Jin, Seok Min; Lazarou, Michael; Wang, Chunxin; Kane, Lesley A; Narendra, Derek P; Youle, Richard J
PINK1 is a mitochondrial kinase mutated in some familial cases of Parkinson's disease. It has been found to work in the same pathway as the E3 ligase Parkin in the maintenance of flight muscles and dopaminergic neurons in Drosophila melanogaster and to recruit cytosolic Parkin to mitochondria to mediate mitophagy in mammalian cells. Although PINK1 has a predicted mitochondrial import sequence, its cellular and submitochondrial localization remains unclear in part because it is rapidly degraded. In this study, we report that the mitochondrial inner membrane rhomboid protease presenilin-associated rhomboid-like protein (PARL) mediates cleavage of PINK1 dependent on mitochondrial membrane potential. In the absence of PARL, the constitutive degradation of PINK1 is inhibited, stabilizing a 60-kD form inside mitochondria. When mitochondrial membrane potential is dissipated, PINK1 accumulates as a 63-kD full-length form on the outer mitochondrial membrane, where it can recruit Parkin to impaired mitochondria. Thus, differential localization to the inner and outer mitochondrial membranes appears to regulate PINK1 stability and function. PMID:21115803
Jin, Seok Min; Lazarou, Michael; Wang, Chunxin; Kane, Lesley A.; Narendra, Derek P.
PINK1 is a mitochondrial kinase mutated in some familial cases of Parkinson’s disease. It has been found to work in the same pathway as the E3 ligase Parkin in the maintenance of flight muscles and dopaminergic neurons in Drosophila melanogaster and to recruit cytosolic Parkin to mitochondria to mediate mitophagy in mammalian cells. Although PINK1 has a predicted mitochondrial import sequence, its cellular and submitochondrial localization remains unclear in part because it is rapidly degraded. In this study, we report that the mitochondrial inner membrane rhomboid protease presenilin-associated rhomboid-like protein (PARL) mediates cleavage of PINK1 dependent on mitochondrial membrane potential. In the absence of PARL, the constitutive degradation of PINK1 is inhibited, stabilizing a 60-kD form inside mitochondria. When mitochondrial membrane potential is dissipated, PINK1 accumulates as a 63-kD full-length form on the outer mitochondrial membrane, where it can recruit Parkin to impaired mitochondria. Thus, differential localization to the inner and outer mitochondrial membranes appears to regulate PINK1 stability and function. PMID:21115803
Cacioppo, Stephanie; Grippo, Angela J.; London, Sarah; Goossens, Luc; Cacioppo, John T.
In 1978, when the Task Panel report to the US President’s Commission on Mental Health emphasized the importance of improving health care and easing the pain of those suffering from emotional distress syndromes including loneliness, few anticipated that this issue would still need to be addressed 40 years later. A meta-analysis (Masi et al., 2011) on the efficacy of treatments to reduce loneliness identified a need for well-controlled randomized clinical trials focusing on the rehabilitation of maladaptive social cognition. We review assessments of loneliness and build on this meta-analysis to discuss the efficacy of various treatments for loneliness. With the advances made over the past 5 years in the identification of the psychobiological and pharmaceutical mechanisms associated with loneliness and maladaptive social cognition, there is increasing evidence for the potential efficacy of integrated interventions that combine (social) cognitive behavioral therapy with short-term adjunctive pharmacological treatments. PMID:25866548
Sukati, Suriyan; Svasti, Saovaros; Stifanese, Roberto; Averna, Monica; Panutdaporn, Nantika; Penglong, Tipparat; Melloni, Edon; Fucharoen, Suthat; Katzenmeier, Gerd
Earlier observations in the literature suggest that proteolytic degradation of excess unmatched α-globin chains reduces their accumulation and precipitation in β-thalassaemia erythroid precursor cells and have linked this proteolytic degradation to the activity of calpain protease. The aim of this study was to correlate the activity of calpain and its inhibitor, calpastatin, with different degrees of disease severity in β-thalassaemia. CD34+ cells were enriched from peripheral blood of healthy individuals (control group) and patients with mild and severe clinical presentations of β0-thalassaemia/Hb E disease. By ex vivo cultivation promoting erythroid cell differentiation for 7 days, proerythroblasts, were employed for the functional characterization of the calpain-calpastatin proteolytic system. In comparison to the control group, enzymatic activity and protein amounts of μ-calpain were found to be more than 3-fold increased in proerythroblasts from patients with mild clinical symptoms, whereas no significant difference was observed in patients with severe clinical symptoms. Furthermore, a 1.6-fold decrease of calpastatin activity and 3.2-fold accumulation of a 34 kDa calpain-mediated degradation product of calpastatin were observed in patients with mild clinical symptoms. The increased activity of calpain may be involved in the removal of excess α-globin chains contributing to a lower degree of disease severity in patients with mild clinical symptoms. PMID:22615919
Ramage, Gordon; Williams, Craig
Fungal biofilms have become an increasingly important clinical problem. The widespread use of antibiotics, frequent use of indwelling medical devices, and a trend toward increased patient immunosuppression have resulted in a creation of opportunity for clinically important yeasts and molds to form biofilms. This review will discuss the diversity and importance of fungal biofilms in the context of clinical medicine, provide novel insights into the clinical management of fungal biofilm infection, present evidence why these structures are recalcitrant to antifungal therapy, and discuss how our knowledge and understanding may lead to novel therapeutic intervention. PMID:23763758
Rice, Louis B.; Bonomo, Robert A.
The introduction of a large array of beta-lactam antibiotics has spawned the emergence of an even larger variety of beta-lactamases designed to confer resistance to these agents. beta-lactamases are produced by both gram-positive and gram-negative bacteria, but their clinical importance is far greater among the gram-negatives. The virtual explosion in our knowledge about the variety of these enzymes can often create confusion and frustration among those not well versed in the field. In this paper, we attempt to focus the discussion of beta-lactamases on those enzymes that are of the greatest clinical importance, the Ambler Class A and C enzymes. We also discuss the growing importance of the Ambler Class B metallo beta-lactamases, which hydrolyze carbapenems and are increasing in prevalence in areas of significant carbapenem usage. Copyright 2000 Harcourt Publishers Ltd. PMID:11498383
Kendler, D L; Bauer, D C; Davison, K S; Dian, L; Hanley, D A; Harris, S T; McClung, M R; Miller, P D; Schousboe, J T; Yuen, C K; Lewiecki, E M
Vertebral fractures are common and can result in acute and chronic pain, decreases in quality of life, and diminished lifespan. The identification of vertebral fractures is important because they are robust predictors of future fractures. The majority of vertebral fractures do not come to clinical attention. Numerous modalities exist for visualizing suspected vertebral fracture. Although differing definitions of vertebral fracture may present challenges in comparing data between different investigations, at least 1 in 5 men and women aged >50 years have one or more vertebral fractures. There is clinical guidance to target spine imaging to individuals with a high probability of vertebral fracture. Radiology reports of vertebral fracture need to clearly state that the patient has a "fracture," with further pertinent details such as the number, recency, and severity of vertebral fracture, each of which is associated with risk of future fractures. Patients with vertebral fracture should be considered for antifracture therapy. Physical and pharmacologic modalities of pain control and exercises or physiotherapy to maintain spinal movement and strength are important components in the care of vertebral fracture patients. PMID:26524708
Griffiths, M. W.; Tellez, A. M.
Lactobacillus helveticus is one of the species of lactic acid bacteria (LAB) most commonly used in the production of fermented milk beverages and some types of hard cheese. The versatile nature of this bacterium is based on its highly efficient proteolytic system consisting of cell-envelope proteinases (CEPs), transport system and intracellular peptidases. Besides use of L. helveticus in cheese processing, the production of fermented milk preparations with health promoting properties has become an important industrial application. Studies have shown that fermented dairy products are able to decrease blood pressure, stimulate the immune system, promote calcium absorption, and exert an anti-virulent effect against pathogens. These beneficial effects are produced by a variety of peptides released during the hydrolysis of milk proteins by the proteolytic system of L. helveticus, which provides the bacterium with its nutritional requirements for growth. In recent years, studies have focused on understanding the factors that affect the kinetics of milk protein hydrolysis by specific strains and have concentrated on the effect of pH, temperature, growth phase, and matrix composition on the bacterial enzymatic system. This review focuses on the role of the proteolytic system of L. helveticus in the production of bioactive compounds formed during fermentation of dairy products. Taking advantage of the powerful proteolytic system of this bacterium opens up future opportunities to search for novel food-derived compounds with potential health promoting properties. PMID:23467265
Gleiss, A; Zeillinger, R; Braicu, E I; Trillsch, F; Vergote, I; Schemper, M
We define the notion of 'importance' of prognostic factors in studies of survival and suggest quantifying it by the Schemper-Henderson measure of explained variation. Conceptual differences to the standard approach for the statistical analysis of oncologic studies of survival are discussed and exemplified by means of a study of ovarian cancer. Explained variation permits to establish a ranking of the importance of factors, also if measured on different scales, or of different types (dichotomous, qualitative or continuous), and permits to compare groups of related factors. In practice, the importance of prognostic factors often is disappointingly low. From this, it follows that even strong and highly significant prognostic factors often do not translate into close determination of individual survival of patients. PMID:27052655
Kessler, Efrat; Safrin, Mary
Pseudomonas aeruginosa secretes into its environment at least seven extracellular proteases: pseudolysin (LasB protease; elastase), aeruginolysin (alkaline proteinase), staphylolysin (staphylolytic endopeptidase; LasA protease), lysyl endopeptidase (protease IV; PrpL), PASP (P. aeruginosa small protease), LepA (Large ExoProtease A), and an aminopeptidase. Their action on host proteins, both individually and synergistically, plays important roles in pathogenesis of P. aeruginosa infections. Methods to measure/detect their activities are fundamental for understanding their physiological functions, roles in pathogenesis, mechanisms of action, regulation, and secretion. Most assays for determination/detection of proteolytic activity employ modified/non-modified casein or gelatin as substrates. In the quantitative assay, fragments generated from azocasein are separated from undigested substrate by trichloroacetic acid precipitation and their absorbance is measured. In non-quantitative assays, proteolytic activity is detected as clearing zones around bacterial growth or samples of culture supernatants on casein containing solid media formed due to local casein degradation. In zymography, individual proteases are detected as clear bands in gelatin/casein containing gels after SDS-PAGE separation, renaturation and protein staining. The elastinolytic capacity of P. aeruginosa is reflected by clearing zones on nutrient agar plates containing insoluble elastin instead of casein. Mueller-Hinton agar plates on which S. aureus cells are grown as a lawn are used to assess the susceptibility of S. aureus isolates to staphylolysin. A clear zone around a staphylolysin-containing sample indicates inhibition of S. aureus growth. Methods for measuring the activity of individual proteases are based on their cleavage specificity. These include assays of elastinolytic activity of pseudolysin and/or staphylolysin using elastin-Congo red as a substrate, a method for determination of
Statistical analysis is one of the foundations of evidence-based clinical practice, a key in conducting new clinical research and in evaluating and applying prior research. In this paper, we review the choice of statistical procedures, analyses of the associations among variables and techniques used when the clinical processes being examined are still in process. We discuss methods for building predictive models in clinical situations, and ways to assess the stability of these models and other quantitative conclusions. Techniques for comparing independent events are distinguished from those used with events in a causal chain or otherwise linked. Attention then turns to study design, to the determination of the sample size needed to make a given comparison, and to statistically negative studies. PMID:25566715
Kim, Eu Suk
The quinolone class of antimicrobial agents is one of most widely used classes of antimicrobial agents in outpatient and inpatient treatment. However, quinolone resistance in gram-positive and gram-negative bacteria has emerged and increased globally. This resistance limits the usefulness of quinolones in clinical practice. The review summarizes mechanisms of quinolone resistance and its epidemiology and implications in the most common clinical settings, urinary tract infections, respiratory tract infections, intraabdominal infections, skin and skin structure infections, and sexually transmitted diseases. PMID:25566402
Levin, Roger P
Simply having excellent clinical skills is not enough to enable you to achieve practice goals. In the end, people will validate the quality of the practice based on the way you and your team communicate. It is amazing to realize how much impact we have on other individuals, based purely on what we say. A well-groomed dentist and staff possessing very attractive features and beautiful teeth almost invariably will work in the practice's favor. However, these traits, powerful as they may be, are incomplete without the ability to say the right thing at the right time. In the practice, the easiest way to ensure consistently excellent communication is to use clinical and management scripts. Nothing you do in your practice will equal the impact of what you say because it affects patient perceptions of quality and overall customer service experiences. Your goal is to have all routine communications in the practice turned into written scripts within 6 months. PMID:15637966
Dartnell, Lewis R.; Roberts, Tom A.; Moore, Ginny; Ward, John M.; Muller, Jan-Peter
Healthcare-associated infections (HCAI/HAI) represent a substantial threat to patient health during hospitalization and incur billions of dollars additional cost for subsequent treatment. One promising method for the detection of bacterial contamination in a clinical setting before an HAI outbreak occurs is to exploit native fluorescence of cellular molecules for a hand-held, rapid-sweep surveillance instrument. Previous studies have shown fluorescence-based detection to be sensitive and effective for food-borne and environmental microorganisms, and even to be able to distinguish between cell types, but this powerful technique has not yet been deployed on the macroscale for the primary surveillance of contamination in healthcare facilities to prevent HAI. Here we report experimental data for the specification and design of such a fluorescence-based detection instrument. We have characterized the complete fluorescence response of eleven clinically-relevant bacteria by generating excitation-emission matrices (EEMs) over broad wavelength ranges. Furthermore, a number of surfaces and items of equipment commonly present on a ward, and potentially responsible for pathogen transfer, have been analyzed for potential issues of background fluorescence masking the signal from contaminant bacteria. These include bedside handrails, nurse call button, blood pressure cuff and ward computer keyboard, as well as disinfectant cleaning products and microfiber cloth. All examined bacterial strains exhibited a distinctive double-peak fluorescence feature associated with tryptophan with no other cellular fluorophore detected. Thus, this fluorescence survey found that an emission peak of 340nm, from an excitation source at 280nm, was the cellular fluorescence signal to target for detection of bacterial contamination. The majority of materials analysed offer a spectral window through which bacterial contamination could indeed be detected. A few instances were found of potential problems
da Silva, A P
Since its discovery in 1817, Selenium has had great biological importance as a key element of cellular protection and in its absence of pathological symptoms. In this revised work, historical aspects of selenium are considered, its characteristics, properties and source as well as its nutritional value, metabolism, physiopathological and biochemical function in humans and finally its future therapeutical application in humans and animals considering some of the traditional ways of treatment. PMID:8379356
Ambhore, Anand; Teo, Swee-Guan; Bin Omar, Abdul Razakjr; Poh, Kian-Keong
Long QT interval is an important finding that is often missed by electrocardiogram interpreters. Long QT syndrome (inherited and acquired) is a potentially lethal cardiac channelopathy that is frequently mistaken for epilepsy. We present a case of long QT syndrome with multiple cardiac arrests presenting as syncope and seizures. The long QTc interval was aggravated by hypomagnesaemia and drugs, including clarithromycin and levofloxacin. Multiple drugs can cause prolongation of the QT interval, and all physicians should bear this in mind when prescribing these drugs. PMID:25630313
Lane, Alison B; Petteys, Sarah; Ginn, Meghan; Nations, Joel A
Thoracic sonography is an important tool in diagnosis and assessment of pleural effusions and can provide valuable information about the characteristics of accumulated pleural fluid, in addition to improving the safety of thoracentesis. In addition to the 4 classic sonographic pleural effusion patterns (anechoic, complex nonseptate, complex septate, and homogeneously echogenic), an echogenic swirling pattern has been previously described, which was originally thought to be associated with malignant effusion. Two cases of pleural effusion with an echogenic swirling pattern are described below, illustrating that this sonographic finding can be seen in both exudative and transudative effusions. PMID:26931787
Behrendt, W; Kunitz, O; Kauhl, W; Lade, R
Hypocaloric parenteral nutrition (HPN) is mainly and frequently used in surgical medicine since it allows a reliable and standardized supply of nutrients. Ready-mix solutions which are suitable for peripheral venous nutrition generally contain about 50 g carbohydrates (glucose and/or xylitol), 25 g amino acids and electrolytes per liter. The osmolarity of the solutions averages between 600 and 800 mosmol/l. HPN has two distinct advantages: firstly the minimal effects on carbohydrate metabolism and secondly the good improvement in nitrogen balance. If 2 g/kg and day glucose are administered, even postoperatively, the mean blood sugar levels are only just above the normal range and an amino acid dosage of 1 g/kg and day, compared with liquid substitution alone or the administration of small amounts of carbohydrates, leads to an approximately 60% improvement in postoperative N-balance. Experience gained with HPN in surgical medicine to date permits the following recommendation: 1. HPN should not be used after small and moderate interventions with short nutritional abstinence; it is not necessary to administer nutrients in such cases. 2. HPN may be used after moderate to serious surgical interventions; e.g. after gastrointestinal resections in the case of elective surgery on patients with a normal nutritional status. However, studies have yet to prove the clinical efficacy of HPN, e.g. as evidenced by shorter hospitalization or a reduced perioperative morbidity or mortality, although this reservation equally applies to the routinely administered complete parenteral or enteral nutrition.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:7975956
Akos, Nagy; Zsolt, Brugoviczky; Péter, Novák; Gábor, Nagy
The origin of halitosis comes from the Latin word "halitus" meaning 'breath, exhaled air', and in the Hungarian terminology it means bad and smelly breath. The human body emits a number of volatile molecules, which have a peculiar odour. Their presence is influenced by several factors, such as genetic, nutritional and psychological factors. Since bad breath belongs to taboo subjects, halitosis can often lead to social isolation. To determine the incidence of halitosis, an exact diagnosis is needed which sometimes predestinates the possible treatment as well. Investigators estimate the incidence about 50% in the whole population. The male/female ratio is the same and the incidence is growing with age. The diagnosis can be genuine halitosis, pseudo halitosis and halitophobia. We can divide the genuine type into physiological and pathophysiological subtypes. The cause of the halitosis usually can be found in the oral cavity. The volatile sulfur compounds (VSC) produced by some of the oral bacteria are responsible for its development. Only 10% of the causes are extraoral, mostly inflammation of airways or gastrointestinal disorders. The judgment of halitosis is based on three objective methods: the organoleptic, the sulphide monitoring and the gas cromatography methods. Since the origin of the halitosis is mainly the oral cavity, dentists should treat them. Beyond the dental treatments the enhancement of the oral hygiene, the continuous motivation and monitoring are also very important, such as the use of tongue cleansing and special anti-malodour rinses. PMID:23240492
Zeanah, Charles H.
The degree to which early adverse experiences exert long term effects on development and how much early adversity may be overcome through subsequent experiences are important mental health questions. The clinical, research and policy perspectives on these questions lead to different answers. From a clinical perspective, change is always possible,…
Missen, Karen; Jacob, Elisabeth R; Barnett, Tony; Walker, Lorraine; Cross, Merylin
The current shortage of health professionals necessitates new approaches to clinical education that can expand the number of undergraduate students undertaking clinical placements without increasing the burden on clinical staff or placing patients at risk. Interprofessional education has the potential to help increase clinical capacity whilst enriching students' clinical experience. This paper reports on a project which investigated the potential for interprofessional education to increase undergraduate clinical placement capacity in clinical settings. The project utilised an exploratory descriptive methodology to obtain the views of health care professionals about the use of interprofessional education in clinical education at three rural health facilities in Victoria, Australia. Participants (n = 57) had a key role with each health care facility in coordinating and facilitating undergraduate clinical placements. This paper examines the clinicians' views about the central role that leadership plays in actioning interprofessional education in the clinical setting. Whilst interprofessional education was regarded favourably by the majority of participants, data indicated that leadership from education providers, health services, and regulatory authorities was crucial to enable interprofessional education to be implemented and sustained within the clinical learning environment. Without leadership from each of these three spheres of influence, interprofessional education will continue to be difficult to implement for undergraduate students and compromise their exposure to an important aspect of the working life of health care professionals. Such a failure will limit graduates' readiness for collaborative and cross-disciplinary practice. PMID:23362604
Paton, James Y; Ranmal, Rita; Dudley, Jan
The use of data to challenge and improve healthcare has a long and distinguished history but has often failed to bring about expected improvements. It has never become fully embedded in clinical practice, probably because data alone are insufficient to drive change. There is now a greater appreciation that changing and improving healthcare requires changing behaviours. Clinical audit remains one of the important tools that can be used to facilitate such change. PMID:25122156
Belushkin, Alexander A; Vinogradov, Dmitry V; Gelfand, Mikhail S; Osterman, Andrei L; Cieplak, Piotr; Kazanov, Marat D
Proteolytic signaling, or regulated proteolysis, is an essential part of many important pathways such as Notch, Wnt, and Hedgehog. How the structure of the cleaved substrate regions influences the efficacy of proteolytic processing remains underexplored. Here, we analyzed the relative importance in proteolysis of various structural features derived from substrate sequences using a dataset of more than 5000 experimentally verified proteolytic events captured in CutDB. Accessibility to the solvent was recognized as an essential property of a proteolytically processed polypeptide chain. Proteolytic events were found nearly uniformly distributed among three types of secondary structure, although with some enrichment in loops. Cleavages in α-helices were found to be relatively abundant in regions apparently prone to unfolding, while cleavages in β-structures tended to be located at the periphery of β-sheets. Application of the same statistical procedures to proteolytic events divided into separate sets according to the catalytic classes of proteases proved consistency of the results and confirmed that the structural mechanisms of proteolysis are universal. The estimated prediction power of sequence-derived structural features, which turned out to be sufficiently high, presents a rationale for their use in bioinformatic prediction of proteolytic events. PMID:24227478
Belushkin, Alexander A.; Vinogradov, Dmitry V.; Gelfand, Mikhail S.; Osterman, Andrei L.; Cieplak, Piotr; Kazanov, Marat D.
Proteolytic signaling, or regulated proteolysis, is an essential part of many important pathways such as Notch, Wnt, and Hedgehog. How the structure of the cleaved substrate regions influences the efficacy of proteolytic processing remains underexplored. Here, we analyzed the relative importance in proteolysis of various structural features derived from substrate sequences using a dataset of more than five thousand experimentally verified proteolytic events captured in CutDB. Accessibility to the solvent was recognized as an essential property of a proteolytically processed polypeptide chain. Proteolytic events were found nearly uniformly distributed among three types of secondary structure, although with some enrichment in loops. Cleavages in α-helices were found to be relatively abundant in regions apparently prone to unfolding, while cleavages in β-structures tended to be located at the periphery of β-sheets. Application of the same statistical procedures to proteolytic events divided into separate sets according to the catalytic classes of proteases proved consistency of the results and confirmed that the structural mechanisms of proteolysis are universal. The estimated prediction power of sequence-derived structural features, which turned out to be sufficiently high, presents a rationale for their use in bioinformatic prediction of proteolytic events. PMID:24227478
Mótyán, János András; Tóth, Ferenc; Tőzsér, József
Proteolytic enzymes (also termed peptidases, proteases and proteinases) are capable of hydrolyzing peptide bonds in proteins. They can be found in all living organisms, from viruses to animals and humans. Proteolytic enzymes have great medical and pharmaceutical importance due to their key role in biological processes and in the life-cycle of many pathogens. Proteases are extensively applied enzymes in several sectors of industry and biotechnology, furthermore, numerous research applications require their use, including production of Klenow fragments, peptide synthesis, digestion of unwanted proteins during nucleic acid purification, cell culturing and tissue dissociation, preparation of recombinant antibody fragments for research, diagnostics and therapy, exploration of the structure-function relationships by structural studies, removal of affinity tags from fusion proteins in recombinant protein techniques, peptide sequencing and proteolytic digestion of proteins in proteomics. The aim of this paper is to review the molecular biological aspects of proteolytic enzymes and summarize their applications in the life sciences. PMID:24970197
Salinas, Claudia A.; Tsodikov, Alex; Ishak-Howard, Miriam; Cooney, Kathleen A.
