successful contact lens wearers can also be considered potential candidates for refractive surgery, provided it can be offered at a cost acceptable to them and if concerns regarding surgical side effects are addressed to satisfaction. This group does not appear to represent "early adapters" to new refractive technologies. The greatest interest was expressed by those younger than 40 years.


Posttraumatic cartilage degradation progresses following anterior cruciate ligament reconstruction: A second-look arthroscopic evaluation.
Several studies have demonstrated that posttraumatic knee osteoarthritis progresses even after anterior cruciate ligament reconstruction. Few reports described zone-specific cartilaginous damages after anterior cruciate ligament reconstruction. This study aimed to compare the status of articular cartilage at anterior cruciate ligament reconstruction with that at second-look arthroscopy. This study included 20 patients (20 knees, 10 males and 10 females, mean age 22.4 years, Body mass index 24.4 kg/m2) that underwent arthroscopic anatomic double-bundle anterior cruciate ligament reconstruction and second-look arthroscopy. Mean periods from injury to reconstruction and from reconstruction to second-look arthroscopy were 3.4 and 15.3 months, respectively. Cartilage lesions were evaluated arthroscopically in the 6 articular surfaces and 40 articular subcompartments independently, and these features were graded with the International Cartilage Repair Society articular cartilage injury classification; comparisons were made between the grades at reconstruction and at second-look arthroscopy. Furthermore, clinical outcomes were assessed at reconstruction and at second-look arthroscopy, using the Lysholm knee score, Tegner activity scale, International Knee Documentation Committee score, Knee injury and Osteoarthritis Outcome Score, side-to-side difference of the KT-2000 arthrometer, and pivot shift test. Each compartment showed a deteriorated condition at second-look arthroscopy compared with the pre-reconstruction period. A significant worsening of the articular cartilage was noted in all compartments except the lateral tibial plateau and was also observed in the central region of the medial femoral condyle and trochlea after reconstruction. However, each clinical outcome was significantly improved postoperatively. Good cartilage conditions were restored in most subcompartments at second-look arthroscopy. Furthermore, posttraumatic osteoarthritic changes in the patellofemoral and medial compartments progressed even in the early postoperative period, although good knee stability and clinical outcomes were obtained. Care is necessary regarding the progression of osteoarthritis and the appearance of knee symptoms in patients undergoing anterior cruciate ligament reconstruction.


Efficient isolation of Swine influenza viruses by age-targeted specimen collection.
The control of swine influenza virus (SIV) infection is paramount for increasing the productivity of pig farming and minimizing the threat of pandemic outbreaks. Thus, SIV surveillance should be conducted by region and on a regular basis. Here, we established a microneutralization assay specific for SIV seroprevalence surveillance by using reporter gene-expressing recombinant influenza viruses. Growth-based SIV seroprevalence revealed that most sows and piglets were positive for neutralizing antibodies against influenza viruses. In contrast, the 90-day-old growing pigs exhibited limited neutralizing activity in their sera, suggesting that this particular age of population is most susceptible to SIV infection and thus is an ideal age group for SIV isolation. From nasal swab specimens of healthy pigs in this age population, we were able to isolate SIVs at a higher incidence (5.3%) than those of previous reports. Nucleotide sequencing and phylogenetic analysis of the hemagglutinin (HA) genes revealed that the isolated SIVs have circulated and evolved in pigs but not have been recently introduced from humans, implying that a large number of SIV lineages may remain "undiscovered" in the global porcine populations. We propose that the 90-day-old growing pig-targeted nasal swab collection presented in this study facilitates global SIV surveillance and contributes to the detection and control of SIV infection.


Predictors of perinatal death in the presence of missing data: A birth registry-based study in northern Tanzania.
More than five million perinatal deaths occur each year globally. Despite efforts put forward during the millennium development goals era, perinatal deaths continue to increase relative to under-five deaths, especially in low- and middle-income countries. This study aimed to determine predictors of perinatal death in the presence of missing data using birth registry data from Kilimanjaro Christian Medical Center (KCMC), between 2000-2015. This was a retrospective cohort study from the medical birth registry at KCMC referral hospital located in Moshi Municipality, Kilimanjaro region, northern Tanzania. Data were analyzed using Stata version 15.1. Multiple imputation by fully conditional specification (FCS) was used to impute missing values. Generalized estimating equations (GEE) were used to determine the marginal effects of covariates on perinatal death using a log link mean model with robust standard errors. An exchangeable correlation structure was used to account for the dependence of observations within mothers. Among 50,487 deliveries recorded in the KCMC medical birth registry between 2000-2015, 4.2% (95%CI 4.0%, 4.3%) ended in perinatal death (equivalent to a perinatal mortality rate (PMR) of 41.6 (95%CI 39.9, 43.3) deaths per 1,000 births). After the imputation of missing values, the proportion of perinatal death remained relatively the same. The risk of perinatal death was significantly higher among deliveries from mothers who resided in rural compared to urban areas (RR = 1.241, 95%CI 1.137, 1.355), with primary education level (RR = 1.201, 95%CI 1.083, 1.332) compared to higher education level, with <4 compared to ≥4 antenatal care (ANC) visits (RR = 1.250, 95%CI 1.146, 1.365), with postpartum hemorrhage (PPH) (RR = 2.638, 95%CI 1.997, 3.486), abruption placenta (RR = 4.218, 95%CI 3.438, 5.175), delivered a low birth weight baby (LBW) (RR = 4.210, 95%CI 3.788, 4.679), male child (RR = 1.090, 95%CI 1.007, 1.181), and were referred for delivery (RR = 2.108, 95%CI 1.919, 2.317). On the other hand, deliveries from mothers who experienced premature rupture of the membranes (PROM) (RR = 0.411, 95%CI 0.283, 0.598) and delivered through cesarean section (CS) (RR = 0.662, 95%CI 0.604, 0.724) had a lower risk of perinatal death. Perinatal mortality in this cohort is higher than the national estimate. Higher risk of perinatal death was associated with low maternal education level, rural residence, <4 ANC visits, PPH, abruption placenta, LBW delivery, child's sex, and being referred for delivery. Ignoring missing values in the analysis of adverse pregnancy outcomes produces biased covariate coefficients and standard errors. Close clinical follow-up of women at high risk of experiencing perinatal death, particularly during ANC visits and delivery, is of high importance to increase perinatal survival.