Prostate cancer is considered a disease of older men, but today over 10% of new diagnoses occur in U.S. men ≤ 55 years. Early onset prostate cancer, i.e., diagnosed at ≤55 years, differs from prostate cancer in older men in several ways. Among men diagnosed with high grade and stage prostate cancer, men with early onset prostate cancer are more likely to die of their cancer, with higher cause-specific mortality than all others except those diagnosed over age 80. This suggests that important biological differences may exist in early onset disease compared to late onset disease. Furthermore, early onset prostate cancer has been shown to have a more significant genetic component indicating that this group may benefit more than most from evaluation of genetic risk. Clinically, although the majority of cases ≤ 55 years are diagnosed with low risk disease, their extended life expectancy exposes them to long-term risk of disease progression resulting in death from prostate cancer, but also to prolonged impact from treatment-related morbidities. These patients pose unique challenges and opportunities for both the research and clinical communities. We therefore suggest that early onset prostate cancer is a distinct phenotype, from both an etiologic and clinical perspective, that deserves further attention. PMID:24818853
Ronnie, George; Ve, Ramesh Sathyamangalam; Velumuri, Lokapavani; Asokan, Rashima; Vijaya, Lingam
In the last decade, there have been reports on the prevalence of glaucoma from the Vellore Eye Survey, Andhra Pradesh Eye Diseases Survey, Aravind Comprehensive Eye Survey, Chennai Glaucoma Study and West Bengal Glaucoma Study. Population-based studies provide important information regarding the prevalence and risk factors for glaucoma. They also highlight regional differences in the prevalence of various types of glaucoma. It is possible to gather important insights regarding the number of persons affected with glaucoma and the proportion with undiagnosed disease. We reviewed the different population-based studies from India and compare their findings. The lacunae in ophthalmic care that can be inferred from these studies are identified and possible reasons and solutions are discussed. We also discuss the clinical relevance of the various findings, and how it reflects on clinical practice in the country. Since India has a significantly high disease burden, we examine the possibility of population-based screening for disease in the Indian context. PMID:21150021
Stawicka, Agnieszka; Zbrzeźniak, Justyna; Świderska, Aleksandra; Kilisińska, Natalia; Świderska, Magdalena; Jaroszewicz, Jerzy; Flisiak, Robert
Minimal hepatic encephalopathy (MHE) encompasses a number of neuropsychological and neurophysiological disorders in patients suffering from liver cirrhosis, who do not display abnormalities during a medical interview or physical examination. A negative influence of MHE on the quality of life of patients suffering from liver cirrhosis was confirmed, which include retardation of ability of operating motor vehicles and disruption of multiple health-related areas, as well as functioning in the society. The data on frequency of traffic offences and accidents amongst patients diagnosed with MHE in comparison to patients diagnosed with liver cirrhosis without MHE, as well as healthy persons is alarming. Those patients are unaware of their disorder and retardation of their ability to operate vehicles, therefore it is of utmost importance to define this group. The term minimal hepatic encephalopathy (formerly "subclinical" encephalopathy) erroneously suggested the unnecessity of diagnostic and therapeutic procedures in patients with liver cirrhosis. Diagnosing MHE is an important predictive factor for occurrence of overt encephalopathy - more than 50% of patients with this diagnosis develop overt encephalopathy during a period of 30 months after. Early diagnosing MHE gives a chance to implement proper treatment which can be a prevention of overt encephalopathy. Due to continuing lack of clinical research there exist no commonly agreed-upon standards for definition, diagnostics, classification and treatment of hepatic encephalopathy. This article introduces the newest findings regarding the importance of MHE, scientific recommendations and provides detailed descriptions of the most valuable diagnostic methods. PMID:27000818
Kalaitzis, Christos; Patris, Emmanuel; Deligeorgiou, Evangelia; Sountoulides, Petros; Bantis, Athanasios; Giannakopoulos, Stilianos; Touloupidis, Stavros
Objective To describe the radiological findings and the clinical importance of megacalycosis. Materials and methods On the basis of a case report and literature review, diagnostic criteria and clinical significance of megacalycosis are presented. Result Megacalycosis is mostly asymptomatic and is usually discovered either accidentally or as a result of its complications, such as stone formation, flank pain, hematuria, infection, and fever. The renal pelvis, infundibulum, and ureter are not dilated. Calyces have a semilunar configuration rather than the conventional triangular or conical form. The tip of each pyramid is flat, and the calyces possess neither fornix nor papillae impressions. The number of calyces is increased compared to the healthy condition, typically from 20–25. The renal parenchyma has a normal width but with a slight narrowing of the renal medulla. The kidney exhibits normal function, in particular with respect to its ability to concentrate the urine. Conclusion Megacalycosis is a rare, usually unilateral dilatation of the kidney calyces in the presence of a normal, undilated renal pelvis and ureter. Its pathological significance lies in the occurrence of complications. PMID:26528455
Purpose: To report the incidence, clinical importance and management of the incompetent gastrocnemius vein. Methods: The incompetency was examined by duplex and pulse-Doppler ultrasound at the popliteal fossa in a standing position between July 2006 and August 2014. Results: Among 1805 legs surveyed, 14 legs showed primary incompetent gastrocnemius vein (0.78%). The incompetency was in medial gastrocnemius vein in 13 legs (93%). Clinical manifestation was varicose vein in the small saphenous territory in nine, varicose vein in great saphenous territory in one, congestive dermatitis in two, calf clamp in one and no symptom in one. The nine cases with varicose vein in the small saphenous territory received surgical management. These included three cases with residual varicose veins after saphenopopliteal disconnection and stripping small saphenous vein. The root of the gastrocnemius vein was divided leaving no complication. In cases without varicose vein in small saphenous territory, an elastic compression socks was useful in some degree. Conclusions: Incompetency of gastrocnemius vein was not so rare. When a case is accompanied by small saphenous varicose veins, division of the root of gastrocnemius vein along with small saphenous vein stripping is recommended in order to reduce residual varicose vein. PMID:27087871
Kötzler, Miriam P; Withers, Stephen G
Proteolytic processing of human host cell factor 1 (HCF-1) to its mature form was recently shown, unexpectedly, to occur in a UDP-GlcNAc-dependent fashion within the transferase active site of O-GlcNAc-transferase (OGT) (Lazarus, M. B., Jiang, J., Kapuria, V., Bhuiyan, T., Janetzko, J., Zandberg, W. F., Vocadlo, D. J., Herr, W., and Walker, S. (2013) Science 342, 1235-1239). An interesting mechanism involving formation and then intramolecular rearrangement of a covalent glycosyl ester adduct of the HCF-1 polypeptide was proposed to account for this unprecedented proteolytic activity. However, the key intermediate remained hypothetical. Here, using a model enzyme system for which the formation of a glycosyl ester within the enzyme active site has been shown unequivocally, we show that ester formation can indeed lead to proteolysis of the adjacent peptide bond, thereby providing substantive support for the mechanism of HCF-1 processing proposed. PMID:26515062
... Enforcement Administration Importer of Controlled Substances; Notice of Application; Fisher Clinical Services..., 2012, Fisher Clinical Services, Inc., 7554 Schantz Road, Allentown, Pennsylvania 18106, made... controlled substance for analytical research and clinical trials. The import of the above listed basic...
... FR 60143, Fisher Clinical Services, Inc., 7554 Schantz Road, Allentown, Pennsylvania 18106, made... Enforcement Administration Importer of Controlled Substances; Notice of Registration; Fisher Clinical Services... registration of Fisher Clinical Services, Inc., to import the basic class of controlled substance is...
... Enforcement Administration Importer of Controlled Substances; Notice of Application; Fisher Clinical Services... 21, 2013, Fisher Clinical Services, Inc., 7554 Schantz Road, Allentown, Pennsylvania 18106, made... for clinical trials, analytical research and testing. The import of the above listed basic classes...
... Enforcement Administration Importer of Controlled Substances; Notice of Application; Fisher Clinical Services..., Fisher Clinical Services, Inc., 7554 Schantz Road, Allentown, Pennsylvania 18106, made application by... substance for analytical research and clinical trials. The import of the above listed basic class...
Samuel, Orit; Tal, Dror
Airsickness is one of the forms of motion sickness, and is of significance in both commercial and military flight. Whereas commercial airline passengers may simply feel poorly, the effect of airsickness on military aircrew may lead to a decrement in performance and adversely affect the mission. This is of major importance in the case of flight safety, when a pilot who is incapacitated may endanger the aircraft. The problem is particularly evident in pilot training, because of the high incidence of airsickness at this stage in the pilot's career. The majority of aircrew undergo habituation to airsickness during their service, with a reduction in symptoms and improved function. Although airsickness is a wellknown problem in aviation, we were unable to locate a review of this topic in the literature. This review focuses on the characteristics, clinical evaluation, and treatment of airsickness. It also presents the experience of the Israeli flight academy, and our solution for Navy pilots who have to contend with the risk of seasickness before taking to the air. PMID:26540704
Chen, Yu-Chih; Cheng, Yu-Heng; Ingram, Patrick; Yoon, Euisik
Proteolytic degradation of the extracellular matrix (ECM) is critical in cancer invasion, and recent work suggests that heterogeneous cancer populations cooperate in this process. Despite the importance of cell heterogeneity, conventional proteolytic assays measure average activity, requiring thousands of cells and providing limited information about heterogeneity and dynamics. Here, we developed a microfluidic platform that provides high-efficiency cell loading and simple valveless isolation, so the proteolytic activity of a small sample (10–100 cells) can be easily characterized. Combined with a single cell derived (clonal) sphere formation platform, we have successfully demonstrated the importance of microenvironmental cues for proteolytic activity and also investigated the difference between clones. Furthermore, the platform allows monitoring single cells at multiple time points, unveiling different cancer cell line dynamics in proteolytic activity. The presented tool facilitates single cell proteolytic analysis using small samples, and our findings illuminate the heterogeneous and dynamic nature of proteolytic activity.
Chen, Yu-Chih; Cheng, Yu-Heng; Ingram, Patrick; Yoon, Euisik
Proteolytic degradation of the extracellular matrix (ECM) is critical in cancer invasion, and recent work suggests that heterogeneous cancer populations cooperate in this process. Despite the importance of cell heterogeneity, conventional proteolytic assays measure average activity, requiring thousands of cells and providing limited information about heterogeneity and dynamics. Here, we developed a microfluidic platform that provides high-efficiency cell loading and simple valveless isolation, so the proteolytic activity of a small sample (10–100 cells) can be easily characterized. Combined with a single cell derived (clonal) sphere formation platform, we have successfully demonstrated the importance of microenvironmental cues for proteolytic activity and also investigated the difference between clones. Furthermore, the platform allows monitoring single cells at multiple time points, unveiling different cancer cell line dynamics in proteolytic activity. The presented tool facilitates single cell proteolytic analysis using small samples, and our findings illuminate the heterogeneous and dynamic nature of proteolytic activity. PMID:27283981
Gaddale, Jagadeeswara Rao
In the clinical trial process, precise and concise data collection at the source is imperative and requires statistical analysis to be performed to derive the primary and secondary endpoints. The quality of raw data collection has a direct impact on the statistical outputs generated as per the statistical analysis plan. Hence, the data collection tools used for data transcription must be clear, understandable, and precise, which helps the investigator to provide the accurate subject data. Clinical Data Acquisition Standards Harmonization (CDASH) provides guidance to develop the case report form (CRF) for domains that are commonly used for the majority of the clinical trials across the therapeutic areas. This white paper describes the importance of CDASH standards, its advantages and its impact on the efforts and the cost in designing the CRF. PMID:26623387
Olson, Heather; Shen, Yiping; Avallone, Jennifer; Sheidley, Beth R.; Pinsky, Rebecca; Bergin, Ann M.; Berry, Gerard T.; Duffy, Frank H.; Eksioglu, Yaman; Harris, David J.; Hisama, Fuki M.; Ho, Eugenia; Irons, Mira; Jacobsen, Christina M.; James, Philip; Kothare, Sanjeev; Khwaja, Omar; Lipton, Jonathan; Loddenkemper, Tobias; Markowitz, Jennifer; Maski, Kiran; Megerian, J. Thomas; Neilan, Edward; Raffalli, Peter C.; Robbins, Michael; Roberts, Amy; Roe, Eugene; Rollins, Caitlin; Sahin, Mustafa; Sarco, Dean; Schonwald, Alison; Smith, Sharon E.; Soul, Janet; Stoler, Joan M.; Takeoka, Masanori; Tan, Wen-Han; Torres, Alcy R.; Tsai, Peter; Urion, David K.; Weissman, Laura; Wolff, Robert; Wu, Bai-Lin; Miller, David T.; Poduri, Annapurna
Objective To evaluate the role of copy number abnormalities detectable by chromosomal microarray (CMA) testing in patients with epilepsy at a tertiary care center. Methods We identified patients with ICD-9 codes for epilepsy or seizures and clinical CMA testing performed between October 2006 and February 2011 at Boston Children’s Hospital. We reviewed medical records and included patients meeting criteria for epilepsy. We phenotypically characterized patients with epilepsy-associated abnormalities on CMA. Results Of 973 patients who had CMA and ICD-9 codes for epilepsy or seizures, 805 patients satisfied criteria for epilepsy. We observed 437 copy number variants (CNVs) in 323 patients (1–4 per patient), including 185 (42%) deletions and 252 (58%) duplications. Forty (9%) were confirmed de novo, 186 (43%) were inherited, and parental data were unavailable for 211 (48%). Excluding full chromosome trisomies, CNV size ranged from 18 kb to 142 Mb, and 34% were over 500 kb. In at least 40 cases (5%), the epilepsy phenotype was explained by a CNV, including 29 patients with epilepsy-associated syndromes and 11 with likely disease-associated CNVs involving epilepsy genes or “hotspots.” We observed numerous recurrent CNVs including 10 involving loss or gain of Xp22.31, a region described in patients with and without epilepsy. Interpretation Copy number abnormalities play an important role in patients with epilepsy. Given that the diagnostic yield of CMA for epilepsy patients is similar to the yield in autism spectrum disorders and in prenatal diagnosis, for which published guidelines recommend testing with CMA, we recommend the implementation of CMA in the evaluation of unexplained epilepsy. PMID:24811917
Baumgartner, Annic; Schuetz, Philipp
Recently, a plenitude of novel laboratory tests has become available for physicians to improve the diagnostic and prognostic work up of patients. Yet, as with all tests, laboratory test can be falsely positive or falsely negative and potentially misguide clinicians and caregivers. Shortcomings of pre-analytical factors, test performance as well as an inappropriate ordering of laboratory tests contributes to diagnostic errors and potentially generate unnecessary costs. Laboratory tests should only be ordered, if results have clinical consequences and improve the assessment of the patient. Within this review focusing on the example of the inflammatory biomarker "Procalcitonin" for antibiotic stewardship and the hormonal marker testosterone, we aim to exemplify important draw backs and shortcomings in laboratory tests and the importance of interpretation of these results in the context of the clinical situation. PMID:25630294
Pinto, Brian; Fox, Brent I
According to the Healthcare Information Management and Systems Society, "Clinical & Business Intelligence (C&BI) is the use and analysis of data captured in the healthcare setting to directly inform decision-making" (http://www.himss.org/library/clinical-business-intelligence). Some say that it is the right information given to the right person at the right time in the right way. No matter how you define it, the fact remains that timely access, synthesis, and visualization of clinical data have become key to how health professionals make patient care decisions and improve care delivery. PMID:27559195
Cough is a unique symptom because, unlike sneeze and other symptoms, it can be under voluntary control and this complicates clinical trials on cough medicines. All over-the-counter cough medicines (OTC) are very effective treatments because of their placebo effect. The placebo effect is enhanced by expectancy related to advertising, brand, packaging, and formulation. This placebo effect creates a problem for the conduct of clinical trials on OTC cough medicines that attempt to demonstrate the efficacy of a pharmacological agent above that of any placebo effect. Up to 85% of the efficacy of some cough medicines can be attributed to a placebo effect. The placebo effect apparent in clinical trials consists of several components: natural recovery, regression of cough response toward mean, demulcent effect, effect of sweetness, voluntary control, and effects related to expectancy and meaning of the treatment. The placebo effect has been studied most in the pain model, and placebo analgesia is reported to depend on the activation of endogenous opioid systems in the brain; this model may be applicable to cough. A balanced placebo design may help to control for the placebo effect, but this trial design may not be acceptable due to deception of patients. The placebo effect in clinical trials may be controlled by use of a crossover design, where feasible, and the changes in the magnitude of the placebo effect in this study design are discussed. PMID:19760296
Sajdak, Rebecca; Trembath, Lisaann; Thomas, Kathy S
This special contribution provides insight into the role that standard operating procedures (SOPs) play in an imaging department and their value in building a high-quality research site. If you have ever participated in a clinical trial, many of the principles described in this article should be familiar. However, this article goes a step further by presenting information from a pharmaceutical or device sponsor's point of view-what the sponsor expects from a site during the course of a research study. This article is intended not to provide a complete set of instructions on how to create a great SOP but, instead, to present guidelines to ensure that the key elements are included. After reading the article, you will be able to define SOPs as they pertain to the clinical trial environment, describe key components of an SOP, list the clinical research SOPs that exist in your institution and imaging department, identify which additional SOPs might improve site performance, and describe how the sponsor relies on SOPs to ensure that the highest quality of research is attained. PMID:23853088
Godoy, J M; Nicaretta, D H; Balassiano, S L; Skacel, M
The authors describe the neurological manifestations of a female patient with hypercholesterolemia who developed myopathy in the course of her treatment with clofibrate. After the drug was tapered off, the neurological signs and symptoms disappeared. Therefore, attention is called for the importance of the differential diagnosis of iatrogenic myopathies with polymyositis. PMID:1307471
Trentin, Danielle S.; Silva, Denise B.; Frasson, Amanda P.; Rzhepishevska, Olena; da Silva, Márcia V.; de L. Pulcini, Elinor; James, Garth; Soares, Gabriel V.; Tasca, Tiana; Ramstedt, Madeleine; Giordani, Raquel B.; Lopes, Norberto P.; Macedo, Alexandre J.
Despite many advances, biomaterial-associated infections continue to be a major clinical problem. In order to minimize bacterial adhesion, material surface modifications are currently being investigated and natural products possess large potential for the design of innovative surface coatings. We report the bioguided phytochemical investigation of Pityrocarpa moniliformis and the characterization of tannins by mass spectrometry. It was demonstrated that B-type linked proanthocyanidins-coated surfaces, here termed Green coatings, reduced Gram-positive bacterial adhesion and supported mammalian cell spreading. The proposed mechanism of bacterial attachment inhibition is based on electrostatic repulsion, high hydrophilicity and the steric hindrance provided by the coating that blocks bacterium-substratum interactions. This work shows the applicability of a prototype Green-coated surface that aims to promote necessary mammalian tissue compatibility, while reducing bacterial colonization. PMID:25655943
Soh, Thomas I Peng; Yong, Wei Peng; Innocenti, Federico
Recent advances have provided unprecedented opportunities to identify prognostic and predictive markers of efficacy of cancer therapy. Genetic markers can be used to exclude patients who will not benefit from therapy, exclude patients at high risk of severe toxicity, and adjust dosing. Genomic approaches for marker discovery now include genome-wide association studies and tumor DNA sequencing. The challenge is now to select markers for which there is enough evidence to transition them to the clinic. The hurdles include the inherent low frequency of many of these markers, the lengthy validation process through trials, as well as legislative and economic hurdles. Attempts to answer questions about certain markers more quickly have led to an increased popularity of trials with enrichment design, especially in the light of the dramatic phase I results seen in recent months. Personalized medicine in oncology is a step closer to reality. PMID:21950596
Provencher, L.; Hogue, J.C.; Desbiens, C.; Poirier, B.; Poirier, E.; Boudreau, D.; Joyal, M.; Diorio, C.; Duchesne, N.; Chiquette, J.
Background Screening clinical breast examination (cbe) is controversial; the use of cbe is declining not only as a screening tool, but also as a diagnostic tool. In the present study, we aimed to assess the value of cbe in breast cancer detection in a tertiary care centre for breast diseases. Methods This retrospective study of all breast cancers diagnosed between July 1999 and December 2010 at our centre categorized cases according to the mean of detection (cbe, mammography, or both). A cbe was considered “abnormal” in the presence of a mass, nipple discharge, skin or nipple retraction, edema, erythema, peau d’orange, or ulcers. Results During the study period, a complete dataset was available for 6333 treated primary breast cancers. Cancer types were ductal carcinoma in situ (15.3%), invasive ductal carcinoma (75.7%), invasive lobular carcinoma (9.0%), or others (2.2%). Of the 6333 cancers, 36.5% (n = 2312) were detected by mammography alone, 54.8% (n = 3470) by mammography and cbe, and 8.7% (n = 551) by physician-performed cbe alone (or 5.3% if considering ultrasonography). Invasive tumours diagnosed by cbe alone were more often triple-negative, her2-positive, node-positive, and larger than those diagnosed by mammography alone (p < 0.05). Conclusions A significant number of cancers would have been missed if cbe had not been performed. Compared with cancers detected by mammography alone, those detected by cbe had more aggressive features. Clinical breast examination is a very low-cost test that could improve the detection of breast cancer and could prompt breast ultrasonography in the case of a negative mammogram. PMID:27536182
McEniery, Carmel M; Cockcroft, John R; Roman, Mary J; Franklin, Stanley S; Wilkinson, Ian B
Pressure measured with a cuff and sphygmomanometer in the brachial artery is accepted as an important predictor of future cardiovascular risk. However, systolic pressure varies throughout the arterial tree, such that aortic (central) systolic pressure is actually lower than corresponding brachial values, although this difference is highly variable between individuals. Emerging evidence now suggests that central pressure is better related to future cardiovascular events than is brachial pressure. Moreover, anti-hypertensive drugs can exert differential effects on brachial and central pressure. Therefore, basing treatment decisions on central, rather than brachial pressure, is likely to have important implications for the future diagnosis and management of hypertension. Such a paradigm shift will, however, require further, direct evidence that selectively targeting central pressure, brings added benefit, over and above that already provided by brachial artery pressure. PMID:24459197
McEniery, Carmel M.; Cockcroft, John R.; Roman, Mary J.; Franklin, Stanley S.; Wilkinson, Ian B.
Pressure measured with a cuff and sphygmomanometer in the brachial artery is accepted as an important predictor of future cardiovascular risk. However, systolic pressure varies throughout the arterial tree, such that aortic (central) systolic pressure is actually lower than corresponding brachial values, although this difference is highly variable between individuals. Emerging evidence now suggests that central pressure is better related to future cardiovascular events than is brachial pressure. Moreover, anti-hypertensive drugs can exert differential effects on brachial and central pressure. Therefore, basing treatment decisions on central, rather than brachial pressure, is likely to have important implications for the future diagnosis and management of hypertension. Such a paradigm shift will, however, require further, direct evidence that selectively targeting central pressure, brings added benefit, over and above that already provided by brachial artery pressure. PMID:24459197
Clark, C. Graham; Diamond, Louis S.
Cultivation of luminal protistan parasites has a long history. In this review we discuss the methods and media that are most widely used for the establishment and maintenance of the following organisms in culture: Entamoeba histolytica, Giardia intestinalis, Trichomonas vaginalis, Dientamoeba fragilis, Blastocystis hominis, and Balantidium coli. While cultivation is of limited importance in the diagnostic laboratory, it is essential to most research laboratories, and it is toward the latter that this review is primarily aimed. PMID:12097242
Porphyromonas gingivalis-derived lysine gingipain enhances osteoclast differentiation induced by tumor necrosis factor-α and interleukin-1β but suppresses that by interleukin-17A: importance of proteolytic degradation of osteoprotegerin by lysine gingipain.
Akiyama, Tomohito; Miyamoto, Yoichi; Yoshimura, Kentaro; Yamada, Atsushi; Takami, Masamichi; Suzawa, Tetsuo; Hoshino, Marie; Imamura, Takahisa; Akiyama, Chie; Yasuhara, Rika; Mishima, Kenji; Maruyama, Toshifumi; Kohda, Chikara; Tanaka, Kazuo; Potempa, Jan; Yasuda, Hisataka; Baba, Kazuyoshi; Kamijo, Ryutaro
Periodontitis is a chronic inflammatory disease accompanied by alveolar bone resorption by osteoclasts. Porphyromonas gingivalis, an etiological agent for periodontitis, produces cysteine proteases called gingipains, which are classified based on their cleavage site specificity (i.e. arginine (Rgps) and lysine (Kgps) gingipains). We previously reported that Kgp degraded osteoprotegerin (OPG), an osteoclastogenesis inhibitory factor secreted by osteoblasts, and enhanced osteoclastogenesis induced by various Toll-like receptor (TLR) ligands (Yasuhara, R., Miyamoto, Y., Takami, M., Imamura, T., Potempa, J., Yoshimura, K., and Kamijo, R. (2009) Lysine-specific gingipain promotes lipopolysaccharide- and active-vitamin D3-induced osteoclast differentiation by degrading osteoprotegerin. Biochem. J. 419, 159-166). Osteoclastogenesis is induced not only by TLR ligands but also by proinflammatory cytokines, including tumor necrosis factor-α (TNF-α), interleukin (IL)-1β, and IL-17A, in inflammatory conditions, such as periodontitis. Although Kgp augmented osteoclastogenesis induced by TNF-α and IL-1β in co-cultures of mouse osteoblasts and bone marrow cells, it suppressed that induced by IL-17A. In a comparison of proteolytic degradation of these cytokines by Kgp in a cell-free system with that of OPG, TNF-α and IL-1β were less susceptible, whereas IL-17A and OPG were equally susceptible to degradation by Kgp. These results indicate that the enhancing effect of Kgp on cytokine-induced osteoclastogenesis is dependent on the difference in degradation efficiency between each cytokine and OPG. In addition, elucidation of the N-terminal amino acid sequences of OPG fragments revealed that Kgp primarily cleaved OPG in its death domain homologous region, which might prevent dimer formation of OPG required for inhibition of receptor activator of nuclear factor κB ligand. Collectively, our results suggest that degradation of OPG by Kgp is a crucial event in the development of
Sridharan, Radhika; Ngiu, Chai Soon; Shaharir, Syahrul Sazliyana; Said, Mohd Shahrir Mohamed
Spondyloarthropathy (SpA) is a group of inflammatory conditions that include spondylitis, sacroiliitis, asymmetrical peripheral arthritis and enthesitis. This condition is known as juvenile SpA when the diagnosis is made in patients up to 16 years of age. Enthesitis is a highly specific feature that occurs more often in juvenile SpA than in the adult form. In contrast to adult onset SpA, the initial manifestation of juvenile SpA rarely presents as inflammatory back pain. Peripheral arthritis is the more common presenting feature. We report a case of a 12-year-old boy who presented with a 1-year history of progressive low back pain, gluteal pain and thigh pain. There were no clinical symptoms of arthropathy of the distal extremities. MRI of the whole spine was performed twice, which, unfortunately, was unyielding. Finally, MRI of the sacroiliac joints revealed asymmetric sacroiliitis as well as enthesitis of the hips and pelvis. Further laboratory data showed negative rheumatoid factor and positive human leucocyte antigen (HLA) B27. A diagnosis of juvenile SpA with sacroiliitis and enthesitis was made. The imaging characteristics of juvenile SpA are highlighted. PMID:26677159
Developmental pharmacodynamics is the study of age-related maturation of the structure and function of biologic systems and how this affects response to pharmacotherapy. This may manifest as a change in the potency, efficacy, or therapeutic range of a drug. The paucity of studies exploring developmental pharmacodynamics reflects the lack of suitable juvenile animal models and the ethical and practical constraints of conducting studies in children. However, where data from animal models are available, valuable insight has been gained into how response to therapy can change through the course of development. For example, animal neurodevelopmental models have revealed that temporal differences in the maturation of norepinephrine and serotonin neurotransmitter systems may explain the lack of efficacy of some antidepressants in children. GABA(A) receptors that switch from an excitatory to inhibitory mode during early development help to explain paradoxical seizures experienced by infants after exposure to benzodiazepines. The increased sensitivity of neonates to morphine may be due to increased postnatal expression of the mu opioid receptor. An age dependency to the pharmacokinetic-pharmacodynamic relationship has also been found in some clinical studies. For example, immunosuppressive effects of ciclosporin (cyclosporine) revealed markedly enhanced sensitivity in infants compared with older children and adults. A study of sotalol in the treatment of children with supraventricular tachycardia showed that neonates exhibited a higher sensitivity towards QTc interval prolongation compared with older children. However, the data are limited and efforts to increase and establish data on developmental pharmacodynamics are necessary to achieve optimal drug therapy in children and to ensure long-term success of pediatric drug development. This requires a dual 'bottom up' (ontogeny knowledge driven) and 'top down' (pediatric pharmacokinetic-pharmacodynamic studies) approach. PMID
Orme, Ian M.
The nontuberculous mycobacteria are a large group of acid-fast bacteria that are very widely distributed in the environment. While Mycobacterium avium was once regarded as innocuous, its high frequency as a cause of disseminated disease in HIV-positive individuals illustrated its potential as a pathogen. Much more recently, there is growing evidence that the incidence of M. avium and related nontuberculous species is increasing in immunocompetent individuals. The same has been observed for M. abscessus infections, which are very difficult to treat; accordingly, this review focuses primarily on these two important pathogens. Like the host response to M. tuberculosis infections, the host response to these infections is of the TH1 type but there are some subtle and as-yet-unexplained differences. PMID:24914222
... on. From the NIH Director: The Importance of Clinical Trials Past Issues / Summer 2011 Table of Contents NIH ... early June to attendees of a 2011 conference, “Clinical Trials: New Challenges and Opportunities,” cosponsored by the National ...
Ligi, Daniela; Mosti, Giovanni; Croce, Lidia; Raffetto, Joseph D; Mannello, Ferdinando
Venous leg ulcers (VLU) are characterized by sustained proteolytic microenvironment impairing the healing process. Wound fluid (WF) reflect the biomolecular activities occurring within the wound area; however, it is unclear if WF from different healing phases have different proteolytic profiles and how VLU microenvironment affects the wound healing mechanisms. We investigated the proteolytic network of WF from distinct VLU phases, and in WF- and LPS-stimulated THP-1 monocytes treated with glycosaminoglycan sulodexide, a well known therapeutic approach for VLU healing. WF were collected from patients with VLU during inflammatory (Infl) and granulating (Gran) phases. WF and THP-1 supernatants were analyzed for nine matrix metalloproteinases (MMP) and four tissue inhibitors of metalloproteinases (TIMP) by multiplex immunoassays. Our results demonstrated that: 1) WF from Infl VLU contained significantly increased concentrations of MMP-2, MMP-9, MMP-12, TIMP-1, and TIMP-2 compared to Gran WF; 2) WF from Gran VLU showed significantly increased levels of MMP-1, MMP-7, MMP-13, and TIMP-4 compared to Infl WF; 3) LPS- and WF-stimulation of THP-1 cells significantly increased the expression of several MMP compared to untreated cells; 4) Sulodexide treatment of both LPS- and WF-stimulated THP-1 significantly down-regulated the release of several MMPs. Our study provides evidence-based medicine during treatment of patients with VLU. WF from Infl and Gran VLU have different MMP and TIMP signatures, consistent with their clinical state. The modulation of proteolytic pathways in wound microenvironment by glycosaminoglycan sulodexide, provide insights for translating research into clinical practice during VLU therapy. PMID:27460704
... FR 67396, Fisher Clinical Services, Inc., 7554 Schantz Road, Allentown, Pennsylvania 18106, made application to the Drug Enforcement Administration (DEA) to be registered as an importer of Tapentadol...
Morcelle, Susana R; Caffini, Néstor O; Priolo, Nora
As part of a screening of latex endopeptidases from plants growing in Argentina, the presence of proteolytic activity in the latex of Funastrum clausum stems is reported. The proteases present in the crude extract showed the main characteristics of the cysteine proteolytic class, i.e. optimum pH at alkaline range, isoelectric point (pI) higher than 9.0, and inhibition of proteolytic activity by thiol blocking reagents. A remarkable thermal stability was also evident in the crude extract. Endosterolytic preference tried on p-nitrophenyl esters of N-alpha-carbobenzoxy-L-amino acids was higher for the alanine, asparagine and tyrosine derivatives. Preliminary peptidase purification by two-step ionic exchange showed the presence of two proteolytic fractions with molecular masses of approximately 24.0 kDa according to SDS-PAGE. PMID:15261386
Williams, Donald C.; Sgarbieri, Valdemiro C.; Whitaker, John R.
The latices of only 13 of a total of 46 species of Ficus examined contained appreciable proteolytic activity. Therefore, high proteolytic activity in the latex is not a distinguishing feature of the genus. The latex of F. stenocarpa had the highest specific activity followed closely by the latices of F. carica and F. glabrata. Latices of 6 species of Ficus were examined by chromatography on CM-cellulose and compared with the results obtained for 9 varieties of F. carica. All of the latices were found to contain multiple proteolytic enzymes. Chromatographically, the multiple enzyme components of the several varieties of F. carica were more similar than those of the several species examined. The latices of 16 varieties of F. carica were all different as determined by free boundary electrophoresis although the specific proteolytic activity of the latices was reasonably constant. PMID:16656886
... FR 72409, Fisher Clinical Services, Inc., 7554 Schantz Road, Allentown, Pennsylvania 18106, made... Enforcement Administration Importer of Controlled Substances: Notice of Registration; Fisher Clinical Services... effect on May 1, 1971. DEA has investigated Fisher Clinical Services, Inc., to ensure that the...
... the Federal Register on September 23, 1975, 40 FR 43745-46, all applicants for registration to import... Enforcement Administration Importer of Controlled Substances; Notice of Application; Clinical Supplies.... Therefore, in accordance with 21 CFR 1301.34(a), this is notice that on November 13, 2011, Clinical...
Huang, Qin; Wang, Jun
Although the importance of clinical data is drawing more attention in drug development in China, the clinical data management is not good enough in the clinical trials right now. With the development of internet and progress of information technology, especially with the setup of the state innovation strategy for drug development, it is necessary and urgent to improve the clinical data quality. Good data quality is the primary basis of technical evaluation of drug at the marketing authorization. So Center for Drug Evaluation of CFDA has made some endeavors to enhance data management in the clinical trials in recent years. This article is focused on these aspects of data managment. PMID:26911033
..., 77 FR 50162, Clinical Supplies Management, Inc., 342 42nd Street South, Fargo, North Dakota 58103... importer of the basic classes of controlled substances: Drug Schedule Methylphenidate (1724) II...
Huffaker, R. C.
Although information has rapidly developed concerning the intracellular localization of plant proteins, relatively few reports concern the intracellular location of endo- and exo-proteolytic activities. Relatively few proteases have been purified, characterized, and associated with a specific cellular location. With the exception of the processing proteases involved in transport of proteins across membranes, little progress has yet been made concerning determination of in vivo products of specific proteases. Information on the turnover of individual proteins and the assessment of rate-limiting steps in pathways as proteins are turned over is steadily appearing. Since chloroplasts are the major site of both protein synthesis and, during senescence, degradation, it was important to show unambiguously that chloroplasts can degrade their own constituents. Another important contribution was to obtain evidence that the chloroplasts contain proteases capable of degrading their constituents. This work has been more tenuous because of the low activities found and the possibility of contamination by vacuolar enzymes during the isolation of organelles. The possible targeting of cytoplasmic proteins for degradation by facilitating their transport into vacuoles is a field which hopefully will develop more rapidly in the future. Information on targeting of proteins for degradation via the ubiquitin (Ub) degradation pathway is developing rapidly. Future research must determine how much unity exists across the different eukaryotic systems. At present, it has important implications for protein turnover in plants, since apparently Ub is involved in the degradation of phytochrome. Little information has been developed regarding what triggers increased proteolysis with the onset of senescence, although it appears to involve protein synthesis. Thus far, the evidence indicates that the complement of proteases prior to senescence is sufficient to carry out the observed protein
Mullins-Sweatt, Stephanie N; Lengel, Gregory J; DeShong, Hilary L
The development of major diagnostic manuals primarily has been guided by construct validity rather than clinical utility. The purpose of this article is to summarize recent research and theory examining the importance of clinical utility when constructing and evaluating a diagnostic manual. We suggest that construct validity is a necessary but not sufficient criterion for diagnostic constructs. This article discusses components of clinical utility and how these have applied to the current and forthcoming diagnostic manuals. Implications and suggestions for future research are provided. PMID:26666967
Nazari-Robati, Mahdieh; Golestani, Abolfazl; Asadikaram, GholamReza
Recently, utilization of the enzyme Chondroitinase ABC I (cABC I) has received considerable attention in treatment of spinal cord injury. cABC I removes chondroitin sulfate proteoglycans which are inhibitory to axon growth and enhances nerve regeneration. Therefore, determination of cABC I resistance to proteolysis and oxidation provides valuable information for optimizing its clinical application. In this work, proteolytic stability of cABC I to trypsin and chymotrypsin as well as its oxidative resistance to H2O2 was measured. Moreover, the effect of cosolvents glycerol, sorbitol and trehalose on cABC I proteolytic and oxidative stability was determined. The results indicated that cABC I is highly susceptible to proteolysis and oxidation. Comparison of proteolytic patterns demonstrated a high degree of similarity which confirmed the exposure of specific regions of cABC I to proteolysis. However, proteolytic degradation was significantly reduced in the presence of cosolvents. In addition, cosolvents decreased the rate of both cABC I proteolytic and oxidative inactivation. Notably, the degree of stabilization provided by these cosolvents varied greatly. These findings indicated the high potential of cosolvents in protein stabilization to proteolysis and oxidative inactivation. PMID:27311501
Wu, R Ryanne; Kinsinger, Linda S; Provenzale, Dawn; King, Heather A; Akerly, Patricia; Barnes, Lottie K; Datta, Santanu K; Grubber, Janet M; Katich, Nicholas; McNeil, Rebecca B; Monte, Robert; Sperber, Nina R; Atkins, David; Jackson, George L
Collaboration between policy, research, and clinical partners is crucial to achieving proven quality care. The Veterans Health Administration has expended great efforts towards fostering such collaborations. Through this, we have learned that an ideal collaboration involves partnership from the very beginning of a new clinical program, so that the program is designed in a way that ensures quality, validity, and puts into place the infrastructure necessary for a reliable evaluation. This paper will give an example of one such project, the Lung Cancer Screening Demonstration Project (LCSDP). We will outline the ways that clinical, policy, and research partners collaborated in design, planning, and implementation in order to create a sustainable model that could be rigorously evaluated for efficacy and fidelity. We will describe the use of the Donabedian quality matrix to determine the necessary characteristics of a quality program and the importance of the linkage with engineering, information technology, and clinical paradigms to connect the development of an on-the-ground clinical program with the evaluation goal of a learning healthcare organization. While the LCSDP is the example given here, these partnerships and suggestions are salient to any healthcare organization seeking to implement new scientifically proven care in a useful and reliable way. PMID:25355086
Viverais-Dresler, G; Kutschke, M
Clinical teachers make a necessary and valuable contribution to clinical nursing courses with non-RN learners. This contribution is often not considered necessary in degree nursing programs with an RN student population. This study describes the perceptions of RN students and the importance they attach to certain clinical teacher behaviors. Fifty-six participants in a distance education baccalaureate nursing program completed a questionnaire, including a rating scale and open-ended questions. Based on the mean values, items were ranked in importance. Sample quotes were provided to elaborate on the highest and lowest-ranked items. Participants rated the four categories in descending order of importance: Evaluation, Professional Competence, Interpersonal Relationships, and Teaching Ability. The top items gave the profile of a teacher who is approachable, fair, open, honest, and who creates mutual respect. The findings support a clinical teacher for RN learners. The data also reflect similarities and differences with findings of studies with non-RN student participants. The findings of this study provide information, not available in the literature, regarding clinical teacher behaviors of significance to RN students. PMID:11868719
Ogle, Curtis T; Mather, William H
Processive proteases, such as ClpXP in E. coli, are conserved enzyme assemblies that can recognize and rapidly degrade proteins. These proteases are used for a number of purposes, including degrading mistranslated proteins and controlling cellular stress response. However, proteolytic machinery within the cell is limited in capacity and can lead to a bottleneck in protein degradation, whereby many proteins compete ('queue') for proteolytic resources. Previous work has demonstrated that such queueing can lead to pronounced statistical relationships between different protein counts when proteins compete for a single common protease. However, real cells contain many different proteases, e.g. ClpXP, ClpAP, and Lon in E. coli, and it is not clear how competition between proteins for multiple classes of protease would influence the dynamics of cellular networks. In the present work, we theoretically demonstrate that a multi-protease proteolytic bottleneck can substantially couple the dynamics for both simple and complex (oscillatory) networks, even between substrates with substantially different affinities for protease. For these networks, queueing often leads to strong positive correlations between protein counts, and these correlations are strongest near the queueing theoretic point of balance. Furthermore, we find that the qualitative behavior of these networks depends on the relative size of the absolute affinity of substrate to protease compared to the cross affinity of substrate to protease, leading in certain regimes to priority queue statistics. PMID:27042892
Ogle, Curtis T.; Mather, William H.
Processive proteases, such as ClpXP in E. coli, are conserved enzyme assemblies that can recognize and rapidly degrade proteins. These proteases are used for a number of purposes, including degrading mistranslated proteins and controlling cellular stress response. However, proteolytic machinery within the cell is limited in capacity and can lead to a bottleneck in protein degradation, whereby many proteins compete (‘queue’) for proteolytic resources. Previous work has demonstrated that such queueing can lead to pronounced statistical relationships between different protein counts when proteins compete for a single common protease. However, real cells contain many different proteases, e.g. ClpXP, ClpAP, and Lon in E. coli, and it is not clear how competition between proteins for multiple classes of protease would influence the dynamics of cellular networks. In the present work, we theoretically demonstrate that a multi-protease proteolytic bottleneck can substantially couple the dynamics for both simple and complex (oscillatory) networks, even between substrates with substantially different affinities for protease. For these networks, queueing often leads to strong positive correlations between protein counts, and these correlations are strongest near the queueing theoretic point of balance. Furthermore, we find that the qualitative behavior of these networks depends on the relative size of the absolute affinity of substrate to protease compared to the cross affinity of substrate to protease, leading in certain regimes to priority queue statistics.
Horváth, Krisztina; Aschermann, Zsuzsanna; Ács, Péter; Deli, Gabriella; Janszky, József; Komoly, Sámuel; Karádi, Kázmér; Kovács, Márton; Makkos, Attila; Faludi, Béla; Kovács, Norbert
Background and Aims. The aim of the present study was to determine the estimates of minimal clinically important difference for Parkinson's Disease Sleep Scale 2nd version (PDSS-2) total score and dimensions. Methods. The subject population consisted of 413 PD patients. At baseline, MDS-UPDRS, Hoehn-Yahr Scale, Mattis Dementia Rating Scale, and PDSS-2 were assessed. Nine months later the PDSS-2 was reevaluated with the Patient-Reported Global Impression Improvement Scale. Both anchor-based techniques (within patients' score change method and sensitivity- and specificity-based method by receiver operating characteristic analysis) and distribution-based approaches (effect size calculations) were utilized to determine the magnitude of minimal clinically important difference. Results. According to our results, any improvements larger than −3.44 points or worsening larger than 2.07 points can represent clinically important changes for the patients. These thresholds have the effect size of 0.21 and −0.21, respectively. Conclusions. Minimal clinically important differences are the smallest change of scores that are subjectively meaningful to patients. Studies using the PDSS-2 as outcome measure should utilize the threshold of −3.44 points for detecting improvement or the threshold of 2.07 points for observing worsening. PMID:26539303
Viverais-Dresler, Gloria; Kutschke, Myrtle
Registered nurses in a bachelor's degree program (n=56) rated the following as important clinical teacher behaviors: evaluation, professional competence, interpersonal relationship, and teaching ability. They valued teachers who were approachable, fair, open, and honest and who fostered mutual respect. (Contains 25 references.) (SK)
El-Missiry, Ahmed; Aboraya, Ahmed Sayed; Manseur, Hader; Manchester, Johnna; France, Cheryl; Border, Katherine
Schizophrenia is a chronic mental illness which poses a tremendous burden on the families, caregivers and the society. The purpose of this paper is to provide an updated review of the epidemiology of schizophrenia with a special attention to the clinically important risk factors such as drug abuse, hormonal factors and the new advances in genetic…
Moxham, Bernard John; Emmanouil-Nikoloussi, Elpida; Standley, Henrietta; Brenner, Erich; Plaisant, Odile; Brichova, Hana; Pais, Diogo; Stabile, Isobel; Borg, Jordy; Chirculescu, Andy
Although there have been many studies reporting the attitudes of medical students to the clinical importance of gross anatomy, little is known about their opinions concerning the clinical importance of embryology. Using Thurstone and Chave methods to assess attitudes, nearly 1,600 medical students across Europe in the early stages of their training provided responses to a survey that tested the hypothesis that they do not regard embryology as highly clinically relevant. Indeed, we further proposed that student attitudes to gross anatomy are much more positive than those toward embryology. Our findings show that our hypotheses hold, regardless of the university and country surveyed and regardless of the teaching methods employed for embryology. Clearly, embryology has a significant part to play in medical education in terms of understanding prenatal life, of appreciating how the organization of the mature human body has developed, and of providing essential information for general medical practice, obstetrics and pediatrics, and teratology. However, while newly recruited medical students understand the importance of gross anatomy in the development of professional competence, understanding the importance of embryology requires teachers, medical educationalists, and devisors of medical curricula to pay special attention to informing students of the significant role played by embryology in attaining clinical competence and achieving the knowledge and understanding of the biomedical sciences that underpins becoming a learned member of a health care profession. PMID:26538399
Apodaca, G; McKerrow, J H
Trichophyton rubrum is the most common dermatophyte of humans and normally colonizes the superficial layers of the epidermis (stratum corneum). Several proteinases with a possible role in the metabolism of host proteins have been purified from this fungus. The regulation of these enzymes and their role in fungal metabolism were studied at the biochemical level. General proteolytic (azocollytic) activity was repressed when log-phase cultures of T. rubrum were grown in a minimal medium that contained readily metabolized sources of carbon, nitrogen, sulfur, and phosphorus. When either carbon, nitrogen, or sulfur was deleted from this minimal medium, azocollytic activity was derepressed. In all cases a high-molecular-weight activity (Mr, greater than 200,000) was expressed. A 71,000-Mr proteinase was observed in nitrogen-depleted cultures, and proteolytic species of Mr 124,000 and 27,000 were secreted in sulfur-depleted cultures. The addition of either inorganic (MgSO4, Na2SO3, NaS2O3) or organic (methionine, cysteine) sulfur to the sulfur-depleted medium repressed the expression of azocollytic activity. In contrast, keratinolytic activity was not repressed by carbon, nitrogen, or sulfur but instead was induced when a protein source was included in the minimal medium. Stationary-phase cultures of T. rubrum secreted all proteolytic activities constitutively. Unlike log-phase cultures, the stationary-phase cultures secreted azocollytic, elastinolytic, and keratinolytic activity in minimal medium. These activities fell in the carbon-, nitrogen-, and phosphorous-depleted media but remained high in sulfur-depleted medium. The following model is proposed for the regulation of T. rubrum proteolytic activity. In the initial stages of infection, T. rubrum grows logarithmically. In this state, proteolytic activity is derepressed whenever carbon, nitrogen, or sulfur is lacking in the fungal milieu. The general proteinases produced would act on the nonkeratinous proteins in the
Lauber, Christine A.; Toth, Powell E.; Leary, Paul A.; Martin, R Daniel; Killian, Clyde B.
OBJECTIVE: To investigate the perceived importance of clinical instructors' behaviors and behavior categories in the roles of program director (PD) and clinical instructor (CI) and to ascertain the relative importance of these items within each role. DESIGN AND SETTING: From the literature, we developed a questionnaire, validated by a panel of experts, to collect data regarding the perceived importance of 30 specific CI behavior statements within 5 categories (instructional, interpersonal, evaluative, professional, and personal). The instrument used in the study had a Cronbach alpha of.92. SUBJECTS: Independent groups of 75 PDs and 242 CIs from Commission on Accreditation of Allied Health Education Programs-accredited entry-level undergraduate athletic training programs returned usable surveys. MEASUREMENTS: We computed mean and variation measures for each behavior and category and analyzed these items for between-role and within-role category differences. RESULTS: Program directors and CIs differed significantly in the perceived importance of the evaluative category of CI behaviors as well as in 3 specific evaluative behaviors. Program directors and CIs did not differ in the other 4 categories. For within-role groupings, we noted significant differences of perceived importance among the behavioral categories. CONCLUSIONS: Program directors and CIs perceived all 5 categories to be very important, and they should work to demonstrate these behaviors in clinical-education settings. Collaboration between the groups enhances the understanding of role responsibility in the delivery of athletic training clinical instruction. PMID:14737217
Toth, Powell E.; Leary, Paul A.; Martin, R. Daniel; Killian, Clyde B.
Objective: To investigate the perceived importance of clinical instructors' behaviors and behavior categories in the roles of program director (PD) and clinical instructor (CI) and to ascertain the relative importance of these items within each role. Design and Setting: From the literature, we developed a questionnaire, validated by a panel of experts, to collect data regarding the perceived importance of 30 specific CI behavior statements within 5 categories (instructional, interpersonal, evaluative, professional, and personal). The instrument used in the study had a Cronbach alpha of .92. Subjects: Independent groups of 75 PDs and 242 CIs from Commission on Accreditation of Allied Health Education Programs–accredited entry-level undergraduate athletic training programs returned usable surveys. Measurements: We computed mean and variation measures for each behavior and category and analyzed these items for between-role and within-role category differences. Results: Program directors and CIs differed significantly in the perceived importance of the evaluative category of CI behaviors as well as in 3 specific evaluative behaviors. Program directors and CIs did not differ in the other 4 categories. For within-role groupings, we noted significant differences of perceived importance among the behavioral categories. Conclusions: Program directors and CIs perceived all 5 categories to be very important, and they should work to demonstrate these behaviors in clinical-education settings. Collaboration between the groups enhances the understanding of role responsibility in the delivery of athletic training clinical instruction. PMID:14737217
Pinilla, Yudi T; Moreno-Pérez, Darwin A; Patarroyo, Manuel A; Bello, Felio J
Sarconesiopsis magellanica (Diptera: Calliphoridae) is a medically important necrophagous fly which is used for establishing the post-mortem interval. Diptera maggots release proteolytic enzymes contained in larval excretion and secretion (ES) products playing a key role in digestion. Special interest in proteolytic enzymes has also been aroused regarding understanding their role in wound healing since they degrade necrotic tissue during larval therapy. This study was thus aimed at identifying and characterising S. magellanica proteolytic enzyme ES products for the first time. These products were obtained from first-, second- and third-instar larvae taken from a previously-established colony. ES proteins were separated by SDS-PAGE and their proteolytic activity was characterised by zymograms and inhibition assays involving BAPNA (Nα-benzoyl-dl-Arg-p-nitroanilide) and SAPNA substrates, using synthetic inhibitors. The protein profile ranged from ∼69kDa to ∼23kDa; several of them coincided with the Lucilia sericata ES protein profile. Serine-protease hydrolysis activity (measured by zymogram) was confirmed when a ∼25kDa band disappeared upon ES incubation with PMSF inhibitor at pH 7.8. Analysis of larval ES proteolytic activity on BAPNA and SAPNA substrates (determined by using TLCK and TPCK specific inhibitors) suggested a greater amount of trypsin-like protease. These results support the need for further experiments aimed at validating S. magellanica use in larval therapy. PMID:24076089
Arnold, Brent L.; Gansneder, Bruce M.; Van Lunen, Bonnie L.; Szczerba, Joseph E.; Mattacola, Carl G.; Perrin, David H.