Betulinic acid exerts potent antitumor effects on paclitaxel-resistant human lung carcinoma cells (H460) via G2/M phase cell cycle arrest and induction of mitochondrial apoptosis.
Betulinic acid is a pentacyclic plant compound obtained from the bark of white birch trees and has been demonstrated to exhibit notable pharmacological properties. In the present study, the anticancer potential of betulinic acid on paclitaxel-resistant lung cancer cell line (H460) was evaluated. Cell viability was evaluated by an MTT assay, and a clonogenic assay was performed to assess the effects on cancer cell colony formation. DAPI staining using fluorescence microscopy and flow cytometry were employed to evaluate the effects of betulinic acid on apoptosis. The effects of betulinic acid on the cell cycle and mitochondrial membrane potential were also evaluated by flow cytometry. The effects of betulinic acid on the protein expression of B-cell lymphoma-2 (Bcl-2)/Bcl-2-associated X (Bax) were evaluated by western blot analysis. The results of the present study indicated that the half-maximal inhibitory concentration value of betulinic acid on paclitaxel-resistant H460 lung cancer cells was 50 µM. The treatment with betulinic acid was able to inhibit the colony formation potential in a dose-dependent manner. A lower cytoxicity by betulinic acid against normal human epithelial FR2 cells was observed compared with H460 cells. The betulinic acid exerted anticancer activity via the induction of apoptosis by regulating the Bcl-2/Bax signaling pathway. Additionally, treatment with betulinic acid resulted in cell cycle arrest of paclitaxel-resistant lung cancer H460 cells at the G2/M phase. Betulinic acid was also reported to cause reductions in the mitochondrial membrane potential in a dose-dependent manner. In conclusion, the results of the present study indicated that betulinic acid may be a useful drug candidate for the management of drug-resistant lung cancer.


Comparison of topical nedocromil sodium and oral terfenadine for the treatment of seasonal allergic conjunctivitis.
This double-masked, comparative, multicenter study was conducted to assess the onset of action and tolerability of nedocromil sodium 2% ophthalmic solution BID, 60-mg terfenadine tablets BID, and placebo in the treatment of seasonal allergic conjunctivitis. Two hundred sixty-eight patients in whom seasonal allergic conjunctivitis was diagnosed were assigned to 1 of 3 groups and administered study medication for 4 weeks. Patients' mean age was 33 years (range, 12 to 68 years); 57.8% (155 of 268) were female. Demographic characteristics were similar in all 3 groups. Although all 3 groups showed improvement in ocular symptoms, nedocromil sodium was associated with a statistically significantly faster onset of action than was terfenadine or placebo (P = 0.038). During the study, 29 nedocromil sodium-treated patients (36.7%) achieved control of symptoms in < or =2 minutes, and 61 (77.2%) achieved control in < or =15 minutes. The corresponding numbers were 21 (24.7%) and 50 (58.8%) in the terfenadine group and 25 (29.1%) and 48 (55.8%) in the placebo group. The frequency of adverse events was low and similar between groups (nedocromil sodium, 26; terfenadine, 32; placebo, 32). No severe treatment-related adverse events were reported. In conclusion, nedocromil sodium had a significantly faster onset of action than did terfenadine or placebo.


Method for Accurate Detection of Amino Acids and Mycotoxins in Planetary Atmospheres.
We present a systematic analysis of a large number of mass spectra accumulated as the number of ion fragments recorded in unit mass-to-charge detector channels. The method retrieves the abundances of detected species using an efficient deconvolution algorithm, which relies on fragment pattern recognition, mass calibration, and background correction. The abundance analysis identifies target species, amino acids, and mycotoxins through their characteristic fragmentation patterns in the presence of an increasing number of interfering species. The method offered robust and efficient retrieval of abundances of metabolic molecules in complex mixtures obscured by a wide range of toxic compounds.