Objective: We examined employer importance ratings of 35 employee characteristics in the collegiate, sports medicine clinic, and high school settings and made comparisons among these settings. Design and Setting: All prospective employers were sent a survey. Of the 472 surveys mailed, 282 (60%) were returned, with a sample error rate of 1.9%. Subjects: All prospective employers listed on the NATA position vacancy notices from January 1, 1994 to October 1, 1994. Measurements: Employers were asked to rate 35 employee characteristics as “not important” “ minimally important,” “ important.” or “very important.” Additionally, employers chose 1 of 15 job descriptors that best identified their position vacancy. These 15 descriptors were then categorized into collegiate, sports medicine clinic, and high school settings. Discriminant analysis and analysis of variance procedures were used to determine if the 35 employee characteristics differed across the 3 settings. Results: The discriminant analysis produced 2 significant discriminant functions (P < .05) with 23 of the original 35 characteristics remaining in the analysis. The first function discriminated between the collegiate setting and the other settings, with the collegiate setting scoring the highest. The second function discriminated among all 3 groups, with the sports medicine clinic and high school settings scoring the highest and lowest, respectively. Additionally, the analyses of variance (ANOVAs) revealed that 21 of the characteristics remaining in the discriminant analysis differed across the 3 settings. Conclusions: Employers from all 3 settings rated educational program reputation, written recommendations, job interview performance, and NATA-BOC certification eligibility as important to very important. For the collegiate setting, 7 characteristics were rated above important and included such characteristics as possession of a master's degree and collegiate experience. For the sports medicine
Honma, Naoko; Horii, Rie; Iwase, Takuji; Saji, Shigehira; Younes, Mamoun; Ito, Yoshinori; Akiyama, Futoshi
BACKGROUND: Despite many studies, the clinicopathological importance of the androgen receptor (AR) in breast cancer is not well established, and its significance as an independent predictor of clinical outcome is controversial. A large and systematic study is needed to address these issues. The aim of the present study was to elucidate whether AR has independent clinical value, examining its importance in a large and well-predefined patient group with a long follow-up period and complete clinicopathological data. METHODS: Archival materials of 403 invasive breast cancers from women treated with adjuvant tamoxifen monotherapy (median follow-up period 11.0 years) were subjected to immunohistochemical study using anti-AR monoclonal antibody. AR expression was compared with established clinicopathological factors, estrogen receptor (ER)-β expression, and clinical outcome. RESULTS: AR positivity was correlated with ER-α positivity, progesterone receptor positivity, ER-β positivity, and a lower nuclear grade. Patients with AR-positive carcinomas exhibited a significantly better clinical outcome than those with AR-negative carcinomas (P = 0.0165 for disease-free survival, P = 0.0344 for overall survival). Multivariate analysis did not yield significant differences in clinical outcome according to the AR status, whereas the ER-β status showed significant differences in multivariate analysis. CONCLUSIONS: Although, and in agreement with previous reports, AR positivity correlated with some established favorable prognostic factors and with ER-β positivity, AR was not an independent predictor of clinical outcome. Controversy regarding the value of AR as an independent predictor of clinical outcome may at least partly reflect the relatively limited power of AR in breast cancer. PMID:22302643
Czarnowicki, Tali; Krueger, James G; Guttman-Yassky, Emma
Atopic dermatitis is the most common chronic inflammatory skin disease. Its pathogenesis combines barrier defects, immune dysregulation, and increased skin infections; however, the relative contribution of each of these components is yet to be determined. Uninvolved atopic dermatitis skin also displays broad immune and barrier abnormalities, which highlights a role for proactive treatment strategy. The residual disease genomic profile that accompanies clinical resolution provides further support for proactive treatment approaches. Although intrinsic and extrinsic atopic dermatitis subtypes share a common clinical phenotype, they show some important differences in their Th22/Th17 cytokine profile, which opens the door for personalized specific therapeutics for each disease category. PMID:25017523
Kim, Jong Seo; Dai, Ziyu; Aryal, Uma K.; Moore, Ronald J.; Camp, David G.; Baker, Scott E.; Smith, Richard D.; Qian, Weijun
Proteolytic processing is a ubiquitous, irreversible posttranslational modification that plays an important role in cellular regulation in all living organisms. Herein we report a resin-assisted positive selection method for specifically enriching protein N-terminal peptides to facilitate the characterization of proteolytic processing events by liquid chromatography-tandem mass spectrometry. In this approach, proteins are initially reduced and alkylated and their lysine residues are converted to homoarginines. Then, protein N-termini are selectively converted to reactive thiol groups. We demonstrate that these sequential reactions were achieved with nearly quantitative efficiencies. Thiol-containing N-terminal peptides are then captured (>98% efficiency) by a thiol-affinity resin, a significant improvement over the traditional avidin/biotin enrichment. Application to cell lysates of Aspergillus niger, a filamentous fungus of interest for biomass degradation, enabled the identification of 1672 unique protein N-termini and proteolytic cleavage sites from 690 unique proteins.
Micevski, Dimce; Dougan, David A
Maintaining correct cellular function is a fundamental biological process for all forms of life. A critical aspect of this process is the maintenance of protein homeostasis (proteostasis) in the cell, which is largely performed by a group of proteins, referred to as the protein quality control (PQC) network. This network of proteins, comprised of chaperones and proteases, is critical for maintaining proteostasis not only during favourable growth conditions, but also in response to stress. Indeed proteases play a crucial role in the clearance of unwanted proteins that accumulate during stress, but more importantly, in the activation of various different stress response pathways. In bacteria, the cells response to stress is usually orchestrated by a specific transcription factor (sigma factor). In Escherichia coli there are seven different sigma factors, each of which responds to a particular stress, resulting in the rapid expression of a specific set of genes. The cellular concentration of each transcription factor is tightly controlled, at the level of transcription, translation and protein stability. Here we will focus on the proteolytic regulation of two sigma factors (σ(32) and σ(S)), which control the heat and general stress response pathways, respectively. This review will also briefly discuss the role proteolytic systems play in the clearance of unwanted proteins that accumulate during stress. PMID:23479439
Page, Brent T.; Kurtzman, Cletus P.
Two rapid diagnostic assays, utilizing two different Luminex flow cytometry methods, were developed for identification of clinically important ascomycetous yeast species. Direct hybridization and allele-specific primer extension methods were both successful in establishing a DNA-based assay that can rapidly and accurately identify Candida albicans, Candida krusei, Candida parapsilosis, Candida glabrata, and Candida tropicalis as well as other clinical species. The direct hybridization assay was designed to identify a total of 19 ascomycetous yeast species, and the allele-specific primer extension assay was designed to identify a total of 34 species. Probes were validated against 438 strains representing 303 species. From culture to identification, the allele-specific primer extension method takes 8 h and the direct hybridization method takes less than 5 h to complete. These assays represent comprehensive, rapid tests that are well suited for the clinical laboratory. PMID:16145099
Wehmeyer, J M; Wehmeyer, S
Clinical psychology has received little attention as a subject in health sciences library collections. This study seeks to demonstrate the relative importance of the monographic literature to clinical psychology through the examination of citations in graduate student theses and dissertations at the Fordham Health Sciences Library, Wright State University. Dissertations and theses were sampled randomly; citations were classified by format, counted, and subjected to statistical analysis. Books and book chapters together account for 35% of the citations in clinical psychology dissertations, 25% in nursing theses, and 8% in biomedical sciences theses and dissertations. Analysis of variance indicates that the citations in dissertations and theses in the three areas differ significantly (F = 162.2 with 2 and 253 degrees of freedom, P = 0.0001). Dissertations and theses in biomedical sciences and nursing theses both cite significantly more journals per book than the dissertations in clinical psychology. These results support the hypothesis that users of clinical psychology literature rely more heavily on books than many other users of a health sciences library. Problems with using citation analyses in a single subject to determine a serials to monographs ratio for a health sciences library are pointed out. PMID:10219478
Trembath, LisaAnn; Opanowski, Adam
Nuclear medicine technologists and investigators who perform imaging procedures in clinical trials often have not received training on clinical research regulations, such as Title 21, part 312, of the Code of Federal Regulations or Good Clinical Practices. These regulations directly affect implementation of the therapeutic or imaging protocol. Lack of understanding of the regulatory expectations in clinical research can lead to unintended errors or omissions in critical data that are needed for development of a new drug. One common error is not following the protocol exactly as written, or modifying the imaging parameters in some way as to make the data nonstandard from site to site. These errors and omissions are a source of delay in the development of new imaging and therapeutic products. Although not following the protocol does not result in criminal penalties per se, errors and omissions can lead to regulatory consequences such as warning letters to the investigator or sponsor, which if not resolved can lead to barring a site or investigator from participation in any future research trials. Pharmaceutical sponsors, device sponsors, and federal granting agencies such as the National Cancer Institute enter into contracts with imaging sites under the expectation that the investigator and all research staff know and understand clinical research regulations. This article is intended to teach imaging personnel what any sponsor (pharmaceutical, device, or federal agency) is expecting from research imaging and how lack of understanding of Good Clinical Practices and federal regulations can impede the optimal success of a research study. After reading this article, nuclear medicine technologists should be able to understand the importance of following the clinical trial protocol to exact specifications, create a list of questions that should be answered by the sponsor or trial organizers before patient enrollment, describe Form FDA 1572, and describe the terms protocol
Wierda, William G.; O'Brien, Susan; Wang, Xuemei; Faderl, Stefan; Ferrajoli, Alessandra; Do, Kim-Anh; Garcia-Manero, Guillermo; Cortes, Jorge; Thomas, Deborah; Koller, Charles; Burger, Jan; Lerner, Susan; Kantarjian, Hagop; Keating, Michael
Purpose Response to front-line treatment and subsequent clinical course for patients with chronic lymphocytic leukemia (CLL) are heterogeneous. Identifying pretreatment patient characteristics or prognostic factors associated with clinical outcomes is important for counseling patients, conducting clinical research, and evaluating trial results. Patients and Methods We evaluated the pretreatment characteristics of 595 previously untreated patients who had National Cancer Institute Working Group indications to initiate front-line therapy for predictors of complete response (CR), time to treatment failure (TTF), and overall survival (OS). Multivariable models were developed for all three end points. Results CR is an important treatment end point correlated with longer TTF and OS. In this retrospective analysis, front-line treatment regimen was a significant independent predictive factor for all three end points; chemoimmunotherapy was the superior treatment regimen. Considering front-line treatment regimen, other independent patient characteristics associated with CR included age and β2-microglobulin (β-2M). TTF was independently associated with age, β-2M, percent lymphocytes in bone marrow, and treatment regimen. Improved OS was independently associated with younger age, lower β-2M, and treatment regimen. Two weighted prognostic models or nomograms, one including and one excluding treatment regimen, were constructed using significant characteristics to predict 5- and 10-year survival probability and estimate median survival time. Conclusion Identifying pretreatment patient characteristics associated with CR, TTF, and OS establishes a baseline to compare and incorporate new prognostic factors. Treatment had an impact on the significance of these factors. Prognostic models may help patients and clinicians in decision making as well as facilitate clinical research through design and analyses of clinical trials. PMID:19224852
Akiyama, Tatsuya; Khan, Ashraf A; Cheng, Chorng-Ming; Stefanova, Rossina
A total of 39 Salmonella enterica serovar Saintpaul strains from imported seafood, pepper and from environmental and clinical samples were analyzed for the presence of virulence genes, antibiotic resistance, plasmid and plasmid replicon types. Pulsed-field gel electrophoresis (PFGE) fingerprinting using the XbaI restriction enzyme and plasmid profiling were performed to assess genetic diversity. None of the isolates showed resistance to ampicillin, chloramphenicol, gentamicin, kanamycin, streptomycin, sulfisoxazole, and tetracycline. Seventeen virulence genes were screened for by PCR. All strains were positive for 14 genes (spiA, sifA, invA, spaN, sopE, sipB, iroN, msgA, pagC, orgA, prgH, lpfC, sitC, and tolC) and negative for three genes (spvB, pefA, and cdtB). Twelve strains, including six from clinical samples and six from seafood, carried one or more plasmids. Large plasmids, sized greater than 50 kb were detected in one clinical and three food isolates. One plasmid was able to be typed as IncI1 by PCR-based replicon typing. There were 25 distinct PFGE-XbaI patterns, clustered to two groups. Cluster A, with 68.5% similarity mainly consists of clinical isolates, while Cluster C, with 67.6% similarity, mainly consisted of shrimp isolates from India. Our findings indicated the genetic diversity of S. Saintpaul in clinical samples, imported seafood, and the environment and that this serotype possesses several virulent genes and plasmids which can cause salmonellosis. PMID:21645810
It has been 20years that the G protein-coupled estrogen receptor (GPER) was cloned as the orphan receptor GPR30 from multiple cellular sources, including vascular endothelial cells. Here, I will provide an overview of estrogen biology and the historical background leading to the discovery of rapid vascular estrogen signaling. I will also review the recent advances in the understanding of the mechanisms underlying GPER function, its role in physiology and disease, some of the currently available GPER-targeting drugs approved for clinical use such as SERMs (selective estrogen receptor modulators) and SERDs (selective estrogen receptor downregulators). Many of currently used drugs such as tamoxifen, raloxifene, or faslodex™/fulvestrant were discovered targeting GPER many years after they had been introduced to the clinics for entirely different purposes. This has important implications for the clinical use of these drugs and their modes of action, which I have termed 'reverse translational medicine'. In addition, environmental pollutants known as 'endocrine disruptors' have been found to bind to GPER. This article also discusses recent evidence in these areas as well as opportunities in translational clinical medicine and GPER research, including medical genetics, personalized medicine, prevention, and its theranostic use. PMID:26921679
Kroenke, Kurt; Monahan, Patrick O.; Kean, Jacob
Objective Measures for assessing patient-reported outcomes (PROs) that may have initially been developed for research are increasingly being recommended for use in clinical practice as well. While psychometric rigor is essential, this paper focuses on pragmatic characteristics of PROs that may enhance uptake into clinical practice. Methods Three sources were drawn upon in identifying pragmatic criteria for PROs: 1) selected literature review including recommendations by other expert groups; 2) key features of several model public domain PROs; 3) the author' experience in developing practical PROs. Results Eight characteristics of a practical PRO include: 1) actionability (i.e., scores guide diagnostic or therapeutic actions/decision-making); 2) appropriateness for the relevant clinical setting; 3) universality (i.e., for screening, severity assessment, and monitoring across multiple conditions); 4) self-administration; 5) item features (number of items and bundling issues); 6) response options (option number and dimensions, uniform vs. varying options, timeframe, intervals between options); 7) scoring (simplicity, interpretability); and 8) accessibility (nonproprietary, downloadable, available in different languages and for vulnerable groups, incorporated into electronic health records) Conclusion Balancing psychometric and pragmatic factors in the development of PROs is important for accelerating the incorporation of PROs into clinical practice. PMID:25962972
Junghanss, Thomas; Bodio, Mauro
Venomous animals are a significant health problem for rural populations in many parts of the world. Given the current level of the international mobility of individuals and the inquisitiveness of travelers, clinicians and travel clinics need to be able to give advice on the prevention, first aid, and clinical management of envenoming. Health professionals often feel overwhelmed by the taxonomy of venomous animals; however, venomous animals can be grouped, using a simple set of criteria, into cnidarians, venomous fish, sea snakes, scorpions, spiders, hymenoterans, and venomous terrestrial snakes. Geographic distribution, habitats, and circumstances of accidents further reduce the range of culprits that need to be considered in any single event. Clinical management of envenomed patients relies on supportive therapy and, if available, specific antivenoms. Supplies of life-saving antivenoms are scarce, and this scarcity particularly affects rural populations in resource-poor settings. Travel clinics and hospitals in highly industrialized areas predominantly see patients with injuries caused by accidents involving marine animals: in particular, stings by venomous fish and skin damage caused by jellyfish. However, globally, terrestrial venomous snakes are the most important group of venomous animals. PMID:17051499
Kokashvili, Tamar; Whitehouse, Chris A.; Tskhvediani, Ana; Grim, Christopher J.; Elbakidze, Tinatin; Mitaishvili, Nino; Janelidze, Nino; Jaiani, Ekaterine; Haley, Bradd J.; Lashkhi, Nino; Huq, Anwar; Colwell, Rita R.; Tediashvili, Marina
Among the more than 70 different Vibrio species inhabiting marine, estuarine, and freshwater ecosystems, 12 are recognized as human pathogens. The warm subtropical climate of the Black Sea coastal area and inland regions of Georgia likely provides a favorable environment for various Vibrio species. From 2006 to 2009, the abundance, ecology, and diversity of clinically important Vibrio species were studied in different locations in Georgia and across seasons. Over a 33-month period, 1,595 presumptive Vibrio isolates were collected from the Black Sea (n = 657) and freshwater lakes around Tbilisi (n = 938). Screening of a subset of 440 concentrated and enriched water samples by PCR-electrospray ionization/mass spectrometry (PCR-ESI/MS) detected the presence of DNA from eight clinically important Vibrio species: V. cholerae, V. parahaemolyticus, V. vulnificus, V. mimicus, V. alginolyticus, V. harveyi, V. metschnikovii, and V. cincinnatiensis. Almost 90% of PCR/ESI-MS samples positive for Vibrio species were collected from June through November. Three important human-pathogenic Vibrio species (V. cholerae, V. parahaemolyticus, and V. vulnificus) were detected in 62.8, 37.8, and 21.4% of samples testing positive for Vibrios, respectively. The results of these activities suggest that natural reservoirs for human-pathogenic Vibrios exist in Georgian aquatic environments. Water temperature at all sampling sites was positively correlated with the abundance of clinically important Vibrio spp. (except V. metschnikovii), and salinity was correlated with species composition at particular Black Sea sites as well as inland reservoirs. PMID:26528464
Hecimovich, Mark D.; Volet, Simone E.
Purpose: One important objective of chiropractic education is to foster student professional confidence and competence in patient communication and clinical skills. Therefore, the aim of this article is to review the extant literature on this topic, stressing the significance of building students' confidence for effective practice and the need for more research in this area. Methods: The authors reviewed MEDLINE and ERIC from 1980 through 2008 using several key words pertinent to confidence and health care. Three distinct, but interrelated, bodies of literature were assessed, including professional confidence in health care research, the nature and development of confidence in educational psychology research, and fostering professional confidence in chiropractic education. Results: It was apparent through the review that chiropractic education has developed educational methods and opportunities that may help develop and build student confidence in patient communication and clinical skills. However, there has not been sufficient research to provide empirical evidence of the impact. Conclusion: Fostering chiropractic students' development of confidence in what they say and do is of paramount importance not only to them as new practitioners but more importantly to the patient. There is no doubt that a better understanding of how confidence can be developed and consolidated during tertiary study should be a major goal of chiropractic education PMID:19826543
Ustun, Berk; Westover, M. Brandon; Rudin, Cynthia; Bianchi, Matt T.
Study Objective: Obstructive sleep apnea (OSA) is a treatable contributor to morbidity and mortality. However, most patients with OSA remain undiagnosed. We used a new machine learning method known as SLIM (Supersparse Linear Integer Models) to test the hypothesis that a diagnostic screening tool based on routinely available medical information would be superior to one based solely on patient-reported sleep-related symptoms. Methods: We analyzed polysomnography (PSG) and self-reported clinical information from 1,922 patients tested in our clinical sleep laboratory. We used SLIM and 7 state-of-the-art classification methods to produce predictive models for OSA screening using features from: (i) self-reported symptoms; (ii) self-reported medical information that could, in principle, be extracted from electronic health records (demographics, comorbidities), or (iii) both. Results: For diagnosing OSA, we found that model performance using only medical history features was superior to model performance using symptoms alone, and similar to model performance using all features. Performance was similar to that reported for other widely used tools: sensitivity 64.2% and specificity 77%. SLIM accuracy was similar to state-of-the-art classification models applied to this dataset, but with the benefit of full transparency, allowing for hands-on prediction using yes/no answers to a small number of clinical queries. Conclusion: To predict OSA, variables such as age, sex, BMI, and medical history are superior to the symptom variables we examined for predicting OSA. SLIM produces an actionable clinical tool that can be applied to data that is routinely available in modern electronic health records, which may facilitate automated, rather than manual, OSA screening. Commentary: A commentary on this article appears in this issue on page 159. Citation: Ustun B, Westover MB, Rudin C, Bianchi MT. Clinical prediction models for sleep apnea: the importance of medical history over symptoms
Motl, Robert W.; Pilutti, Lara A.; Learmonth, Yvonne C.; Goldman, Myla D.; Brown, Ted
Background The number of steps taken per day (steps/day) provides a reliable and valid outcome of free-living walking behavior in persons with multiple sclerosis (MS). Objective This study examined the clinical meaningfulness of steps/day using the minimal clinically important difference (MCID) value across stages representing the developing impact of MS. Methods This study was a secondary analysis of de-identified data from 15 investigations totaling 786 persons with MS and 157 healthy controls. All participants provided demographic information and wore an accelerometer or pedometer during the waking hours of a 7-day period. Those with MS further provided real-life, health, and clinical information and completed the Multiple Sclerosis Walking Scale-12 (MSWS-12) and Patient Determined Disease Steps (PDDS) scale. MCID estimates were based on regression analyses and analysis of variance for between group differences. Results The mean MCID from self-report scales that capture subtle changes in ambulation (1-point change in PDSS scores and 10-point change in MSWS-12 scores) was 779 steps/day (14% of mean score for MS sample); the mean MCID for clinical/health outcomes (MS type, duration, weight status) was 1,455 steps/day (26% of mean score for MS sample); real-life anchors (unemployment, divorce, assistive device use) resulted in a mean MCID of 2,580 steps/day (45% of mean score for MS sample); and the MCID for the cumulative impact of MS (MS vs. control) was 2,747 steps/day (48% of mean score for MS sample). Conclusion The change in motion sensor output of ∼800 steps/day appears to represent a lower-bound estimate of clinically meaningful change in free-living walking behavior in interventions of MS. PMID:24023843
Zhang, Yuanpeng; Wang, Li; Qian, Danmin; Geng, Xingyun; Yao, Dengfu; Dong, Jiancheng
To extract expert clinic information from the Deep Web, there are two challenges to face. The first one is to make a judgment on forms. A novel method based on a domain model, which is a tree structure constructed by the attributes of query interfaces is proposed. With this model, query interfaces can be classified to a domain and filled in with domain keywords. Another challenge is to extract information from response Web pages indexed by query interfaces. To filter the noisy information on a Web page, a block importance model is proposed, both content and spatial features are taken into account in this model. The experimental results indicate that the domain model yields a precision 4.89% higher than that of the rule-based method, whereas the block importance model yields an F1 measure 10.5% higher than that of the XPath method. PMID:26231612
Odds, F C; Bernaerts, R
CHROMagar Candida is a novel, differential culture medium that is claimed to facilitate the isolation and presumptive identification of some clinically important yeast species. We evaluated the use of this medium with 726 yeast isolates, including 82 isolated directly on the medium from clinical material. After 2 days of incubation at 37 degrees C, 285 C. albicans isolates gave distinctive green colonies that were not seen with any of 441 other yeast isolates representing 21 different species. A total of 54 C. tropicalis isolates also developed distinctive dark blue-gray colonies with a halo of dark brownish purple in the surrounding agar. C. krusei isolates (n = 43) also formed highly characteristic rough, spreading colonies with pale pink centers and a white edge that was otherwise encountered only rarely with isolates of C. norvegensis. Trichosporon spp. (n = 34) formed small, pale colonies that became larger and characteristically rough with prolonged incubation. Most of the other 310 yeasts studied formed colonies with a color that ranged from white to pink to purple with a brownish tint. The only exceptions were found among isolates identified as Geotrichum sp. or Pichia sp., some of which formed colonies with a gray to blue color and which in two instances formed a green pigment or a dark halo in the agar. The specificity and sensitivity of the new medium for the presumptive identification of C. albicans, C. krusei, and C. tropicalis exceeded 99% for all three species. A blinded reading test involving four personnel and 57 yeast isolates representing nine clinically important species confirmed that colonial appearance after 48 h of incubation on CHROMagar Candida afforded the correct presumptive recognition of C. albicans, C. tropicalis, C, krusei, and Trichosporon spp. None of nine bacterial isolates grew on CHROMagar Candida within 72 h, and bacteria (Escherichia coli) grew from only 4 of 104 vaginal, 100 oral, and 99 anorectal swabs. The new medium
Samal, Sangram K; Dash, Mamoni; Chiellini, Federica; Kaplan, David L; Chiellini, Emo
The proteolytic enzyme α-chymotrypsin selectively cleaves the amorphous regions of silk fibroin protein (SFP) and allows the crystalline regions to self-assemble into silk microgels (SMGs) at physiological temperature. These microgels consist of lamellar crystals in the micrometer scale, in contrast to the nanometer-scaled crystals in native silkworm fibers. Sodium dodecyl sulfate-polyacrylamide gel electrophoresis and zeta potential results demonstrated that α-chymotrypsin utilized only the non-amorphous domains or segments of the heavy chain of SFP to form negatively charged SMGs. The SMGs were characterized in terms of size, charge, structure, morphology, crystallinity, swelling kinetics, water content and thermal properties. The results suggest that the present technique of preparing SMGs by α-chymotrypsin is simple and efficient, and that the prepared SMGs have useful features for studies related to biomaterial and pharmaceutical needs. This process is also an easy way to obtain the amorphous peptide chains for further study. PMID:23756227
da Cruz Ramos, Geomárcia Feitosa; Ramos, Patricia Locosque; Passarini, Michel Rodrigo Zambrano; Vieira Silveira, Marghuel A; Okamoto, Débora Noma; de Oliveira, Lilian Caroline Gonçalves; Zezzo, Larissa Vieira; Marem, Alyne; Santos Rocha, Rafael Costa; da Cruz, João Batista; Juliano, Luiz; de Vasconcellos, Suzan Pantaroto
The bioprospection for cellulase and protease producers is a promise strategy for the discovery of potential biocatalysts for use in hydrolysis of lignocellulosic materials as well as proteic residues. These enzymes can increment and turn viable the production of second generation ethanol from different and alternative sources. In this context, the goal of this study was the investigation of cellulolytic and proteolytic abilities of bacteria isolated from the gastrointestinal tract of a hippopotamus as well as from its composting process. It is important to highlight that hippopotamus gastrointestinal samples were a non-typical sources of efficient hydrolytic bacteria with potential for application in biotechnological industries, like biofuel production. Looking for this, a total of 159 bacteria were isolated, which were submitted to qualitative and quantitative enzymatic assays. Proteolytic analyzes were conducted through the evaluation of fluorescent probes. Qualitative assays for cellulolytic abilities revealed 70 positive hits. After quantitative analyzes, 44 % of these positive hits were selected, but five (5) strains showed cellulolytic activity up to 11,8 FPU/mL. Regarding to proteolytic activities, six (6) strains showed activity above 10 %, which overpassed results described in the literature. Molecular analyzes based on the identification of 16S rDNA, revealed that all the selected bacterial isolates were affiliated to Bacillus genus. In summary, these results strongly indicate that the isolated bacteria from a hippopotamus can be a potential source of interesting biocatalysts with cellulolytic and proteolytic activities, with relevance for industrial applications. PMID:26931430
A common type of the spectrin alpha I 46-50a-kD peptide abnormality in hereditary elliptocytosis and pyropoikilocytosis is associated with a mutation distant from the proteolytic cleavage site. Evidence for the functional importance of the triple helical model of spectrin.