The horizontal (tangential) fibres system of lamina I of the cerebral neocortex.
Lamina I has two principal components: a meshwork of fine unmyelinated fibres, the so-called horizontal fibres (h.f.); the profusely branching apical dendrites of all pyramidal cells. These dendrites are studded with spines on which the h.f.'s make excitatory synapses in a crossing-over manner. The h.f. system is produced by the fibres that ascend through the modules and bifurcate in lamina I, each branch extending for up to 5 mm from its origin. These ascending fibres are axons of Martinotti cells, and of corticocortical fibre inputs to the module, both ipsilateral and callosal. Electrophysiological investigations have shown that the h.f. system has a powerful excitatory action on the pyramidal cells. There will be developed the hypothesis that the h.f.-pyramidal dendrite system of lamina I is a structure specially designed for the storage of memories. Conjunction of cartridge activation of pyramidal cell dendrites with a selection of impulses in h.f.'s could produce a synaptic potentiation encoding the experience that is dependent on that selection of h.f. impulses. On a later occasion these potentiated synapses could be effective in replaying the coded neuronal pattern and so retrieving the memory.


Mediators of allostasis and systemic toxicity in bipolar disorder.
Bipolar disorder is associated with a high rate of medical and psychiatric comorbidities. This burden of illness, along with cognitive impairment, is seen particularly in late cases, after multiple episodes. These changes in clinical presentation that take place over time have been recently conceptualized as "neuroprogression". The concept of allostatic load is instrumental in understanding how the cumulative stress associated with psychiatric disorders translates into bodily wear and tear, thus providing an underlying explanation for illness progression. Allostatic load is engendered by several factors which interact in a nonlinear manner. Glucocorticoids are fundamental mediators; when chronically in excess, glucocorticoids initiate a series of bodily dysfunctions that may include cortisol-related mitochondrial dysfunction, oxidative stress, inflammation and decrease in the expression of neuroprotective factors. In the present review we examine the role of allostatic load in the illness progression that takes place in bipolar disorder.


Association Study of the 5'UTR Intron of the FAD2-2 Gene With Oleic and Linoleic Acid Content in Olea europaea L.
Cultivated olive (Olea europaea L. subsp. europaea var. europaea) is the most ancient and spread tree crop in the Mediterranean basin. An important quality trait for the extra virgin olive oil is the fatty acid composition. In particular, a high content of oleic acid and low of linoleic, linolenic, and palmitic acid is considered very relevant in the health properties of the olive oil. The oleate desaturase enzyme encoding-gene (FAD2-2) is the main responsible for the linoleic acid content in the olive fruit mesocarp and, therefore, in the olive oil revealing to be the most important candidate gene for the linoleic acid biosynthesis. In this study, an in silico and structural analysis of the 5'UTR intron of the FAD2-2 gene was conducted with the aim to explore the natural sequence variability and its role in the gene expression regulation. In order to identify functional allele variants, the 5'UTR intron was isolated and partially sequenced in 97 olive cultivars. The sequence analysis allowed to find a 117-bp insertion including two long duplications never found before in FAD2-2 genes in olive and the existence of many intron-mediated enhancement (IME) elements. The sequence polymorphism analysis led to detect 39 SNPs. The candidate gene association study conducted for oleic and linoleic acids content revealed seven SNPs and one indel significantly associated able to explain a phenotypic variation ranging from 7% to 16% among the years. Our study highlighted new structural variants within the FAD2-2 gene in olive, putatively involved in the regulation mechanisms of gene expression associated with the variation of the content of oleic and linoleic acid.


Arachidonic acid mediates interferon-gamma-induced sphingomyelin hydrolysis and monocytic marker expression in HL-60 cell line.
The biochemical signaling mechanisms involved in transducing the effects of interferon-gamma (IFN-gamma) on human leukemia-derived HL-60 cell differentiation are not completely understood. Recent studies established the existence of a sphingomyelin (SM) cycle that operates in response to the action of IFN-gamma on HL-60 cells, but the mechanisms by which IFN-gamma induces the SM hydrolysis remain unexplored. In this study, biochemical events mediating IFN-gamma effects on SM turnover and their specificity and role in HL-60 differentiation were investigated. The activation of the SM cycle by IFN-gamma occurred rapidly, with a decrease of approximately 20% in the SM level observed after 60 minutes with a concomitant increase in ceramide level. Treatment of HL-60 cells with IFN-gamma did not influence the 1,2-diacylglycerol concentration, intracellular Ca2+ concentration, or phospholipase D activity. IFN-gamma stimulated a rapid release of arachidonic acid (AA) from HL-60 cells; the effect was abolished by the pretreatment of cells with pertussis toxin, suggesting a role for a pertussis-toxin-sensitive G protein in IFN-gamma-mediated activation of phospholipase A2 (PLA2). At 4 to 120 hours after the stimulation of the cells with IFN-gamma, a significant increase in the particulate and soluble PLA2 activity was observed, corresponding to an increase in the level of immunoreactive cPLA2 in both cytosol and membrane fractions. The treatment of cells with tyrosine kinase inhibitor herbimycin A completely abolished the effect of IFN-gamma on PLA2 activity in membrane and cytosolic fractions, but had no effect on IFN-gamma-mediated early AA release suggesting dual mechanism of PLA2 activation. Melittin, potent activator of PLA2, and AA mimicked the effect of IFN-gamma on SM hydrolysis. Pretreatment of HL-60 cells with the PLA2 inhibitor, bromophenacyl bromide (BPB), or pertussis toxin abolished the effect of IFN-gamma on SM hydrolysis; exogenous addition of AA overcame the effects of BPB and pertussis toxin. Long-term exposure (5 days) of HL-60 cells to IFN-gamma caused an increase in nitroblue tetrazolium (NBT)-reducing and nonspecific esterase (NSE) activity and induced expression of Fc gamma RI (CD64) without significant effects on cell number, adherence, or phagocytic activity. The treatment of cells with AA or melittin induced NBT, NSE, and CD64 expression to the level similar to that observed with IFN-gamma, and no further increase was observed with the combination of IFN-gamma and AA or IFN-gamma and melittin. Treatment of HL-60 cells with indomethacin, an inhibitor of cyclo-oxygenase, and nordihydroguaiaretic acid (NDGA), an inhibitor of lipoxygenase, had no effects on IFN-gamma-mediated induction of CD64 expression. These studies indicate a key role for the phospholipase A2/AA pathway, as an early biochemical signal elicited by the occupation of IFN-gamma-receptor, in mediating IFN-gamma induction of the SM cycle and phenotypic changes associated with differentiation of HL-60 along monocytic lineage.


Association between epicardial adipose tissue and cardiac dysfunction in subjects with severe obesity.
Epicardial adipose tissue (EAT) plays a role in obesity-related heart failure with preserved ejection fraction. However, the association of EAT thickness with the development of cardiac dysfunction in subjects with severe obesity without known cardiovascular disease is unclear. The aim of this study was to determine the association between EAT thickness and cardiac dysfunction and describe the potential value of EAT as an early marker of cardiac dysfunction. Subjects with body mass index ≥35 kg/m2 aged 35 to 65 years, who were referred for bariatric surgery, without suspicion of or known cardiac disease, were enrolled. Conventional transthoracic echocardiography and strain analyses were performed. A total of 186 subjects were divided into tertiles based on EAT thickness, of whom 62 were in EAT-1 (EAT <3.8 mm), 63 in EAT-2 (EAT 3.8-5.4 mm), and 61 in EAT-3 (EAT >5.4 mm). Parameters of systolic and diastolic function were comparable between tertiles. Patients in EAT-3 had the lowest global longitudinal strain (GLS) and left atrial contractile strain (LASct). Linear regression showed that a one-unit increase in EAT thickness (mm) was independently associated with a decrease in GLS (%) (β coefficient -0.404, p = 0.002), and a decrease in LASct (%) (β coefficient -0.544, p = 0.027). Furthermore, EAT-3 independently predicted cardiac dysfunction as defined by a GLS <18% (odds ratio 2.8, p = 0.013) and LASct <14% (odds ratio 2.5, p = 0.045). Increased EAT thickness in subjects with obesity without known cardiac disease was independently associated with subclinical cardiac dysfunction. Our findings suggest that EAT might play a role in the early stages of cardiac dysfunction in obesity before this may progress to overt clinical disease.


[Syndrome distribution among patients with chronic hepatitis C and interventions of integrated traditional Chinese and Western medicine: study protocol].
Chronic hepatitis C is one of the major causes of end-stage liver disease with a high incidence rate, amounting to a grave and serious problem of public health. Currently, interferon-based (with or without ribavirin) antiviral therapy has limited use due to its stringent indications, possible contraindications and side effects. Traditional Chinese medicine (TCM) may have advantages in the prevention and treatment of chronic hepatitis C and it is of significant value to discover the advantages. Through this research, a safe and effective treatment protocol of TCM or integrated TCM and Western medicine for chronic hepatitis C can be formed. To this end, during China's Eleventh Five-Year Plan, special research projects on acquired immune deficiency syndrome (AIDS), viral hepatitis and the other major infectious diseases were established. Our studies on chronic hepatitis C constitute one of the major special research topics. Clinical information of patients with chronic hepatitis C will be first collected in a large, multicenter epidemiological survey. Positive symptoms will be analyzed by rapid cluster analysis, principal constituent analysis and factor analysis, and syndrome types will be diagnosed based on expert advice. Concurrently, a large, multicenter, randomized, parallel-group prospective study will be launched based on evidence-based medical principles to evaluate the effects and safety of the treatment protocol for chronic hepatitis C. The evaluated indexes will include the normalization rate of liver function, virological improvement and quality of life improvement for the short-term efficacy and the incidence of liver cirrhosis and (or) primary liver cancer and mortality for the long-term efficacy. This study will investigate the TCM syndrome differentiation norms and the syndrome distribution rules of chronic hepatitis C and evaluate the efficacy and safety of a treatment protocol for chronic hepatitis C based on TCM theory or combined treatment of TCM and Western medicine. The study results will be helpful to developing a TCM treatment program for chronic hepatitis C. The research program was registered in the Chinese Clinical Trial Registry in English and Chinese in January 2010. ChiCTR-TRC-10000770.