Gallagher, P G; Tse, W T; Coetzer, T; Lecomte, M C; Garbarz, M; Zarkowsky, H S; Baruchel, A; Ballas, S K; Dhermy, D; Palek, J
We studied nine individuals from five unrelated families with alpha I/46-50a hereditary elliptocytosis (HE) or hereditary pyropoikilocytosis (HPP), including one of the original HHP probands first reported by Zarkowsky and colleagues (1975. Br. J. Haematol. 29:537-543). Biochemical analysis of erythrocyte membrane proteins from these patients revealed, as a common abnormality, the presence of the alpha I/46-50a peptide after limited tryptic digestion of spectrin. The polymerase chain reaction was utilized to study the structure of the DNA encoding the alpha I domain of spectrin in the affected individuals. The DNA sequence of the alpha-spectrin gene encoding the region of the alpha-spectrin chain surrounding the abnormal proteolytic cleavage site was normal. We identified a point mutation causing the replacement of a highly conserved leucine residue by proline at position 207 in the alpha-spectrin chain, a site 51 residues to the amino-terminal side of the abnormal proteolytic cleavage site. Analysis of the proposed triple helical model of spectrin repeats reveals that the mutation occurs in helix 2 at a position directly opposite the abnormal proteolytic cleavage site in helix 3, making this the first report of a mutation occurring in helix 2 of a repeat in the alpha I domain of spectrin. These results add to the molecular heterogeneity of mutations associated with HE/HPP and provide further support for the proposed triple helical model of spectrin. Disruption of this proposed alpha-helical structure by helix-breaking proline substitutions may result in a functionally defective spectrin chain. Images PMID:1541680
Hamid, Mohamed E.; Assiry, Mohammed M.; Joseph, Martin R.; Haimour, Waleed O.; Abdelrahim, Ihab M.; Al-Abed, Fatin; Fadul, Abdalla N.; Al-Hakami, Ahmed M.
Objectives: To isolate, identify, and determine the prevalence of Candida and other yeasts of clinical importance in Aseer region, Saudi Arabia. Methods: This is a cross-sectional study involving retrospective analysis of 6100 samples submitted to the Microbiology Laboratory, Aseer Central Hospital, Abha, Saudi Arabia between 2011 and 2012, and prospective isolation and identification of 84 isolates recovered from various clinical specimens presented to the Microbiology Laboratory between 2012 and 2013 using the classic morphological schemes and the Vitek 2 automated system. Results: The results of the retrospective analysis (2011-2012) indicated that of the 6100 various clinical specimens submitted to the routine microbiology analysis, 143 (2.35%) revealed the presence of Candida spp. The distribution of the 143 Candida spp. according to specimens was as follows: urine 72%, sputum 10.5%, endotracheal tube 7%, blood 4.2%, catheter tip 2.1%, throat swab 2.1%, eye swab 0.7%, wound exudates 0.7%, and cerebrospinal fluid 0.7%. The results of the prospective study (2012-2013), which involved the identification of yeast recovered from 84 specimens indicated that Candida albicans 28.6% was the predominant species, followed by Candida parapsilosis 21.4%, Candida tropicalis 14.3%, and Candida lusitaniae 9.5%. Conclusions: Along with the commonly encountered Candida albicans, Candida parapsilosis, Candida tropicalis, and Candida lusitaniae were detected with significant rates. Many other Candida species and some other pathogenic yeasts have been detected for the first time in the region. Urinary tract samples were the main source of Candida species. PMID:25316465
Hall, Barry G; Cardenas, Heliodoro; Barlow, Miriam
In clinical settings it is often important to know not just the identity of a microorganism, but also the danger posed by that particular strain. For instance, Escherichia coli can range from being a harmless commensal to being a very dangerous enterohemorrhagic (EHEC) strain. Determining pathogenic phenotypes can be both time consuming and expensive. Here we propose a simple, rapid, and inexpensive method of predicting pathogenic phenotypes on the basis of the presence or absence of short homologous DNA segments in an isolate. Our method compares completely sequenced genomes without the necessity of genome alignments in order to identify the presence or absence of the segments to produce an automatic alignment of the binary string that describes each genome. Analysis of the segment alignment allows identification of those segments whose presence strongly predicts a phenotype. Clinical application of the method requires nothing more that PCR amplification of each of the set of predictive segments. Here we apply the method to identifying EHEC strains of E. coli and to distinguishing E. coli from Shigella. We show in silico that with as few as 8 predictive sequences, if even three of those predictive sequences are amplified the probability of being EHEC or Shigella is >0.99. The method is thus very robust to the occasional amplification failure for spurious reasons. Experimentally, we apply the method to screening a set of 98 isolates to distinguishing E. coli from Shigella, and EHEC from non-EHEC E. coli strains and show that all isolates are correctly identified. PMID:23935901
Ağır, Ismail; Aytekin, Mahmut Nedim; Küçükdurmaz, Fatih; Gökhan, Servan; Cavuş, Umut Yücel
The dorsal tubercle of the radius, once called Lister's tubercle, is used as a landmark in wrist arthroscopy, wrist joint injections, and similar surgical and clinical procedures. However, there is no useful information in the reference anatomy books and literature. The aim of this study was to identify the anatomical localization of Lister's tubercle on the dorsum of radius in relation to the radial styloid process and the ulnar notch of radius and to demonstrate the clinical and surgical importance of these relationships. We studied 20 dried cadaver radius specimens. The distances from Lister's tubercle to the radial styloid process and to the ulnar notch were measured by using a digital micrometer caliber and the ratio of the two measures was calculated. The dorsal tubercle of the radius is variable in position and can be either closer to the radial styloid process or to the ulnar notch. The present study showed that in 11 of the radii the dorsal tubercle of the radius was nearer to the radial styloid process than the ulnar notch, while in 9 subjects it was nearer to the ulnar notch. This anatomical variation may be relevant for wrist injections, wrist artroscopy or wrist surgery. PMID:24843388
Ağır, İsmail; Aytekin, Mahmut Nedim; Küçükdurmaz, Fatih; Gökhan, Servan; Çavuş, Umut Yücel
The dorsal tubercle of the radius, once called Lister’s tubercle, is used as a landmark in wrist arthroscopy, wrist joint injections, and similar surgical and clinical procedures. However, there is no useful information in the reference anatomy books and literature. The aim of this study was to identify the anatomical localization of Lister’s tubercle on the dorsum of radius in relation to the radial styloid process and the ulnar notch of radius and to demonstrate the clinical and surgical importance of these relationships. We studied 20 dried cadaver radius specimens. The distances from Lister’s tubercle to the radial styloid process and to the ulnar notch were measured by using a digital micrometer caliber and the ratio of the two measures was calculated. The dorsal tubercle of the radius is variable in position and can be either closer to the radial styloid process or to the ulnar notch. The present study showed that in 11 of the radii the dorsal tubercle of the radius was nearer to the radial styloid process than the ulnar notch, while in 9 subjects it was nearer to the ulnar notch. This anatomical variation may be relevant for wrist injections, wrist artroscopy or wrist surgery. PMID:24843388
Gabay, Cem; McInnes, Iain B
A better understanding of cytokine biology over the last two decades has allowed the successful development of cytokine inhibitors against tumour necrosis factor and interleukin (IL)-1 and IL-6. The introduction of these therapies should be considered a breakthrough in the management of several rheumatic diseases. However, many patients will exhibit no or only partial response to these therapies, thus emphasising the importance of exploring other therapeutic strategies. In this article, we review the most recent information on novel cytokines that are often members of previously described cytokine families such as the IL-1 superfamily (IL-18 and IL-33), the IL-12 superfamily (IL-27 and IL-35), the IL-2 superfamily (IL-15 and IL-21), and IL-17. Several data derived from experimental models and clinical samples indicate that some of these cytokines contribute to the pathophysiology of arthritis and other inflammatory diseases. Targeting of some of these cytokines has already been tested in clinical trials with interesting results. PMID:19519923
Apt, Werner; Arribada, Arturo; Zulantay, Inés; Saavedra, Miguel; Muñoz, Catalina; Toro, Bruno; Vega, Bastián; Rodríguez, Jorge
Currently there are no biological markers to indicate which individuals with chronic indeterminate period of Chagas disease develop heart disease and who will remain all his life in this phase. The aim of this survey was to determine if Trypanosoma cruzi burden is related to the presence of heart disease in patients with chronic Chagas disease. 200 patients who had not been treated, 100 with cardiopathy and 100 without, groups A and B respectively, were submitted to clinical study and electrocardiogram, Echo-Doppler was performed for group A in which all important known causes of cardiopathy were discarded. In both groups xenodiagnosis, conventional PCR and quantitative PCR were undertaken. The 100 cardiopaths had 133 electrocardiographic alterations most of them in grade II of the New York Heart Association classification. 98 cardiopaths were classified in grade I by Echo-Doppler and only 2 cases were in grade III due to low ejection fraction. The difference in average parasitemia in patients of group A and B was not significant and no statistically differences were observed between average parasitemia of cardiopaths grade II versus grade I of NYHA. This results allow to characterize same clinical, electrocardiographical and parasitological features in chagasic cardiopaths of Chile. PMID:27353063
Lacerda, Letícia da Silva; Alves, Úrsula David; Zanier, José Fernando Cardona; Machado, Dequitier Carvalho; Camilo, Gustavo Bittencourt; Lopes, Agnaldo José
Overgrowth syndromes comprise a heterogeneous group of diseases that are characterized by excessive tissue development. Some of these syndromes may be associated with dysfunction in the receptor tyrosine kinase (RTK)/PI3K/AKT pathway, which results in an increased expression of the insulin receptor. In the current review, four overgrowth syndromes were characterized (Proteus syndrome, Klippel-Trenaunay-Weber syndrome, Madelung's disease, and neurofibromatosis type I) and illustrated using cases from our institution. Because these syndromes have overlapping clinical manifestations and have no established genetic tests for their diagnosis, radiological methods are important contributors to the diagnosis of many of these syndromes. The correlation of genetic discoveries and molecular pathways that may contribute to the phenotypic expression is also of interest, as this may lead to potential therapeutic interventions. PMID:25009745
Hill, Philip C; Whalen, Christopher C
Initial optimism that DOTS (Directly Observed Treatment, Short-course) would have a dramatic effect on TB incidence rates in developing countries has not been supported by the evidence accumulated so far. Indeed, where TB incidence rates have decreased, non-clinical socio-economic factors appear to have played at least as great a role. We postulate that in those settings with little or no decrease in TB incidence, there are likely to be common pathway blockages that interfere with the effectiveness of DOTS implementation as socio-economic factors evolve. Measuring socio-economic trends, as well as DOTS implementation, is important for understanding TB control and opens up the opportunity for broader public health engagement. PMID:25059524
Lakoski, Susan G; Jones, Lee W; Krone, Ronald J; Stein, Phyllis K; Scott, Jessica M
Autonomic dysfunction represents a loss of normal autonomic control of the cardiovascular system associated with both sympathetic nervous system overdrive and reduced efficacy of the parasympathetic nervous system. Autonomic dysfunction is a strong predictor of future coronary heart disease, vascular disease, and sudden cardiac death. In the current review, we will discuss the clinical importance of autonomic dysfunction as a cardiovascular risk marker among breast cancer patients. We will review the effects of antineoplastic therapy on autonomic function, as well as discuss secondary exposures, such as psychological stress, sleep disturbances, weight gain/metabolic derangements, and loss of cardiorespiratory fitness, which may negatively impact autonomic function in breast cancer patients. Lastly, we review potential strategies to improve autonomic function in this population. The perspective can help guide new therapeutic interventions to promote longevity and cardiovascular health among breast cancer survivors. PMID:26299219
Lakoski, Susan G.; Jones, Lee W.; Krone, Ronald J.; Stein, Phyllis K.; Scott, Jessica M.
Autonomic dysfunction represents a loss of normal autonomic control of the cardiovascular system associated with both sympathetic nervous system overdrive and reduced efficacy of the parasympathetic nervous system. Autonomic dysfunction is a strong predictor of future coronary heart disease, vascular disease and sudden cardiac death. In the current review, we will discuss the clinical importance of autonomic dysfunction as a cardiovascular risk marker among breast cancer patients. We will review the effects of antineoplastic therapy on autonomic function, as well as discuss secondary exposures, such as psychological stress, sleep disturbances, weight gain/metabolic derangements, and loss of cardiorespiratory fitness which may negatively impact autonomic function in breast cancer patients. Lastly, we review potential strategies to improve autonomic function in this population. The perspective can help guide new therapeutic interventions to promote longevity and cardiovascular health among breast cancer survivors. PMID:26299219
Coretti, Silvia; Ruggeri, Matteo; McNamee, Paul
The European Quality of Life-5 Dimensions Questionnaire (EQ-5D) is the most common instrument to value health outcomes under the patient's perspective. Several studies have investigated whether observed changes are meaningful to patients, using a variety of approaches to estimate the minimum clinically important difference (MCID). This study provides an overview of the state of art of the estimation of the MCID for the three-level EQ-5D index based on the UK scoring algorithm, critically assessing the available evidence. The interest in estimation of MCID for the EQ-5D has been increasing in recent years. However, some additional standardization in the estimation procedures may be of value, in order to enhance the ability to make comparisons across measures and disease areas. Further methodological research might also contribute to reducing gaps between theory and practice. PMID:24625040
Maqbool, Talha; Raju, Sneha; In, Eunji
Gulshan & Nanji Orthopaedic and Plastics Center at the North York General Hospital is the second busiest site after the emergency department serving more than 26,000 patients annually. Increase in patient flow, overworked staff, and recent renovations to the hospital have resulted in patients experiencing long wait times, and thusly patient dissatisfaction and stress. Several factors contribute to patient dissatisfaction and stress: i) poor and unfriendly signage; ii) inconsistent utilization of the numbering system; and iii) difficulty navigating to and from the imaging center. A multidisciplinary QI team was assembled to improve the patient experience. We developed a questionnaire to assess patient stress levels at the baseline. Overall, more than half of the patients (54.8%) strongly agreed or agreed to having a stressful waiting experience. Subsequently, based on patient feedback and staff perspectives, we implemented two PDSA cycles. For PDSA 1, we placed a floor graphic (i.e. black tape) to assist patients in navigating from the clinic to the imaging centre and back. For PDSA 2, we involved creating a single 21”×32” patient-friendly sign at the entrance to welcome patients, with clear instructions outlining registration procedures. Surveys were re-administered to assess patient stress levels. A combination of both interventions caused a statistically significant reduction in patient stress levels based on the Kruskal-Wallis and Mann-Whitney U Tests. The present project highlighted the importance of involving stakeholders as well as frontline staff when undertaking quality improvement projects as a way to identify bottlenecks as well as establish sustainable solutions. Additionally, the team recognized the importance of incorporating empirical based solutions and involving experts in the field to optimize results. The present project successfully implemented strategies to improve patient satisfaction and reduce stress in a high flow community clinic
Field, Matthew A; Cho, Vicky; Andrews, T Daniel; Goodnow, Chris C
A diversity of tools is available for identification of variants from genome sequence data. Given the current complexity of incorporating external software into a genome analysis infrastructure, a tendency exists to rely on the results from a single tool alone. The quality of the output variant calls is highly variable however, depending on factors such as sequence library quality as well as the choice of short-read aligner, variant caller, and variant caller filtering strategy. Here we present a two-part study first using the high quality 'genome in a bottle' reference set to demonstrate the significant impact the choice of aligner, variant caller, and variant caller filtering strategy has on overall variant call quality and further how certain variant callers outperform others with increased sample contamination, an important consideration when analyzing sequenced cancer samples. This analysis confirms previous work showing that combining variant calls of multiple tools results in the best quality resultant variant set, for either specificity or sensitivity, depending on whether the intersection or union, of all variant calls is used respectively. Second, we analyze a melanoma cell line derived from a control lymphocyte sample to determine whether software choices affect the detection of clinically important melanoma risk-factor variants finding that only one of the three such variants is unanimously detected under all conditions. Finally, we describe a cogent strategy for implementing a clinical variant detection pipeline; a strategy that requires careful software selection, variant caller filtering optimizing, and combined variant calls in order to effectively minimize false negative variants. While implementing such features represents an increase in complexity and computation the results offer indisputable improvements in data quality. PMID:26600436
Field, Matthew A.; Cho, Vicky
A diversity of tools is available for identification of variants from genome sequence data. Given the current complexity of incorporating external software into a genome analysis infrastructure, a tendency exists to rely on the results from a single tool alone. The quality of the output variant calls is highly variable however, depending on factors such as sequence library quality as well as the choice of short-read aligner, variant caller, and variant caller filtering strategy. Here we present a two-part study first using the high quality ‘genome in a bottle’ reference set to demonstrate the significant impact the choice of aligner, variant caller, and variant caller filtering strategy has on overall variant call quality and further how certain variant callers outperform others with increased sample contamination, an important consideration when analyzing sequenced cancer samples. This analysis confirms previous work showing that combining variant calls of multiple tools results in the best quality resultant variant set, for either specificity or sensitivity, depending on whether the intersection or union, of all variant calls is used respectively. Second, we analyze a melanoma cell line derived from a control lymphocyte sample to determine whether software choices affect the detection of clinically important melanoma risk-factor variants finding that only one of the three such variants is unanimously detected under all conditions. Finally, we describe a cogent strategy for implementing a clinical variant detection pipeline; a strategy that requires careful software selection, variant caller filtering optimizing, and combined variant calls in order to effectively minimize false negative variants. While implementing such features represents an increase in complexity and computation the results offer indisputable improvements in data quality. PMID:26600436
Alma, Harma; de Jong, Corina; Jelusic, Danijel; Wittmann, Michael; Schuler, Michael; Blok, Bertine Flokstra-de; Kocks, Janwillem; Schultz, Konrad; Molen, Thys van der
The minimal clinically important difference (MCID) defines to what extent change on a health status instrument is clinically relevant, which aids scientists and physicians in measuring therapy effects. This is the first study that aimed to establish the MCID of the Clinical chronic obstructive pulmonary disease (COPD) Questionnaire (CCQ), the COPD Assessment Test (CAT) and the St George's Respiratory Questionnaire (SGRQ) in the same pulmonary rehabilitation population using multiple approaches. In total, 451 COPD patients participated in a 3-week Pulmonary Rehabilitation (PR) programme (58 years, 65% male, 43 pack-years, GOLD stage II/III/IV 50/39/11%). Techniques used to assess the MCID were anchor-based approaches, including patient-referencing, criterion-referencing and questionnaire-referencing, and the distribution-based methods standard error of measurement (SEM), 1.96SEM and half standard deviation (0.5s.d.). Patient- and criterion-referencing led to MCID estimates of 0.56 and 0.62 (CCQ); 3.12 and 2.96 (CAT); and 8.40 and 9.28 (SGRQ). Questionnaire-referencing suggested MCID ranges of 0.28-0.61 (CCQ), 1.46-3.08 (CAT) and 6.86-9.47 (SGRQ). The SEM, 1.96SEM and 0.5s.d. were 0.29, 0.56 and 0.46 (CCQ); 3.28, 6.43 and 2.80 (CAT); 5.20, 10.19 and 6.06 (SGRQ). Pooled estimates were 0.52 (CCQ), 3.29 (CAT) and 7.91 (SGRQ) for improvement. MCID estimates differed depending on the method used. Pooled estimates suggest clinically relevant improvements needing to exceed 0.40 on the CCQ, 3.00 on the CAT and 7.00 on the SGRQ for moderate to very severe COPD patients. The MCIDs of the CAT and SGRQ in the literature might be too low, leading to overestimation of treatment effects for patients with COPD. PMID:27597571
Alma, Harma; de Jong, Corina; Jelusic, Danijel; Wittmann, Michael; Schuler, Michael; Blok, Bertine Flokstra-de; Kocks, Janwillem; Schultz, Konrad; Molen, Thys van der
The minimal clinically important difference (MCID) defines to what extent change on a health status instrument is clinically relevant, which aids scientists and physicians in measuring therapy effects. This is the first study that aimed to establish the MCID of the Clinical chronic obstructive pulmonary disease (COPD) Questionnaire (CCQ), the COPD Assessment Test (CAT) and the St George’s Respiratory Questionnaire (SGRQ) in the same pulmonary rehabilitation population using multiple approaches. In total, 451 COPD patients participated in a 3-week Pulmonary Rehabilitation (PR) programme (58 years, 65% male, 43 pack-years, GOLD stage II/III/IV 50/39/11%). Techniques used to assess the MCID were anchor-based approaches, including patient-referencing, criterion-referencing and questionnaire-referencing, and the distribution-based methods standard error of measurement (SEM), 1.96SEM and half standard deviation (0.5s.d.). Patient- and criterion-referencing led to MCID estimates of 0.56 and 0.62 (CCQ); 3.12 and 2.96 (CAT); and 8.40 and 9.28 (SGRQ). Questionnaire-referencing suggested MCID ranges of 0.28–0.61 (CCQ), 1.46–3.08 (CAT) and 6.86–9.47 (SGRQ). The SEM, 1.96SEM and 0.5s.d. were 0.29, 0.56 and 0.46 (CCQ); 3.28, 6.43 and 2.80 (CAT); 5.20, 10.19 and 6.06 (SGRQ). Pooled estimates were 0.52 (CCQ), 3.29 (CAT) and 7.91 (SGRQ) for improvement. MCID estimates differed depending on the method used. Pooled estimates suggest clinically relevant improvements needing to exceed 0.40 on the CCQ, 3.00 on the CAT and 7.00 on the SGRQ for moderate to very severe COPD patients. The MCIDs of the CAT and SGRQ in the literature might be too low, leading to overestimation of treatment effects for patients with COPD. PMID:27597571
Wicht, Oliver; Li, Wentao; Willems, Lione; Meuleman, Tom J.; Wubbolts, Richard W.; van Kuppeveld, Frank J. M.; Rottier, Peter J. M.
ABSTRACT Isolation of porcine epidemic diarrhea coronavirus (PEDV) from clinical material in cell culture requires supplementation of trypsin. This may relate to the confinement of PEDV natural infection to the protease-rich small intestine of pigs. Our study focused on the role of protease activity on infection by investigating the spike protein of a PEDV isolate (wtPEDV) using a reverse genetics system based on the trypsin-independent cell culture-adapted strain DR13 (caPEDV). We demonstrate that trypsin acts on the wtPEDV spike protein after receptor binding. We mapped the genetic determinant for trypsin-dependent cell entry to the N-terminal region of the fusion subunit of this class I fusion protein, revealing a conserved arginine just upstream of the putative fusion peptide as the potential cleavage site. Whereas coronaviruses are typically processed by endogenous proteases of the producer or target cell, PEDV S protein activation strictly required supplementation of a protease, enabling us to study mechanistic details of proteolytic processing. IMPORTANCE Recurring PEDV epidemics constitute a serious animal health threat and an economic burden, particularly in Asia but, as of recently, also on the North-American subcontinent. Understanding the biology of PEDV is critical for combatting the infection. Here, we provide new insight into the protease-dependent cell entry of PEDV. PMID:24807723
Wicht, Oliver; Li, Wentao; Willems, Lione; Meuleman, Tom J; Wubbolts, Richard W; van Kuppeveld, Frank J M; Rottier, Peter J M; Bosch, Berend Jan
Isolation of porcine epidemic diarrhea coronavirus (PEDV) from clinical material in cell culture requires supplementation of trypsin. This may relate to the confinement of PEDV natural infection to the protease-rich small intestine of pigs. Our study focused on the role of protease activity on infection by investigating the spike protein of a PEDV isolate (wtPEDV) using a reverse genetics system based on the trypsin-independent cell culture-adapted strain DR13 (caPEDV). We demonstrate that trypsin acts on the wtPEDV spike protein after receptor binding. We mapped the genetic determinant for trypsin-dependent cell entry to the N-terminal region of the fusion subunit of this class I fusion protein, revealing a conserved arginine just upstream of the putative fusion peptide as the potential cleavage site. Whereas coronaviruses are typically processed by endogenous proteases of the producer or target cell, PEDV S protein activation strictly required supplementation of a protease, enabling us to study mechanistic details of proteolytic processing. Importance: Recurring PEDV epidemics constitute a serious animal health threat and an economic burden, particularly in Asia but, as of recently, also on the North-American subcontinent. Understanding the biology of PEDV is critical for combatting the infection. Here, we provide new insight into the protease-dependent cell entry of PEDV. PMID:24807723
Atanasova, Jivka; Moncheva, Penka; Ivanova, Iskra
We examined 62 strains and 21 trade starter cultures from the collection of LB Bulgaricum PLC for proteolytic and antimicrobial activity of lactic acid bacteria (LAB) grown in goat milk. The aim of this study was to investigate the fermentation of caseins, α-lactalbumin and β-lactoglobulin by LAB, using the o-phthaldialdehyde (OPA) spectrophotometric assay and sodium dodecyl sulphate polyacrylamide gel electrophoresis (SDS-PAGE). The proteolysis targeted mainly caseins, especially β-casein. Whey proteins were proteolyzed, essentially β-lactoglobulin. The proteolytic activity of Lactococcus lactis l598, Streptococcus thermophilus t3D1, Dt1, Lactobacillus lactis 1043 and L. delbrueckii subsp. bulgaricus b38, b122 and b24 was notably high. The proteolysis process gave rise to medium-sized peptide populations. Most of the examined strains showed antimicrobial activity against some food pathogens, such as Escherichia coli, Staphylococcus aureus, Salmonella cholere enteridis, Listeria monocytogenes, Listeria innocua and Enterobacter aerogenes. The most active producers of antimicrobial-active peptides were strains of L. delbrueckii subsp. bulgaricus and S. thermophilus, which are of practical importance. The starter cultures containing the examined species showed high proteolytic and antimicrobial activity in skimmed goat milk. The greatest antimicrobial activity of the cultures was detected against E. aerogenes. The obtained results demonstrated the significant proteolytic potential of the examined strains in goat milk and their potential for application in the production of dairy products from goat's milk. The present results could be considered as the first data on the proteolytic capacity of strains and starter cultures in goat milk for the purposes of trade interest of LB Bulgaricum PLC. PMID:26019593
Marslin, Gregory; Revina, Ann Mary; Khandelwal, Vinoth Kumar Megraj; Balakumar, Krishnamoorthy; Sheeba, Caroline J; Franklin, Gregory
The rise of bacterial resistance against important drugs threatens their clinical utility. Fluoroquinones, one of the most important classes of contemporary antibiotics has also reported to suffer bacterial resistance. Since the general mechanism of bacterial resistance against fluoroquinone antibiotics (e.g. ofloxacin) consists of target mutations resulting in reduced membrane permeability and increased efflux by the bacteria, strategies that could increase bacterial uptake and reduce efflux of the drug would provide effective treatment. In the present study, we have compared the efficiencies of ofloxacin delivered in the form of free drug (OFX) and as nanoparticles on bacterial uptake and antibacterial activity. Although both poly(lactic-co-glycolic acid) (OFX-PLGA) and methoxy poly(ethylene glycol)-b-poly(lactic-co-glycolic acid) (OFX-mPEG-PLGA) nanoformulations presented improved bacterial uptake and antibacterial activity against all the tested human bacterial pathogens, namely, Escherichia coli, Proteus vulgaris, Salmonella typhimurium, Pseudomonas aeruginosa, Klebsiella pneumoniae and Staphylococcus aureus, OFX-mPEG-PLGA showed significantly higher bacterial uptake and antibacterial activity compared to OFX-PLGA. We have also found that mPEG-PLGA nanoencapsulation could significantly inhibit Bacillus subtilis resistance development against OFX. PMID:26005932
Espinel-Ingroff, A; Goldson, P R; McGinnis, M R; Kerkering, T M
A total of 123 isolates of Cladosporium spp., Exophiala spp., Fonsecaea spp., Lecythophora hoffmannii, Phaeoannellomyces werneckii, Phialophora spp., Wangiella dermatitidis, and Xylohypha bantiana were tested for proteolytic activity by using 26 different formulations of gelatin, milk, casein, and Loeffler media. Other physiological properties examined included hydrolysis of tyrosine and xanthine, sodium nitrate utilization in Czapek Dox agar, and thermotolerance. Isolates of Exophiala jeanselmei, Fonsecaea compacta, Fonsecaea pedrosoi, W. dermatitidis, and X. bantiana lacked proteolytic activity. Proteolytic activity was variable among the remaining species, depending on the type of medium used. Thermotolerance had value in distinguishing some taxa. PMID:3343325
Ku, Minhee; Hong, Yoochan; Heo, Dan; Lee, Eugene; Hwang, Seungyeon; Suh, Jin-Suck; Yang, Jaemoon
Biomedical in vivo sensing methods in the near-infrared (NIR) range, which that provide relatively high photon transparency, separation from auto-fluorescence background, and extended sensitivity, are being used increasingly for non-invasive mapping and monitoring of molecular events in cancer cells. In this study, we fabricated an NIR fluorogenic nanosensor based on the nanoparticle surface energy transfer effect, by conjugation of fluorescent proteolytic enzyme-specific cleavable peptides with gold nanorods (GNRs). Membrane-anchored membrane type 1-matrix metalloproteinases (MT1-MMPs), a family of zinc-dependent proteolytic enzymes, can induce the metastatic potential of cancer cells by promoting degradation of the extracellular matrix. Therefore, sensitive detection of MT1-MMP activity can provide essential information in the clinical setting. We have applied in vivo NIR sensing to evaluate MT1-MMP activity, as an NIR imaging target, in an MT1-MMP-expressing metastatic tumor mouse model. PMID:26454829
Andersen, Jack Gunnar; Stokke, Mali Victoria; Tennstrand, Anne Lise; Aamodt, Rolf; Heggelund, Thomas; Dahl, Fredrik A; Sandbæk, Gunnar; Hurlen, Petter
Background Misinterpretation of radiological examinations is an important contributing factor to diagnostic errors. Consultant radiologists in Norwegian hospitals frequently request second reads by colleagues in real time. Our objective was to estimate the frequency of clinically important changes to radiology reports produced by these prospectively obtained double readings. Methods We retrospectively compared the preliminary and final reports from 1071 consecutive double-read abdominal CT examinations of surgical patients at five public hospitals in Norway. Experienced gastrointestinal surgeons rated the clinical importance of changes from the preliminary to final report. The severity of the radiological findings in clinically important changes was classified as increased, unchanged or decreased. Results Changes were classified as clinically important in 146 of 1071 reports (14%). Changes to 3 reports (0.3%) were critical (demanding immediate action), 35 (3%) were major (implying a change in treatment) and 108 (10%) were intermediate (requiring further investigations). The severity of the radiological findings was increased in 118 (81%) of the clinically important changes. Important changes were made less frequently when abdominal radiologists were first readers, more frequently when they were second readers, and more frequently to urgent examinations. Conclusion A 14% rate of clinically important changes made during double reading may justify quality assurance of radiological interpretation. Using expert second readers and a targeted selection of urgent cases and radiologists reading outside their specialty may increase the yield of discrepant cases. PMID:27013638
Marine, W.M.; Gurr, D.; Jacobsen, M.
A unique data set of 3380 British coal miners has been reanalyzed with major focus on nonpneumoconiotic respiratory conditions. The aim was to assess the independent contribution of smoking and exposure to respirable dust to clinically significant measures of respiratory dysfunction. Exposure to coal-mine dust was monitored over a 10-yr period. Medical surveys provided estimates of prior dust exposure and recorded respiratory symptoms. Each man's FEV1 was compared with the level predicted for his age and height by an internally derived prediction equation for FEV1. Four respiratory indices were considered at the end of the 10-yr period: FEV1 less than 80%, chronic bronchitis, chronic bronchitis with FEV1 less than 80%, and FEV1 less than 65%. Results were uniformly incorporated into logistic regression equations for each condition. The equations include coefficients for age, dust, and when indicated, an interaction term for age and dust. Dust-related increases in prevalence of each of the 4 conditions were statistically significant and were similar for smokers and nonsmokers at the mean age (47 yr). There was no evidence that smoking potentiates the effect of exposure to dust. Estimates of prevalences at the mean age of all 4 measures of respiratory dysfunction were greater in smokers. At intermediate and high dust exposure the prevalence of the 4 conditions in nonsmokers approached the prevalence in smokers at hypothetically zero dust exposure. Both smoking and dust exposure can cause clinically important respiratory dysfunction and their separate contributions to obstructive airway disease in coal miners appear to be additive.
Cleophas, Ton J
Canonical analysis assesses the combined effects of a set of predictor variables on a set of outcome variables, but it is little used in clinical trials despite the omnipresence of multiple variables. The aim of this study was to assess the performance of canonical analysis as compared with traditional multivariate methods using multivariate analysis of covariance (MANCOVA). As an example, a simulated data file with 12 gene expression levels and 4 drug efficacy scores was used. The correlation coefficient between the 12 predictor and 4 outcome variables was 0.87 (P = 0.0001) meaning that 76% of the variability in the outcome variables was explained by the 12 covariates. Repeated testing after the removal of 5 unimportant predictor and 1 outcome variable produced virtually the same overall result. The MANCOVA identified identical unimportant variables, but it was unable to provide overall statistics. (1) Canonical analysis is remarkable, because it can handle many more variables than traditional multivariate methods such as MANCOVA can. (2) At the same time, it accounts for the relative importance of the separate variables, their interactions and differences in units. (3) Canonical analysis provides overall statistics of the effects of sets of variables, whereas traditional multivariate methods only provide the statistics of the separate variables. (4) Unlike other methods for combining the effects of multiple variables such as factor analysis/partial least squares, canonical analysis is scientifically entirely rigorous. (5) Limitations include that it is less flexible than factor analysis/partial least squares, because only 2 sets of variables are used and because multiple solutions instead of one is offered. We do hope that this article will stimulate clinical investigators to start using this remarkable method. PMID:23591025
Fakhar, Kaihan; Hastings, Erin; Butson, Christopher R.; Foote, Kelly D.; Zeilman, Pam; Okun, Michael S.
Objective We aimed in this investigation to study deep brain stimulation (DBS) battery drain with special attention directed toward patient symptoms prior to and following battery replacement. Background Previously our group developed web-based calculators and smart phone applications to estimate DBS battery life (http://mdc.mbi.ufl.edu/surgery/dbs-battery-estimator). Methods A cohort of 320 patients undergoing DBS battery replacement from 2002–2012 were included in an IRB approved study. Statistical analysis was performed using SPSS 20.0 (IBM, Armonk, NY). Results The mean charge density for treatment of Parkinson’s disease was 7.2 µC/cm2/phase (SD = 3.82), for dystonia was 17.5 µC/cm2/phase (SD = 8.53), for essential tremor was 8.3 µC/cm2/phase (SD = 4.85), and for OCD was 18.0 µC/cm2/phase (SD = 4.35). There was a significant relationship between charge density and battery life (r = −.59, p<.001), as well as total power and battery life (r = −.64, p<.001). The UF estimator (r = .67, p<.001) and the Medtronic helpline (r = .74, p<.001) predictions of battery life were significantly positively associated with actual battery life. Battery status indicators on Soletra and Kinetra were poor predictors of battery life. In 38 cases, the symptoms improved following a battery change, suggesting that the neurostimulator was likely responsible for symptom worsening. For these cases, both the UF estimator and the Medtronic helpline were significantly correlated with battery life (r = .65 and r = .70, respectively, both p<.001). Conclusions Battery estimations, charge density, total power and clinical symptoms were important factors. The observation of clinical worsening that was rescued following neurostimulator replacement reinforces the notion that changes in clinical symptoms can be associated with battery drain. PMID:23536810
Singh, Dave; Maleki-Yazdi, M Reza; Tombs, Lee; Iqbal, Ahmar; Fahy, William A; Naya, Ian
Background Minimizing the risk of disease progression and exacerbations is the key goal of COPD management, as these are well-established indicators of poor COPD prognosis. We developed a novel composite end point assessing three important aspects (lung function, health status, and exacerbations) of worsening in COPD. The objective was to determine whether dual bronchodilation with umeclidinium/vilanterol (UMEC/VI) reduces clinically important deteriorations (CIDs) in COPD versus placebo or bronchodilator monotherapy. Methods This study is a post hoc analysis of two 24-week trials comparing UMEC/VI 62.5/25 µg with UMEC 62.5 µg, VI 25 µg, or placebo (Study A; NCT01313650), or UMEC/VI 62.5/25 µg with tiotropium (TIO) 18 µg (Study B; NCT01777334) in patients with symptomatic COPD, without a history of frequent exacerbations. Deterioration was assessed as the time to a first CID, a composite measure defined as a decrease of ≥100 mL in trough forced expiratory volume in 1 second or ≥4-unit increase in St George’s Respiratory Questionnaire total score or an on-treatment moderate-to-severe COPD exacerbation. Results In Study A, fewer patients experienced a first CID with UMEC/VI (44%) versus UMEC (50%), VI (56%), and placebo (75%). The risk of a first CID was reduced with UMEC/VI (hazard ratio [HR]: 0.37 [95% confidence interval, CI: 0.30, 0.45]), UMEC (HR: 0.46 [95% CI: 0.38, 0.56]), and VI (HR: 0.55 [95% CI: 0.45, 0.66]; all P<0.001) versus placebo, and with UMEC/VI versus UMEC (HR: 0.80 [95% CI: 0.65, 0.97]; P<0.05) and versus VI (HR: 0.67 [95% CI: 0.55, 0.81]; P<0.001). In Study B, fewer patients experienced a first CID with UMEC/VI (41%) versus TIO (59%). UMEC/VI reduced the risk of a first composite CID by 43% versus TIO (HR: 0.57 [95% CI: 0.47, 0.69]; P<0.001). Conclusion This exploratory analysis, using a new assessment of clinical deterioration in COPD, revealed that a majority of symptomatic patients with low exacerbation risk experienced a
Payrol, Juan Abreu; Obregón, Walter D; Natalucci, Claudia L; Caffini, Néstor O
Pinguinain is the name given to a proteolytic enzyme preparation obtained from Bromelia pinguin fruits that has been scarcely studied. The present paper deals on the reexamination of the proteases present in fruits of B. pinguin grown in Cienfuegos, Cuba. The preparation (partially purified pinguinain, PPP) showed the main characteristics of the cysteine proteases, i.e., optimum pH within alkaline range (pH 7.2-8.8), inhibition of proteolytic activity by thiol blocking reagents, which is usually reverted by addition of cysteine, a remarkable thermal stability and notable stability at high ionic strength values. Isoelectric focusing and zymogram of PPP revealed the presence of several proteolytic components between pI 4.6 and 8.1. Preliminary peptidase purification by cationic exchange chromatography showed the presence of two main proteolytic fractions with molecular masses of approximately 20.0 kDa, according to SDS-PAGE. PMID:15978746
Trojánek, Milan; Dědičová, Daniela; Žemličková, Helena; Jakubů, Vladislav; Malíková, Eliška; Reisingerová, Marie; Gabrielová, Alice; Papagiannitsis, Costas C; Hrabák, Jaroslav; Horová, Blanka; Urbášková, Pavla; Marešová, Vilma; Stejskal, František
The aim of this study was to describe epidemiological and clinical characteristics of imported enteric fever in Czech travellers and to determine the antimicrobial susceptibility of isolated strains. Retrospective descriptive study included adult patients treated with enteric fever at Hospital Na Bulovce during January 2004-December 2012. A case of typhoid or paratyphoid fever was defined as isolation of Salmonella Typhi or Paratyphi from blood or stool. During the study period, there have been diagnosed 19 cases of enteric fever (12 males and 7 females) with age median of 30 years; 14 cases were caused by Salmonella Typhi and 5 cases by S. Paratyphi A. The infection has been acquired in South Asia (16 patients; 84.2 %), in Africa (Egypt, Angola) in two cases (10.5 %), and in Mexico (1; 5.3 %). Symptoms included fever (all patients), diarrhoea (16 cases; 84.2 %), headache (9; 47.4 %), and abdominal pain (7; 36.8 %). Seventeen patients (89.5 %) were treated with fluoroquinolones; however, the treatment failure was observed in seven of them (41.2 %). Decreased ciprofloxacin susceptibility was detected in eight strains (66.7 %), and one strain (8.3 %) was multidrug resistant. Sequence analysis of quinolone resistance-determining regions (QRDR) of the gyrA gene revealed the presence of amino acid substitutions in all tested isolates with decreased ciprofloxacin susceptibility. Typhoid and paratyphoid fevers represent epidemiologically important diseases that may lead to potentially life-threatening complications. Major issue in the management of enteric fever represents the non-susceptibility of Salmonella strains to fluoroquinolones and other antimicrobials. PMID:25394534
Banis, S.; Suurmeijer, Th. P. B. M.; van Peer, D. R.
Addresses the relative importance of clinical characteristics of the child and parental emotional reactions, to child-rearing practices towards children with hemophilia. Results indicate that mother's emotional reactions appear to have a stronger influence on child-rearing uncertainty and overprotection than clinical characteristics of the child.…
Chen, Mei-Kuang; Hung, Mien-Chie
Intracellular localization has been reported for over three-quarters of receptor tyrosine kinase (RTK) families in response to environmental stimuli. Internalized RTK may bind to non-canonical substrates and affect various cellular processes. Many of the intracellular RTKs exist as fragmented forms that are generated by γ-secretase cleavage of the full-length receptor, shedding, alternative splicing, or alternative translation initiation. Soluble RTK fragments are stabilized and intracellularly transported into subcellular compartments, such as the nucleus, by binding to chaperone or transcription factors, while membrane-bound RTKs (full-length or truncated) are transported from the plasma membrane to the ER through the well-established Rab- or clathrin adaptor protein-coated vesicle retrograde trafficking pathways. Subsequent nuclear transport of membrane-bound RTK may occur via two pathways, INFS or INTERNET, with the former characterized by release of receptors from the ER into the cytosol and the latter characterized by release of membrane-bound receptor from the ER into the nucleoplasm through the inner nuclear membrane. Although most non-canonical intracellular RTK signaling is related to transcriptional regulation, there may be other functions that have yet to be discovered. In this review, we summarize the proteolytic processing, intracellular trafficking and nuclear functions of RTKs, and discuss how they promote cancer progression, and their clinical implications. PMID:26096795
Sivaraman, K; Chopra, A; Venkatesh, S B
The mandible has a property to flex inwards around the mandibular symphysis with change in shape and decrease in mandibular arch width during opening and protrusion of the mandible. The mandibular deformation may range from a few micrometres to more than 1 mm. The movement occurs because of the contraction of lateral pterygoid muscles that pulls mandibular condyles medially and causes a sagittal movement of the posterior segments. This movement of mandible can have a profound influence on prognosis and treatment outcome for various restorative, endodontics, fixed, removable and implant-related prosthesis. The review unfolds the causes, importance and clinical implications of median mandibular flexure in oral rehabilitation. This review also highlights the appropriate preventive measures and techniques that should be adopted by clinicians to minimise the effect of flexural movement of the jaw during oral rehabilitation. This would not only help clinicians to achieve a good prosthesis with accurate fit and longevity but also maintain the health of the surrounding periodontal or periimplant gingival tissues and bone. PMID:26498998
Background Herbs and spices are very important and useful as therapeutic agent against many pathological infections. Increasing multidrug resistance of pathogens forces to find alternative compounds for treatment of infectious diseases. Methods In the present study the antimicrobial potency of garlic and ginger has been investigated against eight local clinical bacterial isolates. Three types of extracts of each garlic and ginger including aqueous extract, methanol extract and ethanol extract had been assayed separately against drug resistant Escherichia coli, Pseudomonas aeruginosa, Bacillus subtilis, Staphylococcus aureus, Klebsiella pneumoniae, Shigella sonnei, Staphylococcusepidermidis and Salmonella typhi. The antibacterial activity was determined by disc diffusion method. Results All tested bacterial strains were most susceptible to the garlic aqueous extract and showed poor susceptibility to the ginger aqueous extract. The (minimum inhibitory concentration) MIC of different bacterial species varied from 0.05 mg/ml to 1.0 mg/ml. Conclusion In the light of several socioeconomic factors of Pakistan mainly poverty and poor hygienic condition, present study encourages the use of spices as alternative or supplementary medicine to reduce the burden of high cost, side effects and progressively increasing drug resistance of pathogens. PMID:22540232
Kishida, Ken; Funahashi, Tohru; Shimomura, Iichiro
Type 2 diabetes mellitus (T2DM) is a complex heterogeneous group of metabolic disorders including hyperglycemia and impaired insulin action and/or insulin secretion. Obesity T2DM has become a serious problem in Japan as in Western countries, with over-eating and physical inactivity. Obese Asians have mild degree of adiposity, compared with Western subjects. Unlike total body fat, body fat distribution, especially excess accumulation of visceral fat, correlates with various diabetogenic, atherogenic, prothrombotic and proinflammatory metabolic abnormalities, which increase the risk of atherosclerotic cardiovascular disease (ACVD). Obese patients with T2DM have poor glycemic control with disordered eating behaviors, and complications of hypertension and dyslipidemia, leading to ACVD. The major therapies in obese T2DM, hyperinsulinemia and low insulin sensitivity, available for weight loss, especially visceral fat reduction, include caloric restriction, physical activity and behavior modification. On the other hand, the major therapies in non-obese T2DM with insufficient insulin secretion, are insulin-secretory agents and injectable insulin. For clinically meaningful prevention/reduction in the rate of future ACVD in T2DM, it may be important to stratify T2DM subjects into those with and without visceral obesity and design specific management protocols for each group. PMID:22309596
Johansson, Ann-Katrin; Omar, Ridwaan; Carlsson, Gunnar E.; Johansson, Anders
Since the mid-1990s, the focus of studies on tooth wear has steadily shifted from the general condition towards the more specific area of dental erosion; equally, a shift has occurred from studies in adults to those in children and adolescents. During this time, understanding of the condition has increased greatly. This paper attempts to provide a critical overview of the development of this body of knowledge, from earlier perceptions to the present. It is accepted that dental erosion has a multifactorial background, in which individual and lifestyle factors have great significance. Notwithstanding methodological differences across studies, data from many countries confirm that dental erosion is common in children and young people, and that, when present, it progresses rapidly. That the condition, and its ramifications, warrants serious consideration in clinical dentistry, is clear. It is important for the oral healthcare team to be able to recognize its early signs and symptoms and to understand its pathogenesis. Preventive strategies are essential ingredients in the management of patients with dental erosion. When necessary, treatment aimed at correcting or improving its effects might best be of a minimally invasive nature. Still, there remains a need for further research to forge better understanding of the subject. PMID:22505907
Treatment of chronic hepatitis C virus (HCV) infection with direct-acting antiviral agents (DAA) is associated with high rates of sustained virologic response. Remaining factors associated with treatment failure include advanced stages of liver fibrosis, response to previous antiviral therapy and viral factors such as baseline viral load and suboptimal interaction of the DAA with the target based on viral variants. Heterogeneity within NS3, NS5A, and NS5B areas interacting with DAAs exist between HCV geno- and subtypes as well as HCV isolates of the same geno- and subtype and amino acid polymorphisms associated with suboptimal efficacy of DAAs are termed resistance-associated variants (RAVs). RAVs may be associated with virologic treatment failure. However, virologic treatment failure typically occurs only if other negative predictive host or viral factors are present at the same time, susceptibility to additional antiviral agents is reduced or duration of treatment is suboptimal. In this review geno- and phenotypic resistance testing as well as clinical data on the importance of RAVs for conventional triple therapies with sofosbuvir, simeprevir, and daclatasvir and available interferon-free DAA combinations are discussed. PMID:26409317
Cellier, Marie; James, Arthur L; Orenga, Sylvain; Perry, John D; Rasul, Ari K; Robinson, Shaun N; Stanforth, Stephen P
A series of amino acid derivatives 8-10, 42 and 43 have been prepared as chromogenic enzyme substrates in order to detect aminopeptidase activity in clinically important Gram-negative and Gram-positive bacteria. Enzymatic hydrolysis liberates the amino acid moiety and either a 4-aminophenol or a 4-dialkylaminoaniline derivative which undergoes oxidative coupling with 1-naphthol or a substituted 1-naphthol giving an indophenol dye. Substrates and 1-naphthols were incorporated into an agar-based culture medium and this allowed growth of intensely coloured bacterial colonies based on hydrolysis by specific enzymes. Red/pink coloured colonies were produced by the substrates 8-10 and blue coloured colonies were formed by the substrates 42 and 43. The L-alanyl aminopeptidase substrates 8 targeted L-alanyl aminopeptidase activity and gave coloured colonies with a range of Gram-negative bacteria. Substrates 9 targeted β-alanyl aminopeptidase activity and generated coloured colonies with selected Gram-negative species including Pseudomonas aeruginosa. Three substrates for L-pyroglutamyl acid aminopeptidase (10a, 10c and 43) were hydrolysed by enterococci and Streptococcus pyogenes to generate coloured colonies. Two yeasts were also included in the study, but they did not produce coloured colonies with any of the substrates examined. PMID:25172150
O’Connell, Timothy D.; Jensen, Brian C.; Baker, Anthony J.