Exploring antibody repurposing for COVID-19: beyond presumed roles of therapeutic antibodies.
The urgent need for a treatment of COVID-19 has left researchers with limited choice of either developing an effective vaccine or identifying approved/investigational drugs developed for other medical conditions for potential repurposing, thus bypassing long clinical trials. In this work, we compared the sequences of experimentally verified SARS-CoV-2 neutralizing antibodies and sequentially/structurally similar commercialized therapeutic monoclonal antibodies. We have identified three therapeutic antibodies, Tremelimumab, Ipilimumab and Afasevikumab. Interestingly, these antibodies target CTLA4 and IL17A, levels of which have been shown to be elevated during severe SARS-CoV-2 infection. The candidate antibodies were evaluated further for epitope restriction, interaction energy and interaction surface to gauge their repurposability to tackle SARS-CoV-2 infection. Our work provides candidate antibody scaffolds with dual activities of plausible viral neutralization and immunosuppression. Further, these candidate antibodies can also be explored in diagnostic test kits for SARS-CoV-2 infection. We opine that this in silico workflow to screen and analyze antibodies for repurposing would have widespread applications.


Transgenic analysis of the BmBLOS2 gene that governs the translucency of the larval integument of the silkworm, Bombyx mori.
The larval integument of the silkworm, Bombyx mori, is opaque because urate granules accumulate in the epidermis. Although the biosynthetic pathway of uric acid is well studied, little is known about how uric acid accumulates as urate granules in epidermal cells. In the distinct oily (od) mutant silkworm, the larval integument is translucent because of the inability to construct urate granules. Recently, we have found that the od mutant has a genomic deletion in the B. mori homologue of the human biogenesis of lysosome-related organelles complex1, subunit 2 (BLOS2) gene (BmBLOS2). Here, we performed a molecular and functional characterization of BmBLOS2. Northern blot analysis showed that BmBLOS2 was ubiquitously expressed in various tissues. We analysed the structure of a newly isolated mutant (od(B) ) allelic to od and found a premature stop codon in the coding sequence of BmBLOS2 in this new mutation. Moreover, the translucent phenotype was rescued by the germ-line transformation of the wild-type BmBLOS2 allele into the od mutant. Our results suggest that BmBLOS2 is responsible for the od mutant phenotype and plays a crucial role in biogenesis of urate granules in the larval epidermis of the silkworm. The relationships amongst Hermansky-Pudlak syndrome (HPS) genes in mammals, granule group genes in Drosophila and translucent mutant genes in B. mori are discussed.


Copper-catalyzed trifluoromethylazidation and rearrangement of aniline-linked 1,7-enynes: access to CF3-substituted azaspirocyclic dihydroquinolin-2-ones and furoindolines.
A set of reactions involving copper-catalyzed trifluoromethylazidation and then rearrangement of aniline-linked 1,7-enynes with the relatively poorly reactive Togni reagent I and TMSN3 was developed, and provided facile access to structurally diverse and useful CF3-substituted azaspirocyclic dihydroquinolin-2-ones bearing two adjacent quaternary carbon centers. We were also able to obtain these products on a large scale. Moreover, the obtained products were further transformed into a range of synthetically valuable furoindolines bearing three consecutive quaternary carbon centers after reduction by NaBH4. Also, the delivery of multi-functionalized aziridines as a result of alcoholysis and LiAlH4-reduction of corresponding dihydroquinolin-2-ones 2ba demonstrated the synthetic value of this newly developed protocol.


A case of successful management of portosystemic shunt with autosomal dominant polycystic kidney disease by balloon-occluded retrograde transvenous obliteration and partial splenic embolization.
We describe a patient with autosomal dominant polycystic kidney disease who was successfully managed for severe abdominal distension, impaired liver function and a portosystemic shunt by interventional therapies. The patient's intra-hepatic portal vein was compressed and narrowed by multiple liver cysts, which resulted in a decrease of the portal blood flow and portal hypertension due to a huge gastro-renal shunt These haemodynamic changes were assumed to contribute to insufficient protein synthesis in the liver. Therefore, we first repeatedly performed minocycline hydrochloride instillations to treat the multiple liver cysts. Then, we conducted a partial splenic embolization to prevent elevation of the portal vein pressure prior to balloon-occluded retrograde transvenous obliteration which was performed to increase the portal blood flow. The portal blood flow markedly increased, and protein synthesis in the liver also recovered and the clinical symptoms improved. The patient has been monitored for more than two years up to the present and her liver function parameters have remained within the normal range. Renal insufficiency is known to be a major prognostic factor in autosomal dominant polycystic kidney disease. In some cases, however, liver involvement with multiple cysts may result in a fatal outcome. In such cases, interventional therapies, as provided to this patient, should be considered.