Adrenergic receptors (AR) are G-protein-coupled receptors (GPCRs) that have a crucial role in cardiac physiology in health and disease. Alpha1-ARs signal through Gαq, and signaling through Gq, for example, by endothelin and angiotensin receptors, is thought to be detrimental to the heart. In contrast, cardiac alpha1-ARs mediate important protective and adaptive functions in the heart, although alpha1-ARs are only a minor fraction of total cardiac ARs. Cardiac alpha1-ARs activate pleiotropic downstream signaling to prevent pathologic remodeling in heart failure. Mechanisms defined in animal and cell models include activation of adaptive hypertrophy, prevention of cardiac myocyte death, augmentation of contractility, and induction of ischemic preconditioning. Surprisingly, at the molecular level, alpha1-ARs localize to and signal at the nucleus in cardiac myocytes, and, unlike most GPCRs, activate “inside-out” signaling to cause cardioprotection. Contrary to past opinion, human cardiac alpha1-AR expression is similar to that in the mouse, where alpha1-AR effects are seen most convincingly in knockout models. Human clinical studies show that alpha1-blockade worsens heart failure in hypertension and does not improve outcomes in heart failure, implying a cardioprotective role for human alpha1-ARs. In summary, these findings identify novel functional and mechanistic aspects of cardiac alpha1-AR function and suggest that activation of cardiac alpha1-AR might be a viable therapeutic strategy in heart failure. PMID:24368739
Mokris, Rebecca L.
The affective domain represents a set of learning objectives that are difficult to assess and instruct. Affective behaviors consist of different attributes such as interpersonal relationships, professionalism, trust, empathy, and integrity to name a few. This study surveyed athletic training clinical instructors' perception of the importance…
Enright Md, Paul
Measurement of diffusing capacity of the lungs for carbon monoxide (DLCO), also known as transfer factor, is the second most important pulmonary function test (PFT), after spirometry. Previously available only in hospital-based PFT labs, DLCO testing is now available at outpatient clinics using a portable device. Compared to spirometry tests, assessments with these devices require very little effort. The patient breathes quietly, inhales the test gas, holds the breath for ten seconds, and then exhales. In adult smokers with post-bronchodilator airway obstruction, a low DLCO greatly increases the probability of the emphysema phenotype of COPD due to cigarette smoking, while a normal DLCO makes chronic asthma more likely. In patients with spirometric restriction (a low FVC with a normal FEV1/FVC), a low DLCO increases the pre-test probability of an interstitial lung disease (ILD), while a normal DLCO makes a chest wall type of restriction more likely. A normal TLC (VA from the single-breath helium dilution provided by a DLCO test) rules out restriction of lung volumes without the need for a body box measurement. In patients with dyspnea of unknown cause, the pattern of a low DLCO with normal spirometry increases the likelihood of pulmonary vascular disease, but this pattern also occurs with several other diseases such as a mild ILD. Once a diagnosis is made, the percent predicted DLCO provides an objective index of disease severity and prognosis. A DLCO below 40% predicted, or a decline in DLCO of more than 4 units, is associated with increased morbidity and mortality. PMID:27566377
Kumar, Sandeep; Sharma, Akanksha; Das, Mukul; Jain, S K; Dwivedi, Premendra D
Red kidney bean (Phaseolus vulgaris) is consumed worldwide as a vegetarian protein source. But, at the same time the allergenicity potential of red kidney bean is a matter of concern. This study is aimed towards purification, characterization, thermal stability, proteolytic digestion and allergenicity assessment of one of the clinically relevant allergens of red kidney bean. The purification of red kidney bean allergic protein was carried out with the help of column chromatography, IgE immunoblotting and reverse phase high-pressure liquid chromatography (RP-HPLC). The purified protein was characterized by peptide mass finger printing (PMF) and studied for its thermal stability, and proteolytic resistance using simulated gastric fluid (SGF) assay. The allergenicity potential of the purified protein was studied in BALB/c mice. The purified protein was identified as leucoagglutinating phytohemagglutinin (PHA-L) with molecular weight 29.5 kDa. The PHA-L showed resistance to heat as well as proteolytic enzyme. Higher levels of total IgE, specific IgE, and histamine were observed in PHA-L treated BALB/c mice when compared to control. Overall, PHA-L possesses characteristics of allergens and may play a potential role in the red kidney bean induced allergy. PMID:24548135
... U.S.C. 823(a) and 952(a) and determined that the registration of Clinical Supplies Management, Inc... laws, and a review of the company's background and history. Therefore, pursuant to 21 U.S.C. 952(a) and... FR 24984, Clinical Supplies Management, Inc., 342 42nd Street South, Fargo, North Dakota 58103,...
Carter, Andrew T; Paul, Catherine J; Mason, David R; Twine, Susan M; Alston, Mark J; Logan, Susan M; Austin, John W; Peck, Michael W
Background Proteolytic Clostridium botulinum is the causative agent of botulism, a severe neuroparalytic illness. Given the severity of botulism, surprisingly little is known of the population structure, biology, phylogeny or evolution of C. botulinum. The recent determination of the genome sequence of C. botulinum has allowed comparative genomic indexing using a DNA microarray. Results Whole genome microarray analysis revealed that 63% of the coding sequences (CDSs) present in reference strain ATCC 3502 were common to all 61 widely-representative strains of proteolytic C. botulinum and the closely related C. sporogenes tested. This indicates a relatively stable genome. There was, however, evidence for recombination and genetic exchange, in particular within the neurotoxin gene and cluster (including transfer of neurotoxin genes to C. sporogenes), and the flagellar glycosylation island (FGI). These two loci appear to have evolved independently from each other, and from the remainder of the genetic complement. A number of strains were atypical; for example, while 10 out of 14 strains that formed type A1 toxin gave almost identical profiles in whole genome, neurotoxin cluster and FGI analyses, the other four strains showed divergent properties. Furthermore, a new neurotoxin sub-type (A5) has been discovered in strains from heroin-associated wound botulism cases. For the first time, differences in glycosylation profiles of the flagella could be linked to differences in the gene content of the FGI. Conclusion Proteolytic C. botulinum has a stable genome backbone containing specific regions of genetic heterogeneity. These include the neurotoxin gene cluster and the FGI, each having evolved independently of each other and the remainder of the genetic complement. Analysis of these genetic components provides a high degree of discrimination of strains of proteolytic C. botulinum, and is suitable for clinical and forensic investigations of botulism outbreaks. PMID:19298644
Complete and limited proteolysis represents key events that regulate many biological processes. At least 5% of the human genome codes for components of proteolytic processes if proteases, inhibitors, and cofactors are taken into account. Accordingly, disruption of proteolysis is involved in numerous pathological conditions. In particular, molecular genetic studies have identified a growing number of monogenic disorders caused by mutations in protease coding genes, highlighting the importance of this class of enzymes in development, organogenesis, immunity, and brain function. This review provides insights into the current knowledge about the molecular genetic causes of these disorders. It should be noted that most are due to loss of function mutations, indicating absolute requirement of proteolytic activities for normal cellular functions. Recent progress in understanding the function of the implicated proteins and the disease pathogenesis is detailed. In addition to providing important clues to the diagnosis, treatment, and pathophysiology of disease, functional characterisation of mutations in proteolytic systems emphasises the pleiotropic functions of proteases in the body homeostasis. PMID:15994873
Davies, T J; McCormick, R J
The majority of dental care for military personnel is carried out in clinics that would be familiar to all dental professionals. In times of conflict, however, dental care is often required to travel to those in need. Dental morbidity has a detrimental effect on a fighting force, both at the personal level and for maintaining combat efficiency. In Afghanistan, two main dental centres provided the majority of emergency care to coalition forces, but from March to September 2012, 23 peripatetic clinics also took place with 472 dental casualties treated. Assessment of these peripatetic clinics demonstrates both quantitative and qualitative benefits. Return travel to main base clinics takes between three to five days. If all personnel during this period had attended a main base and returned to their duty station in only three days, over 1,000 duty days would have been lost. This compares to the 32 days actually lost by attending peripatetic clinics instead and illustrates the considerable time that was saved. Additionally, time spent travelling in a hostile environment is also time at risk of attack. Forty-one anonymous comments about the clinics were left by personnel. All were positive and enthusiastic. The results of this review demonstrate that these clinics save considerable mission time, reduce risk to military personnel, and were greatly valued by those suffering dental problems. PMID:25766173
Shora, W; Forstner, G G; Forstner, J F
Intestinal goblet cell mucus (GCM) was added to incubations of casein and trypsin (or chymotrypsin) to discover whether mucus could inhibit proteolysis. Contrary to expectation, GCM stimulated casein hydrolysis, reaching a maximum effect at a GCM to casein ratio (w/w) of 0.083. GCM did not contain proteolytic enzymes or proenzymes as contaminants, nor did GCM serve as a substrate for trypsin. Stimulation was not reduced by removing 85% of the sialic acid from GCM. Harsh physical treatment (boiling and freezing) of casein decreased (50%) the GCM effect, as did partial predigestion of casein by trypsin, and elevation of trypsin concentration beyond 3 mug per ml. Thus the undegraded structure of casein appeared to be important for the stimulation of proteolysis by GCM. GCM also enhanced the hydrolysis by trypsin of intestinal brush border membrane protein, but had no effect on the hydrolysis of hemoglobin, albumin, or benzoyl arginine ethyl ester. These results suggest that GCM reacts with specific substrates, in a fashion which promotes their digestion by trypsin or chymotrypsin. PMID:1112451
Ng, Ee Xien; Miller, Miles A; Jing, Tengyang; Chen, Chia-Hung
Cellular enzymes interact in a post-translationally regulated fashion to govern individual cell behaviors, yet current platform technologies are limited in their ability to measure multiple enzyme activities simultaneously in single cells. Here, we developed multi-color Förster resonance energy transfer (FRET)-based enzymatic substrates and use them in a microfluidics platform to simultaneously measure multiple specific protease activities from water-in-oil droplets that contain single cells. By integrating the microfluidic platform with a computational analytical method, Proteolytic Activity Matrix Analysis (PrAMA), we are able to infer six different protease activity signals from individual cells in a high throughput manner (~100 cells/experimental run). We characterized protease activity profiles at single cell resolution for several cancer cell lines including breast cancer cell line MDA-MB-231, lung cancer cell line PC-9, and leukemia cell line K-562 using both live-cell and in-situ cell lysis assay formats, with special focus on metalloproteinases important in metastasis. The ability to measure multiple proteases secreted from or expressed in individual cells allows us to characterize cell heterogeneity and has potential applications including systems biology, pharmacology, cancer diagnosis and stem cell biology. PMID:26995287
... thousands of babies who would otherwise die of respiratory failure are saved each year. Clinical trials showed that giving antiretroviral therapy (AZT) to pregnant women with HIV-AIDS prevents ...
... number of participants from each organization. If time and space permits, onsite registration on Day 1 of... medicine guidelines advise the use of PRO instruments for assessing the successes of clinical treatment...
Walsh, Joseph C.; Lebedev, Artem; Aten, Edward; Madsen, Kathleen; Marciano, Liane
I. Introduction II. The Clinical Importance of Tumor Hypoxia A. Pathophysiology of hypoxia B. Hypoxia's negative impact on the effectiveness of curative treatment 1. Hypoxic tumors accumulate and propagate cancer stem cells 2. Hypoxia reduces the effectiveness of radiotherapy 3. Hypoxia increases metastasis risk and reduces the effectiveness of surgery 4. Hypoxic tumors are resistant to the effects of chemotherapy and chemoradiation C. Hypoxia is prognostic for poor patient outcomes III. Diagnosis of Tumor Hypoxia A. Direct methods 1. Oxygen electrode—direct pO2 measurement most used in cancer research 2. Phosphorescence quenching—alternative direct pO2 measurement 3. Electron paramagnetic resonance 4. 19F-magnetic resonance spectroscopy 5. Overhauser-enhanced MRI B. Endogenous markers of hypoxia 1. Hypoxia-inducible factor-1α 2. Carbonic anhydrase IX 3. Glucose transporter 1 4. Osteopontin 5. A combined IHC panel of protein markers for hypoxia 6. Comet assay C. Physiologic methods 1. Near-infrared spectroscopy/tomography—widely used for pulse oximetry 2. Photoacoustic tomography 3. Contrast-enhanced color duplex sonography 4. MRI-based measurements 5. Blood oxygen level-dependent MRI 6. Pimonidazole 7. EF5 (pentafluorinated etanidazole) 8. Hypoxia PET imaging—physiologic hypoxia measurement providing tomographic information a. 18F-fluoromisonidazole b. 18F-fluoroazomycinarabinofuranoside c. 18F-EF5 (pentafluorinated etanidazole) d. 18F-flortanidazole e. Copper (II) (diacetyl-bis (N4-methylthiosemicarbazone)) f. 18F-FDG imaging of hypoxia IV. Modifying Hypoxia to Improve Therapeutic Outcomes A. Use of hypoxia information in radiation therapy planning B. Use of hypoxia assessment for selection of patients responsive to nimorazole C. Use of hypoxia assessment for selection of patients responsive to tirapazamine D. Use of hypoxia assessment for selection of patients
Zulet, Amaia; Gil-Monreal, Miriam; Villamor, Joji Grace; Zabalza, Ana; van der Hoorn, Renier A. L.; Royuela, Mercedes
Background The herbicides glyphosate (Gly) and imazamox (Imx) inhibit the biosynthesis of aromatic and branched-chain amino acids, respectively. Although these herbicides inhibit different pathways, they have been reported to show several common physiological effects in their modes of action, such as increasing free amino acid contents and decreasing soluble protein contents. To investigate proteolytic activities upon treatment with Gly and Imx, pea plants grown in hydroponic culture were treated with Imx or Gly, and the proteolytic profile of the roots was evaluated through fluorogenic kinetic assays and activity-based protein profiling. Results Several common changes in proteolytic activity were detected following Gly and Imx treatment. Both herbicides induced the ubiquitin-26 S proteasome system and papain-like cysteine proteases. In contrast, the activities of vacuolar processing enzymes, cysteine proteases and metacaspase 9 were reduced following treatment with both herbicides. Moreover, the activities of several putative serine protease were similarly increased or decreased following treatment with both herbicides. In contrast, an increase in YVADase activity was observed under Imx treatment versus a decrease under Gly treatment. Conclusion These results suggest that several proteolytic pathways are responsible for protein degradation upon herbicide treatment, although the specific role of each proteolytic activity remains to be determined. PMID:24040092
Wyrwich, Kathleen W; Fihn, Stephan D; Tierney, William M; Babu, Ajit N; Wolinsky, Fredric D; Kroenke, Kurt
OBJECTIVE Without clinical input on what constitutes a significant change, health-related quality of life (HRQoL) measures are less likely to be adopted by clinicians for use in daily practice. Although standards can be determined empirically by within-person change studies based on patient self-reports, these anchor-based methods incorporate only the patients' perspectives of important HRQoL change, and do not reflect an informed clinical evaluation. The objective of this study was to establish clinically important difference standards from the physician's perspective for use of 2 HRQoL measures among patients with chronic obstructive pulmonary disease (COPD). DESIGN We assembled a 9-person expert panel of North American physicians familiar with the use of the Chronic Respiratory Questionnaire (CRQ), a disease-specific HRQoL measure, or the generic Medical Outcomes Study Short-Form 36-Item Health Survey (SF-36, Version 2.0) among patients with COPD. RESULTS Using 2 rounds of the Delphi process, 1 in-person meeting, and an iterative improvement process for circulating and correcting the final report, the expert panel established small, moderate, and large clinically important change levels for the CRQ and SF-36. CONCLUSIONS For this expert physician panel, levels for detecting clinically important differences on the CRQ were equal to or slightly higher than previous studies based on patient-reported differences. Clinically important differences on the SF-36, Version 2.0, were noticeably larger than previous estimates based on cross-sectional differences between clinically defined patient groups. PMID:12648251
Grainger, Rebecca; Stuckey, Stephen; O'Sullivan, Richard; Davis, Susan R; Ebeling, Peter R; Wluka, Anita E
Introduction Magnetic resonance imaging (MRI) is increasingly used to examine joints for research purposes. It may detect both suspected and unsuspected abnormalities. This raises both clinical and ethical issues, especially when incidental abnormalities are detected. The prevalence of incidental, potentially clinically significant abnormalities identified by MRI and their clinical significance in a population undergoing knee MRI in research studies are unknown. Methods We examined the prevalence of such lesions in healthy asymptomatic adults and those with symptomatic knee osteoarthritis (OA) undergoing knee MRI with limited sequences for the purpose of research. The MRI findings in 601 asymptomatic subjects and 132 with knee OA who underwent at least one limited knee MRI scan for cartilage volume measurement were examined by an MRI radiologist for the presence of potentially clinically significant abnormalities. Results These were present in 2.3% of healthy and 2.3% of OA subjects. All required further investigation to exclude non-benign disease, including four with bone marrow expansion (0.7%), requiring further investigation and management. A single potentially life-threatening lesion, a myeloma lesion, was identified in a subject with symptomatic knee OA on their second MRI scan in a longitudinal study. Conclusion As musculoskeletal MRI is increasingly used clinically and for research purposes, the potential for detecting unsuspected abnormalities that require further investigation should be recognized. Incorporating a system to detect these, to characterize unexpected findings, and to facilitate appropriate medical follow-up when designing studies using this technology should be considered ethical research practice. PMID:18252003
Akerström, Finn; Arias, Miguel A; Pachón, Marta; Jiménez-López, Jesús; Puchol, Alberto; Juliá-Calvo, Justo
Symptomatic bradycardia is effectively treated with the implantation of a cardiac pacemaker. Although a highly successful therapy, during recent years there has been a focus on the negative effects associated with long-term pacing of the apex of the right ventricle (RV). It has been shown in both experimental and clinical studies that RV pacing leads to ventricular dyssynchrony, similar to that of left bundle branch block, with subsequent detrimental effects on cardiac structure and function, and in some cases adverse clinical outcomes such as atrial fibrillation, heart failure and death. There is substantial evidence that patients with reduced left ventricular function (LVEF) are at particular high risk of suffering the detrimental clinical effects of long-term RV pacing. The evidence is, however, incomplete, coming largely from subanalyses of pacemaker and implantable cardiac defibrillator studies. In this group of patients with reduced LVEF and an expected high amount of RV pacing, biventricular pacing (cardiac resynchronization therapy) devices can prevent the negative effects of RV pacing and reduce ventricular dyssynchrony. Therefore, cardiac resynchronization therapy has emerged as an attractive option with promising results and more clinical studies are underway. Furthermore, specific pacemaker algorithms, which minimize RV pacing, can also reduce the negative effects of RV stimulation on cardiac function and may prevent clinical deterioration. PMID:24340139
Domingues, A P; Moura, P; Vieira, D N
To appreciate the Portuguese circumstances concerning situations of obstetric medico-legal conflicts and to evaluate the influence of the quality of files in expert conclusions, an analysis of all cases of obstetric medical responsibility from 2001-11 was carried out. File quality was evaluated by absence or insufficiency of clinical information supplied, by poor quality of document copies and by the registered incongruities among all the health professionals involved. Clinical files sent for forensic analysis were defective in most cases (89.5%). In about 11% of cases, expert opinion was inconclusive as a result of the poor quality of the clinical files sent for technical and scientific analysis. This situation is particularly serious in cases where the reason for the dispute was asphyxia, traumatic lesions of the newborn following instrumented delivery or shoulder dystocia and maternal sequelae, where the lack or absence of information, and poor quality copies were significantly associated with inconclusive opinions. PMID:25153007
Rockwell, S.; Kapp, D.S.
The nitroimidazoles metronidazole, misonidazol, and desmethyl misonidazole are currently undergoing clinical trials as possible adjuncts to radiotherapy. Ongoing clinical trials are evaluating the effectiveness of these agents and also documenting the pharmacokinetics and toxicities of radiosensitizing doses of these drugs in man. A variety of toxic effects have been noted in man, including anorexia, nausea and vomiting, peripheral neuropathy, central nervous system symptoms, ototoxicity, allergy, and fear. Laboratory studies have also suggested that these agents have potential to be mutagenic, carcinogenic, and teratogenic. In the editorial presented, the author attempts to draw attention to an additional toxic effect of nitroimidazoles - the inhibition of cell-mediated immune responses. (JMT)
Samir, Mohamed; Pessler, Frank
MicroRNAs (miRNAs) represent a class of small non-coding RNA (sncRNA) molecules that can regulate mRNAs by inducing their degradation or by blocking translation. Considering that miRNAs are ubiquitous, stable, and conserved across animal species, it seems feasible to exploit them for clinical applications. Unlike in human viral diseases, where some miRNA-based molecules have progressed to clinical application, in veterinary medicine, this concept is just starting to come into view. Clinically, miRNAs could represent powerful diagnostic tools to pinpoint animal viral diseases and/or prognostic tools to follow up disease progression or remission. Additionally, the possible consequences of miRNA dysregulation make them potential therapeutic targets and open the possibilities to use them as tools to generate viral disease-resistant livestock. This review presents an update of preclinical studies on using sncRNAs to combat viral diseases that affect pet and farm animals. Moreover, we discuss the possibilities and challenges of bringing these bench-based discoveries to the veterinary clinic. PMID:27092305
Duncan, Kelly; Brown-Rice, Kathleen; Bardhoshi, Gerta
This study explored rural school counselors' perceptions of clinical supervision. School counselors working in rural communities commonly encounter issues that challenge their ability to provide competent counseling services to the students they serve. School counselors serving in these areas are often the only rural mental health provider in…
... independent of, the procedures described in 21 CFR 1301.34(b), (c), (d), (e), and (f). As noted in a previous...(a); 21 U.S.C. 823(a); and 21 CFR 1301.34(b), (c), (d), (e), and (f) are satisfied. Dated: April 10... controlled substances will be granted only for analytical testing and clinical trials. This...
Körei, A E; Istenes, I; Papanas, N; Kempler, P
Damage of small nerve fibers may lead to a large variety of clinical symptoms. Small-fiber neuropathy underlies the symptoms of painful diabetic neuropathy, which may decrease quality of life. It also contributes to the poor prognosis of diabetic neuropathy because it plays a key role in the pathogenesis of foot ulceration and autonomic neuropathy. Impairment of small nerve fibers is considered the earliest alteration in the course of diabetic neuropathy. Therefore, assessment of functional and morphological abnormalities of small nerve fibers may enable timely diagnosis. The definition, symptoms, and clinical significance of small-fiber neuropathy are considered in the present review. An apparently more complex interaction between small-fiber impairment and microcirculation is extensively discussed. Diagnostic modalities include morphometric and functional methods. Corneal confocal microscopy and punch skin biopsy are considered gold standards, but noninvasive functional tests are also diagnostically useful. However, in routine clinical practice, small-fiber neuropathy is diagnosed by its typical clinical presentation. Finally, prompt treatment should be initiated following diagnosis. PMID:25957257
Senior, B W
Many diverse clinical isolates of Proteus mirabilis (48 strains), P. penneri (25), P. vulgaris biogroup 2 (48) and P. vulgaris biogroup 3 (21) from man were examined for their ability to produce proteolytic enzymes and the nature and characteristics of the proteases were studied. All the P. penneri isolates, most (94-90%) of the P. mirabilis and P. vulgaris biogroup 2 isolates, but only 71% of the P. vulgaris biogroup 3 isolates, secreted proteolytic enzymes. These were detected most readily at pH 8 with gelatin as substrate. A strong correlation was found between the ability of a strain to form swarming growth and its ability to secrete proteases. Non-swarming isolates invariably appeared to be non-proteolytic. However, some isolates, particularly of P. vulgaris biogroup 3, were non-proteolytic even when they formed swarming growth. Analysis of the secreted enzymes of the different Proteus spp. on polyacrylamide-gelatin gels under various constraints of pH and other factors showed that they were all EDTA-sensitive metalloproteinases. Analysis of the kinetics of production of the proteases revealed the formation of an additional protease of undefined type and function that was cell-associated and formed before the others were secreted. The secreted protease was subsequently modified to two isoforms whose mass (53-46 kDa) varied with the Proteus spp. and the strain. There was no evidence that the secreted proteases of strains of Proteus spp. were of types other than metalloproteinases. PMID:10403412
Ennis, Gary; Happell, Brenda; Broadbent, Marc; Reid-Searl, Kerry
Communication has been identified as an important attribute of clinical leadership in nursing. However, there is a paucity of research on its relevance in mental health nursing. This article presents the findings of a grounded theory informed study exploring the attributes and characteristics required for effective clinical leadership in mental health nursing, specifically the views of nurses working in mental health about the importance of effective communication in day to day clinical leadership. In-depth interviews were conducted to gain insight into the participants' experiences and views on clinical leadership in mental health nursing. The data that emerged from these interviews were constantly compared and reviewed, ensuring that any themes that emerged were based on the participants' own experiences and views. Participants recognized that effective communication was one of the attributes of effective clinical leadership and they considered communication as essential for successful working relationships and improved learning experiences for junior staff and students in mental health nursing. Four main themes emerged: choice of language; relationships; nonverbal communication, and listening and relevance. Participants identified that clinical leadership in mental health nursing requires effective communication skills, which enables the development of effective working relationships with others that allows them to contribute to the retention of staff, improved outcomes for clients, and the development of the profession. PMID:24131413
Lee, Eung-Bin; Lee, Yun Young; Lee, Jae Min; Son, Su Min; Hwang, Su-Kyeong; Kwon, Soonhak
Purpose A limited number of studies have examined the link between F-wave abnormalities and clinical presentation in pediatric Guillain-Barré syndrome (GBS). Therefore, this study examined the importance of F-wave abnormalities as a prognostic factor in pediatric GBS patients. Methods The records and electrodiagnostic studies (EDS) of 70 GBS patients were retrospectively evaluated, and divided into 2 groups according to the results of EDS. Group A (n=33) presented with F-wave abnormalities, and group B (n=26) exhibited normal findings. We compared laboratory reports, clinical features, response to treatment, and prognosis between the 2 groups. Results Motor weakness was the most frequently observed symptom for either group. Clinically, the incidence of fever and upper respiratory symptoms differed between the 2 groups, while the prevalence of abnormal deep tendon reflex (DTR) was significantly higher in group A than B (P<0.05). Patients diagnosed with GBS had received intravenous immunoglobulin treatment: 94% in group A and 58% in group B. Furthermore, significantly greater numbers of patients in group A showed H-reflex abnormalities and poor prognosis compared with group B (P<0.05). Conclusion This study demonstrated that F-waves are a clinically important prognostic factor in GBS. F-wave abnormalities were associated with abnormal DTR and poor prognosis in patients. Limited studies have examined the link between F-wave abnormalities and clinical results; therefore, further randomized controlled studies are needed to confirm the clinical characteristics and efficacy of treatments. PMID:27462356
Tom, Raymond A.; Crisan, Eli V.