Effect of fluticasone propionate and salmeterol on Pseudomonas aeruginosa infection of the respiratory mucosa in vitro.
The purpose of this study was to investigate the effect of the corticosteroid, fluticasone propionate (FP), on Pseudomonas aeruginosa infection of the respiratory mucosa of an organ culture model in vitro. Organ cultures infected with P. aeruginosa had significantly (p< or =0.05) elevated levels of mucosal damage and significantly (p< or =0.05) less ciliated cells compared to controls. Preincubation of tissue with FP (10(-6) or 10(-5) but not 10(-7) M) prior to P. aeruginosa infection significantly (p< or =0.05) reduced the bacterially induced mucosal damage in a concentration-dependent manner. FP (10(-5) M) also significantly (p< or =0.05) prevented loss of ciliated cells. FP did not alter the density of bacteria adherent to the different mucosal features of the organ cultures, but did reduce total bacterial numbers due to the reduced amount of damaged tissue, which is a preferred site of P. aeruginosa adherence. It has previously been shown that the long-acting beta2-agonist salmeterol (4 x 10(-7)M) also reduces the mucosal damage caused by P. aeruginosa infection, probably via elevation of intracellular cyclic adenosine monophosphate concentrations. Preincubation of tissue with both 10(-7)M FP and 10(-7)M salmeterol, concentrations at which they did not by themselves influence the effect of P. aeruginosa infection, significantly (p< or =0.05) reduced P. aeruginosa-induced loss of cilia. However, there was no additional benefit from adding 4 x 10(-7)M salmeterol to 10(-6)M FP. In conclusion fluticasone propionate reduced mucosal damage caused by P. aeruginosa infection in vitro and preserved ciliated cells. There was a synergistic action with salmeterol in the preservation of ciliated cells.


Absence of mechanical loading in utero influences bone mass and architecture but not innervation in Myod-Myf5-deficient mice.
Although the responses of bone to increased loading or exercise have been studied in detail, our understanding of the effects of decreased usage of the skeleton has been limited by the scarcity of suitable models. Such models should ideally not affect bone innervation, which appears to be a mediator of physiological responses of bone to unloading. MyoD-/-/Myf5-/- (dd/ff) mice lack skeletal muscle, so the fetuses develop without any active movement in utero and die soon after birth. We used micro-compter tomography and histology to analyse their bone development and structure during endochondral ossification in parallel with the establishment of bone innervation. Long bones from mutant mice were found to be profoundly different from controls, with shorter mineralized zones and less mineralization. They lacked many characteristics of adult bones - curvatures, changes in shaft diameter and traction epiphyses where muscles originate or insert - that were evident in the controls. Histologically, dd/ff mice showed the same degree of endochondral development as wild-type animals, but presented many more osteoclasts in the newly layed bone. Innervation and the expression pattern of semaphorin-3A signalling molecules were not disturbed in the mutants. Overall, we have found no evidence for a major defect of development in dd/ff mice, and specifically no alteration or delay in endochondral ossification and bone innervation. The altered morphological features of dd/ff mice and the increased bone resorption show the role of muscle activity in bone shaping and the consequences of bone unloading.


Evaluation of bread crumbs as a potential carbon source for the growth of thraustochytrid species for oil and omega-3 production.
The utilization of food waste by microorganisms to produce omega-3 fatty acids or biofuel is a potentially low cost method with positive environmental benefits. In the present study, the marine microorganisms Thraustochytrium sp. AH-2 and Schizochytrium sp. SR21 were used to evaluate the potential of breadcrumbs as an alternate carbon source for the production of lipids under static fermentation conditions. For the Thraustochytrium sp. AH-2, submerged liquid fermentation with 3% glucose produced 4.3 g/L of biomass and 44.16 mg/g of saturated fatty acids after seven days. Static fermentation with 0.5% and 1% breadcrumbs resulted in 2.5 and 4.7 g/L of biomass, and 42.4 and 33.6 mg/g of saturated fatty acids, respectively. Scanning electron microscopic (SEM) studies confirmed the growth of both strains on breadcrumbs. Attenuated total reflection Fourier transform infrared (ATR-FTIR) spectroscopy for both strains were consistent with the utilization of breadcrumbs for the production of unsaturated lipids, albeit at relatively low levels. The total lipid yield for static fermentation with bread crumbs was marginally lower than that of fermentation with glucose media, while the yield of unsaturated fatty acids was considerably lower, indicating that static fermentation may be more appropriate for the production of biodiesel than for the production of omega-3 rich oils in these strains.


Modified technique of robotic-assisted simple prostatectomy: advantages of a vesico-urethral anastomosis.
To describe a technical modification during robotic-assisted simple prostatectomy (RASP) aiming to decrease perioperative blood loss, shorten the length of hospital stay and eliminate the need of postoperative continuous bladder irrigation. To describe perioperative outcomes, pathological findings and functional outcomes of our single-surgeon series using this technique. We analysed six consecutive patients who underwent RASP using our technical modification between February and September 2010. Transrectal ultrasonography (TRUS) guided prostate biopsy was performed in all cases and revealed benign prostatic hyperplasia in two cases and benign prostatic hyperplasia plus chronic prostatitis in four cases. The mean estimated prostate volume in the TRUS was 157 ± 74 (range 90-300) mL and the average preoperative International Prostate Symptom score was 19.8 ± 9.6 (10-32). Two patients were in urinary retention before surgery. Our technique of RASP includes the standard operative steps reported during open and laparoscopic simple prostatectomy; however, with the addition of some technical modifications during the reconstructive part of the procedure. Following the resection of the adenoma, instead of performing the classical 'trigonization' of the bladder neck and closure of the prostatic capsule, we propose three modified surgical steps: plication of the posterior prostatic capsule, a modified van Velthoven continuous vesico-urethral anastomosis and, finally, suture of the anterior prostatic capsule to the anterior bladder wall. The patients' average age was 69 ± 4.9 (63-74) years; the mean estimated blood loss was 208 ± 66 (100-300) mL and the mean operative time was 90 ± 17.6 (75-120) min. All patients were discharged on postoperative day 1 without the need of continuous bladder irrigation at any time after RASP. No blood transfusion or perioperative complications were reported. The mean weight of the surgical specimen was 145 ± 41.6 (84-186) g. Histopathological evaluation revealed benign prostatic hyperplasia plus chronic prostatitis in five patients and prostatic adenocarcinoma (Gleason score 3+3, pT1a) with negative surgical margins in one patient. The mean serum prostate-specific antigen level decreased from 7 ± 2.5 (4.2-11) ng/mL preoperatively to 1.05 ± 0.8 (0.2-2.5) after RASP. Significant improvement from baseline was reported in the average International Prostate Symptom score (average preoperative vs postoperative, 19.8 ± 9.6 vs 5.5 ± 2.5, P= 0.01) and in mean maximum urine flow (average preoperative vs postoperative 7.75 ± 3.3 vs 19 ± 4.5 mL/s, P= 0.019) at 2 months after RASP. All patients were continent (defined as the use of no pads) at 2 months after RASP. Our modified technique of RASP is a safe and feasible option for treatment of lower urinary tract symptoms caused by large prostatic adenomas. Potential advantages of our technique include reduced blood loss, lower blood transfusion rates and shorter length of hospital stay with no need of postoperative continuous bladder irrigation. Larger series with longer follow-up are necessary to determine long-term outcomes in comparison to open simple prostatectomy or to the standard technique of RASP.


Risedronate rapidly reduces the risk for nonvertebral fractures in women with postmenopausal osteoporosis.
Prevention of nonvertebral fractures, which account for a substantial proportion of osteoporotic fractures, is an important goal of osteoporosis treatment. Risedronate, a pyridinyl bisphosphonate, significantly reduces clinical vertebral fracture incidence within 6 months. To determine the effect of risedronate on osteoporosis-related nonvertebral fractures, data from four large, randomized, double-blind, placebo-controlled, Phase III studies were pooled and analyzed. The population analyzed consisted of postmenopausal women, with and without vertebral fractures, who had low bone mineral density (lumbar spine T-score <-2.5). Patients received placebo (N = 608) or risedronate 5 mg daily (N = 564) for 1 to 3 years. At baseline, 58% had at least one prevalent vertebral fracture, and the mean lumbar spine T-score was -3.4. Among placebo-treated patients, the presence of prevalent vertebral fractures did not increase the risk of incident nonvertebral fractures overall, although fractures of the humerus and hip and pelvis were more common in patients who had prevalent vertebral fractures than in those who did not. Risedronate 5 mg significantly reduced the incidence of nonvertebral fractures within 6 months compared with control. After 1 year, nonvertebral fracture incidence was reduced by 74% compared with control ( P = 0.001), and after 3 years, the incidence was reduced by 59% ( P = 0.002). The results indicate that risedronate significantly reduces the incidence of osteoporosis-related nonvertebral fractures within 6 months.


Oxidative resistance of the plasma and electrophysiological remodeling of the myocardium in coronary patients.
The diagnostic and prognostic potentialities of the parameters of free-radical processes and high resolution ECG in coronary disease were evaluated. A relationship between oxidative resistance of the plasma (MDA concentration after 24-h copper-induced oxidation) and clinical characteristics of coronary disease (functional class of angina and high-resolution ECG parameters) was detected. Changes in ECG parameters directly correlated with MDA levels, the frequency of their registration reflects the severity of coronary disease. The absolute values of ECG, MDA, and their dynamics correlated with the severity of coronary disease and outcome of acute coronary syndrome, the prognosis was unfavorable for patients with MDA level >100 nmol/ml. The level of MDA increased by days 5-7 of observation in all patients with acute coronary syndrome, indicating exhaustion of the plasma antioxidant system during exacerbation of the coronary syndrome. Hence, evaluation of the plasma oxidative resistance and high resolution ECG can serve as a new diagnostic complex approach for detecting coronary patients with an unfavorable prognosis.


Texting is caring: a content analysis of clinical text messages by hospitalists.
Clinical texting systems (CTS) are widely used in hospitals for team communication about patients. With more institutions adopting such systems, there is a need to understand how texting is being used in clinical practice. We conducted content analysis of 809 randomly selected message threads sent to and from hospitalists in a 9-month window. The process, purpose and content of messages were analysed. We also examined messages for personal content (to identify whether CTS was being used for professional matters) and discussion of near miss errors. The risk levels of these near misses were also assessed. Most messages focused on clinical management of patient needs (62%; n=498) and functioned to provide a notification or update regarding clinical care (64%; n=518) or make a request of the recipient (63%; n=510). Personal content was infrequent in message threads (10%; n=80). Five per cent (n=38) of message threads included discussion of a near miss, and most near misses posed low clinical risk overall (66%; n=25). Most CTS communication centred around direct clinical management. Fewer messages were focused on non-clinical areas such as administrative tasks or personal communication. Further examination of care delivery, error communication and the consequences of the care discussed in messages would help clinical leaders understand the impact of clinical texting on teamwork and quality of care.


Exocrine pancreatic function in hepatic cirrhosis.
Exocrine pancreatic function was assessed by the standard test meal method of Lundh in a control group, and 13 patients with nonalcoholic, postnecrotic cirrhosis of the liver. In six of these patients, splenorenal shunts were performed and exocrine pancreatic function was assessed before and three months after operation. In three of the six, the secretin-pancreozymin stimulation test was also performed. An increased volume but normal trypsin output was observed in the unoperated cirrhotic patients. An increase both in volume and in trypsin was found in the cirrhotic patients after shunting using the test meal stimulation. There was no appreciable difference, however, when tested with secretin and pancreozymin. Hypersecretion in cirrhotics, with or without shunts, is probably due to a by-pass of the hepatic degradation of normal pancreatic secretogogues produced by the intestine.


[Current status of the diagnosis and treatment of urinary incontinence in Spain].
To perform a review of the available literature about urinary incontinence (UI) epidemiology, diagnosis, treatment and results, mainly focusing on the stress UI, to expose the features about which may there be a consensus, and those that will need future research work. Systematic review of the available spanish bibliography about the proposed topic. They prevalence of female UI in Spain varies between 20 and 50%, depending on age. There are no available data about incidence. The onset age of this disease has not been directly studied in any of the works reviewed, although from them it can be deduced that it is around 55 years. The patient with UI tends to hide the problem, and generally, doctors tend to not recognize it as a treatable pathology, so that supposedly there is a high prevalence off occult UI. UI is frequently related to many other pathologies. The diagnosis of UI in Spain is generally made following the international criteria collected in the available clinical practice guidelines, which describe the diagnostic process to be followed in detail. Diagnostic tests generally used in the diagnosis of UI have a sensitivity higher than 70% and a specificity around 65%. First choice treatment is conservative, including the use of physiotherapy by means of pelvic muscle exercises. It is considered that pharmacological treatment has not much effect, although it doesn't seem to have been investigated in depth in Spain. Surgery, in any of its various techniques, is the second choice treatment. Although studies on health results for UI are scarce, it is known that about one-quarter of all patients declare that their quality of life is affected. Economic studies about UI are very rare also and only offer results about some treatment items. To better precise the incidence and prevalence of UI in Spain, the performance of population epidemiological studies seems necessary. The weakness of the diagnostic process of UI in Spain appears to be detection in the initial stages. It is also necessary to have studies evaluating conservative and pharmacological therapies currently performed; these studies would allow to establish comparisons with the surgical treatments usually performed. It is also necessary to have studies that include cost calculation for integrated costs for UI.


[Dilated and ischemic cardiomyopathy: differential diagnosis].
A uniform set of differential-diagnostic methods was used in 45 patients with dilated cardiomyopathy (DCMP) and 36 patients with ischemic cardiomyopathy (ICMP). The following parameters, significant for differentiation of the above diseases, have been defined: case history data, more deep decrease of global myocardial contractility and dilation of cardiac chambers, prevalence of increased linear sizes of the right ventricle, reduction of linear sizes of the aorta and left ventricular hypertrophy in DCMP; a different direction of left ventricular contractility index in dobutamine test.


Increased ERK signalling promotes inflammatory signalling in primary airway epithelial cells expressing Z α1-antitrypsin.
Overexpression of Z α1-antitrypsin is known to induce polymer formation, prime the cells for endoplasmic reticulum stress and initiate nuclear factor kappa B (NF-κB) signalling. However, whether endogenous expression in primary bronchial epithelial cells has similar consequences remains unclear. Moreover, the mechanism of NF-κB activation has not yet been elucidated. Here, we report excessive NF-κB signalling in resting primary bronchial epithelial cells from ZZ patients compared with wild-type (MM) controls, and this appears to be mediated by mitogen-activated protein/extracellular signal-regulated kinase, EGF receptor and ADAM17 activity. Moreover, we show that rather than being a response to protein polymers, NF-κB signalling in airway-derived cells represents a loss of anti-inflammatory signalling by M α1-antitrypsin. Treatment of ZZ primary bronchial epithelial cells with purified plasma M α1-antitrypsin attenuates this inflammatory response, opening up new therapeutic options to modulate airway inflammation in the lung.