Nondestructive assay procedures for determining microbial lipolytic and proteolytic activity on marine substrates were developed and tested with 287 isolates of bacteria, filamentous fungi, and yeasts. A definite substrate specificity was noted when the enzymatic activities on marine and nonmarine substrates was compared. Of 170 lipolytic isolates, 14 were only active on menhaden oil, 11 could hydrolyze menhaden oil and Tween 80 and/or tributyrin, and 145 isolates could only hydrolyze one or both of the nonmarine lipids. Of the 198 proteolytic isolates, 10 were specific for codfish extract, 152 were active against the marine substrate plus casein and/or gelatin, and 36 were specific for nonmarine substrates. PMID:1167775
Ferrari, Michel D
The introduction of 5-HT(1B/1D) agonists, i.e. triptans, the first drugs specifically developed for the treatment of acute migraine, has revolutionized the treatment of migraine attacks. Triptans have met the needs of many migraine patients, however given the lack of direct comparative trials including all triptans, a meta-analysis of results with all available triptans needed to be conducted. Similar clinical trial design, patient population characteristics and main endpoints certainly facilitated the performance of this meta-analysis. Results from 53 randomized, double-blind, controlled clinical trials on acute triptan therapy in 24,089 patients were compared with respect to the main efficacy and tolerability variables. At recommended doses, almotriptan 12.5 mg, eletriptan 80 mg and rizatriptan 10 mg provided the highest likelihood of consistent success. PMID:15071619
Christofides, Elena A
In acromegaly, achieving biochemical control (growth hormone [GH] level <1.0 ng/mL and age- and sex-normalized levels of insulin-like growth factor 1 [IGF-1]) through timely diagnosis and appropriate treatment provides an opportunity to improve patient outcomes. Diagnosis of acromegaly is challenging because it is rooted in observing subtle clinical manifestations, and it is typical for acromegaly to evolve for up to 10 years before it is recognized. This results in chronic exposure to elevated levels of GH and IGF-1 and delay in patients receiving appropriate treatment, which consequently increases mortality risk. In this review, the clinical impact of elevated GH and IGF-1 levels, the effectiveness of current therapies, and the potential role of novel treatments for acromegaly will be discussed. Clinical burden of acromegaly and benefits associated with management of GH and IGF-1 levels will be reviewed. Major treatment paradigms in acromegaly include surgery, medical therapy, and radiotherapy. With medical therapies, such as somatostatin analogs, dopamine agonists, and GH receptor antagonists, a substantial proportion of patients achieve reduced GH and normalized IGF-1 levels. In addition, signs and symptoms, quality of life, and comorbidities have also been reported to improve to varying degrees in patients who achieve biochemical control. Currently, there are several innovative therapies in development to improve patient outcomes, patient use, and access. Timely biochemical control of acromegaly ensures that the patient can ultimately improve morbidity and mortality from this disease and its extensive consequences. PMID:27471378
Austin, Bryan Scott
Given the importance of clinical judgment in rehabilitation counseling (Strohmer & Leierer, 2000), prevalence and consequences of rehabilitation counselor biases (Berven & Rosenthal, 1999), and the emerging trend to educate rehabilitation counselors in evidence-based practice (EBP) (Leahy & Arokiasamy, 2010), the explicit teaching of…
..., Inc. By Notice dated April 17, 2012, and published in the Federal Register on April 26, 2012, 77 FR... Tapentadol (9780) II Fentanyl (9801) II The company plans to import small quantities of the listed...
... noted in a previous notice published in the Federal Register on September 23, 1975, 40 FR 43745-46, all... application to the Drug Enforcement Administration (DEA) for registration as an importer of Tapentadol...
..., Inc. By Notice dated April 10, 2013, and published in the Federal Register on April 19, 2013, 78 FR... Tapentadol (9780) II Fentanyl (9801) II The company plans to import small quantities of the listed...
... September 23, 1975, 40 FR 43745-46, all applicants for registration to import the basic class of any... controlled substances: Drug Schedule Oxycodone (9143) II Hydromorphone (9150) II Tapentadol (9780)...
Turk, Dennis C; Dworkin, Robert H; Revicki, Dennis; Harding, Gale; Burke, Laurie B; Cella, David; Cleeland, Charles S; Cowan, Penney; Farrar, John T; Hertz, Sharon; Max, Mitchell B; Rappaport, Bob A
This two-phase study was conducted to identify relevant domains of patient-reported outcomes from the perspective of people who experience chronic pain. In Phase 1, focus groups were conducted to generate a pool of patient outcome-related domains and their components. The results of the focus groups identified 19 aspects of their lives that were significantly impacted by the presence of their symptoms and for which improvements were important criteria they would use in evaluating the effectiveness of any treatment. Phase 2 was conducted to examine the importance and relevance of domains identified from a much larger and diverse sample of people with chronic pain. A survey was developed and posted on the American Chronic Pain Association website. Participants were asked to rate the importance of each item or domain identified by the focus groups on a scale of 0 to10 (i.e., 0="not at all important" and 10="extremely important"). The survey was completed by 959 individuals. The results indicate that all 19 aspects of daily life derived from the focus groups were considered important with a majority of respondents indicating a score of 8 or greater. In addition to pain reduction, the most important aspects were enjoyment of life, emotional well-being, fatigue, weakness, and sleep-related problems. Chronic pain clearly impacts health-related quality of life. The results of the two phases of the study indicate that people with chronic pain consider functioning and well-being as important areas affected by the presence of symptoms and as appropriate targets of treatment. These multiple outcomes should be considered when evaluating the efficacy and effectiveness of chronic pain treatments. PMID:17937976
Modrzewska, B; Kurnatowski, P; Khalid, K
The aim of the research was to evaluate the proteolytic activity of various Candida strains isolated from the oral cavity of persons without clinical symptoms of fungal infection, outpatients with oral cavity disorders and patients hospitalized due to head and neck tumors. A secondary aim was to confirm the presence of secreted aspartyl protease (SAP) genes in the isolated strains and then to compare it depending on the fungal species. Material consisted of 134 fungal strains that were analysed by a modified Staib method and polymerase chain reaction (PCR) with the use of specific primer pairs. The greatest proteolytic activity of fungi was observed at pH 3.5. The proteolysis were the strongest for strains isolated from dental patients and the weakest from persons without changes in the oral cavity. In total, 61.9% of the strains exhibited the presence of at least one of the SAP1-3 genes in all examined groups, SAP1 being the most common; SAP4-6 genes were not observed. All genes were more frequent in the strains isolated from the dental patients than from other groups. SAP1-3 genes were present in Candida albicans, C. tropicalis, C. parapsilosis, C. glabrata, C. humicola and C. lipolytica, but were not noted in other isolated species. The lowest activity of proteolytic enzymes and the least number of aspartyl protease genes are observed among strains isolated from patients without clinical symptoms of mycosis. SAP1-3 genes are most frequently detected in the strains isolated from the oral cavity; their presence varies depending on the species of the fungi. PMID:26922385
Biderman, Aya; Herman, Joseph
During the decade from 1977 to 1986, four models of care pertaining to ambulatory medicine and certain aspects of clinical epidemiology were proposed. All were concerned with the frequently heard accusation that medicine was becoming dehumanized by being overly dependent on powerful new technologies. Some of the authors went so far as to suggest that the view, according to which medical science must restrict itself to "hard" data of the kind provided by the serum multichannel analyzer, should be considered outdated and, in fact, unscientific. Their plea was to develop a science of the clinical encounter that would shift the emphasis from explication to prediction and management, the latter term being virtually synonymous with decision making. For this change to come about, they wrote, it would be necessary to collect "soft" data on such subjects as family relationships, psychic traits and states, perceptions of life quality, patient expectations and many others. We believe that some of these subjects as well as the models themselves were anticipated in the writings, both medical and fictional, of Weir Mitchell, nearly a century earlier. This paper, after presenting a brief overview of the career of a colorful and commanding figure from the annals of American medicine, will seek to illustrate his extraordinary farsightedness as a practitioner of primary care and his relevance for some aspects of clinical epidemiology. Because the attempts to link his ideas to modern concepts are ours, we accept the possibility that, here and there, we may have read things into his writings that he did not intend. PMID:11927212
Mahanty, Arabinda; Sankar, T. V.; Chakraborty, Kajal; Rangasamy, Anandan; Paul, Baidyanath; Sarma, Debajit; Mathew, Suseela; Asha, Kurukkan Kunnath; Behera, Bijay; Aftabuddin, Md.; Debnath, Dipesh; Vijayagopal, P.; Sridhar, N.; Akhtar, M. S.; Sahi, Neetu; Mitra, Tandrima; Banerjee, Sudeshna; Das, Debajeet; Das, Pushpita; Vijayan, K. K.; Laxmanan, P. T.; Sharma, A. P.
Proteins and amino acids are important biomolecules which regulate key metabolic pathways and serve as precursors for synthesis of biologically important substances; moreover, amino acids are building blocks of proteins. Fish is an important dietary source of quality animal proteins and amino acids and play important role in human nutrition. In the present investigation, crude protein content and amino acid compositions of important food fishes from different habitats have been studied. Crude protein content was determined by Kjeldahl method and amino acid composition was analyzed by high performance liquid chromatography and information on 27 food fishes was generated. The analysis showed that the cold water species are rich in lysine and aspartic acid, marine fishes in leucine, small indigenous fishes in histidine, and the carps and catfishes in glutamic acid and glycine. The enriched nutrition knowledge base would enhance the utility of fish as a source of quality animal proteins and amino acids and aid in their inclusion in dietary counseling and patient guidance for specific nutritional needs. PMID:25379285
Badali, Hamid; Mohammadi, Rasoul; Mashedi, Olga; de Hoog, G Sybren; Meis, Jacques F
Despite the common, worldwide, occurrence of dermatophytes, little information is available regarding susceptibility profiles against currently available and novel antifungal agents. A collection of sixty-eight clinical Trichophyton species and Epidermophyton floccosum were previously identified and verified to the species level by sequencing the internal transcribed spacer (ITS) regions of rDNA. MICs of amphotericin B, fluconazole, itraconazole, voriconazole, posaconazole, isavuconazole, terbinafine and MECs of caspofungin and anidulafungin were performed based on CLSI M38-A2. The resulting MIC90 s of all strains were, in increasing order, as follows: terbinafine (0.063 mg l(-1) ); posaconazole (1 mg l(-1) ); isavuconazole and anidulafungin (2 mg l(-1) ); itraconazole, voriconazole, amphotericin B, and caspofungin (4 mg l(-1) ) and fluconazole (>64 mg l(-1) ). These results confirm that terbinafine is an excellent agent for treatment of dermatophytosis due to T. rubrum, T. mentagrophytes, T. verrucosum, T. schoenleinii and E. floccosum. In addition, the new azoles POS and ISA are potentially useful antifungals to treat dermatophytosis. However, the clinical effectiveness of these novel antifungals remains to be determined. PMID:25757042
Elden, Nesreen Mohamed Kamal; Ismail, Amira
Introduction: Medication errors have significant implications on patient safety. Error detection through an active management and effective reporting system discloses medication errors and encourages safe practices. Objectives: To improve patient safety through determining and reducing the major causes of medication errors (MEs), after applying tailored preventive strategies. Methodology: A pre-test, post-test study was conducted on all inpatients at a 177 bed hospital where all medication procedures in each ward were monitored by a clinical pharmacist. The patient files were reviewed, as well. Error reports were submitted to a hospital multidisciplinary committee to identify major causes of errors. Accordingly, corrective interventions that consisted of targeted training programs for nurses and physicians were conducted. Results: Medication errors were higher during ordering/prescription stage (38.1%), followed by administration phase (20.9%). About 45% of errors reached the patients: 43.5% were harmless and 1.4% harmful. 7.7% were potential errors and more than 47% could be prevented. After the intervention, error rates decreased from (6.7%) to (3.6%) (P≤0.001). Conclusion: The role of a ward based clinical pharmacist with a hospital multidisciplinary committee was effective in recognizing, designing and implementing tailored interventions for reduction of medication errors. A systematic approach is urgently needed to decrease organizational susceptibility to errors, through providing required resources to monitor, analyze and implement effective interventions. PMID:27045415
Ghiadoni, Lorenzo; Salvetti, Massimo; Muiesan, Maria Lorenza; Taddei, Stefano
Endothelium plays a primary role in the control of vascular function and structure by protective properties of nitric oxide, which have stimulated the development of methods to assess of endothelial function. Flow-mediated dilation is the most widely used method to test endothelial function since it is non-invasive, and measures by ultrasounds the response to increased shear stress, commonly in the brachial artery. This review focuses on available evidence on FMD, which has been tested for the association with risk factors, target organ damage and the predictive value for future cardiovascular events. FMD has been studied widely in clinical research as it enables serial evaluation, also testing the effect of lifestyle and pharmacological interventions on endothelial function at an early preclinical stage, when the disease process is most likely to be reversible. Despite these advantages, endothelial tests, including FMD, are not yet recommended by guidelines for cardiovascular prevention, for the absence of clear additional prognostic value and particularly the poorly standardized non-invasive methodology. However, recent multicenter studies suggest that accurate methodology ensures reproducible FMD measurements, which can be used in future clinical research to test whether interventions ameliorating FMD function are associated to better cardiovascular prognosis. PMID:24619864
Jepsen, Peter; Vilstrup, Hendrik; Andersen, Per Kragh
Multistate models are models of disease progression that, for a patient group, define multiple outcome events, each of which may affect the time to develop another outcome event. Multistate models are highly relevant for studies of patients with cirrhosis; both the classical perception of cirrhosis as either compensated or decompensated and the recent, more complex models of cirrhosis progression are multistate models. Therefore, researchers who conduct clinical studies of patients with cirrhosis must realize that most of their research questions assume a multistate disease model. Failure to do so can result in severely biased results and bad clinical decisions. The analyses that can be used to study disease progression in a multistate disease model may be called competing risks analysis, named after the competing risks disease model, which is the simplest multistate disease model. In this review article, we introduce multistate disease models and competing risks analysis and explain why the standard armamentarium of Kaplan-Meier survival estimates and Cox regression sometimes gives bad answers to good questions. We also use real data to answer typical research questions about the course of cirrhosis and illustrate biases resulting from inadequate methods. Finally, we suggest statistical software packages that are helpful and accessible to the clinician-researcher. PMID:25376655
Freed, Curt R; Zhou, Wenbo; Breeze, Robert E
Transplantation of human fetal dopamine neurons into the brain of Parkinson's disease patients started in the late 1980s, less than 10 years after experiments in rats showed that embryonic dopamine neurons from a narrow window of development are suitable for transplantation. For human transplantation, the critical stage of development is 6 to 8 weeks after conception. Because putamen is the basal ganglia structure most depleted of dopamine in Parkinson's disease and because it is the structure most closely mapped to the motor cortex, it has been the primary target for neurotransplantation. The double blind trial conducted at the University of Colorado, Columbia University, and North Shore University is the first controlled surgical trial performed in the field of neurosurgery. Results have shown that transplants of fetal dopamine neurons can survive transplantation without immunosuppression and without regard to the age of the patients. Transplants improved objective signs of Parkinson's disease to the best effects of L-DOPA seen preoperatively. Placebo surgery produced no clinical changes. In subjects in whom transplants replaced the need for L-DOPA, the implants replicated the preoperative effects of L-DOPA, including dyskinesias in susceptible patients. Our trial has provided the first controlled evidence that dopamine cell transplants can improve the clinical state of patients with Parkinson's disease. PMID:21997523
Ndreu, Arben; Hajdari, Diana; Ndoni, Anduena; Shkurti, Klodiana; Kraja, Dhimiter; Çomo, Najada; Bino, Silva; Gjermeni, Nevila; Domi, Rudin; Mingomataj, Ervin Çerçiz
This is a case-report of two patients with cerebral malaria (CM) imported from West-African countries. Notably, this form of malaria was developed as a second disease episode, while the first episode was experienced in West Africa. These findings suggest that the second episode of malaria was caused by a different strain of Plasmodium falciparum as compared to the first one. They are the first cerebral malaria cases imported in Albania after the eradication and absence of Plasmodium for five decades. Early treatment of cerebral malaria is decisive on the duration of coma and disease's outcome. PMID:26927463
Koscielska-Kasprzak, Katarzyna; Otlewski, Jacek
We demonstrated that amyloid-forming peptides could be selected from phage-displayed library via proteolysis-based selection protocol. The library of 28-residue peptides based on a sequence of the second zinc finger domain of Zif268, and computationally designed betabetaalpha peptide, FSD-1, was presented monovalently on the surface of M13 phage. The library coupled the infectivity of phage particles to proteolytic stability of a peptide introduced into the coat protein III linker. It was designed to include variants with a strong potential to fold into betabetaalpha motif of zinc finger domains, as expected from secondary structure propensities, but with no structure stabilization via zinc ion coordination. As our primary goal was to find novel monomeric betabetaalpha peptides, the library was selected for stable domains with the assumption that folded proteins are resistant to proteolysis. After less than four rounds of proteolytic selection with trypsin, chymotrypsin, or proteinase K, we obtained a number of proteolysis-resistant phage clones containing several potential sites for proteolytic attack with the proteinases. Eight peptides showing the highest proteolysis resistance were expressed and purified in a phage-free form. When characterized, the peptides possessed proteolytic resistance largely exceeding that of the second zinc finger domain of Zif268 and FSD-1. Six of the characterized peptides formed fibrils when solubilized at high concentrations. Three of them assembled into amyloids as determined through CD measurements, Congo red and thioflavin T binding, and transmission electron microscopy. PMID:12876317
Sampaio-Marques, Belém; Ludovico, Paula
Insoluble and fibrillar forms of α-synuclein are the major components of Lewy bodies, a hallmark of several sporadic and inherited neurodegenerative diseases known as synucleinopathies. α-Synuclein is a natural unfolded and aggregation-prone protein that can be degraded by the ubiquitin-proteasomal system and the lysosomal degradation pathways. α-Synuclein is a target of the main cellular proteolytic systems, but it is also able to alter their function further, contributing to the progression of neurodegeneration. Aging, a major risk for synucleinopathies, is associated with a decrease activity of the proteolytic systems, further aggravating this toxic looping cycle. Here, the current literature on the basic aspects of the routes for α-synuclein clearance, as well as the consequences of the proteolytic systems collapse, will be discussed. Finally, particular focus will be given to the sirtuins’s role on proteostasis regulation, since their modulation emerged as a promising therapeutic strategy to rescue cells from α-synuclein toxicity. The controversial reports on the potential role of sirtuins in the degradation of α-synuclein will be discussed. Connection between sirtuins and proteolytic systems is definitely worth of further studies to increase the knowledge that will allow its proper exploration as new avenue to fight synucleinopathies. PMID:25946078
Leverrier, Sabrina; Vallentin, Alice; Joubert, Dominique
In contrast with protein kinase Calpha (PKCalpha) and PKCepsilon, which are better known for promoting cell survival, PKCdelta is known for its pro-apoptotic function, which is exerted mainly through a caspase-3-dependent proteolytic activation pathway. In the present study, we used the rat GH3B6 pituitary adenoma cell line to show that PKCalpha and PKCepsilon are activated and relocalized together with PKCdelta when apoptosis is induced by a genotoxic stress. Proteolytic activation is a crucial step used by the three isoforms since: (1) the catalytic domains of the PKCalpha, PKCepsilon or PKCdelta isoforms (CDalpha, CDepsilon and CDdelta respectively) accumulated, and this accumulation was dependent on the activity of both calpain and caspase; and (2) transient expression of CDalpha, CDepsilon or CDdelta sufficed to induce apoptosis. However, following this initial step of proteolytic activation, the pathways diverge; cytochrome c release and caspase-3 activation are induced by CDepsilon and CDdelta, but not by CDalpha. Another interesting finding of the present study is the proteolysis of PKCdelta induced by CDepsilon expression that revealed the existence of a cross-talk between PKC isoforms during apoptosis. Hence the PKC family may participate in the apoptotic process of pituitary adenoma cells at two levels: downstream of caspase and calpain, and via retro-activation of caspase-3, resulting in the amplification of its own proteolytic activation. PMID:12238950
Hojat, Mohammadreza; Xu, Gang
Effect Sizes (ES) are an increasingly important index used to quantify the degree of practical significance of study results. This paper gives an introduction to the computation and interpretation of effect sizes from the perspective of the consumer of the research literature. The key points made are: (1) "ES" is a useful indicator of the…
de Hoog, G. Sybren; Chaturvedi, Vishnu; Denning, David W.; Dyer, Paul S.; Frisvad, Jens Christian; Geiser, David; Gräser, Yvonne; Guarro, Josep; Haase, Gerhard; Kwon-Chung, Kyung-Joo; Meyer, Wieland; Pitt, John I.; Samson, Robert A.; Tintelnot, Kathrin; Vitale, Roxana G.; Walsh, Thomas J.
Recent changes in the Fungal Code of Nomenclature and developments in molecular phylogeny are about to lead to dramatic changes in the naming of medically important molds and yeasts. In this article, we present a widely supported and simple proposal to prevent unnecessary nomenclatural instability. PMID:25297326
Metra, Marco; Cas, Livio Dei; di Lenarda, Andrea; Poole-Wilson, Philip
Beta-blockers are not an homogeneous group of agents. Only three beta-blockers, carvedilol, bisoprolol and metoprolol succinate, have had favorable effects on prognosis in controlled clinical trials in the patients with chronic heart failure. However, pharmacological differences exist between them. Metoprolol and bisoprolol are selective for beta(1)-adrenergic receptors while carvedilol blocks also beta(2)-, and alpha(1)- adrenergic receptors, and has associated antioxidant, anti-endothelin and antiproliferative properties. In COMET carvedilol was associated with a significant reduction in mortality compared to metoprolol tartrate further showing that different beta-blockers may have different effects on the outcome. These differences may be related to the ancillary properties of carvedilol or to its broader antiadrenergic profile. However, also more effective and prolonged blockade of beta1 adrenergic receptors may occur with carvedilol compared to metoprolol. PMID:15516860
Jain, Deepanshu; Momeni, Mojdeh; Krishnaiah, Mahesh; Anand, Sury; Singhal, Shashideep
AIM: To evaluate the impact of reporting bowel preparation using Boston Bowel Preparation Scale (BBPS) in clinical practice. METHODS: The study was a prospective observational cohort study which enrolled subjects reporting for screening colonoscopy. All subjects received a gallon of polyethylene glycol as bowel preparation regimen. After colonoscopy the endoscopists determined quality of bowel preparation using BBPS. Segmental scores were combined to calculate composite BBPS. Site and size of the polyps detected was recorded. Pathology reports were reviewed to determine advanced adenoma detection rates (AADR). Segmental AADR’s were calculated and categorized based on the segmental BBPS to determine the differential impact of bowel prep on AADR. RESULTS: Three hundred and sixty subjects were enrolled in the study with a mean age of 59.2 years, 36.3% males and 63.8% females. Four subjects with incomplete colonoscopy due BBPS of 0 in any segment were excluded. Based on composite BBPS subjects were divided into 3 groups; Group-0 (poor bowel prep, BBPS 0-3) n = 26 (7.3%), Group-1 (Suboptimal bowel prep, BBPS 4-6) n = 121 (34%) and Group-2 (Adequate bowel prep, BBPS 7-9) n = 209 (58.7%). AADR showed a linear trend through Group-1 to 3; with an AADR of 3.8%, 14.8% and 16.7% respectively. Also seen was a linear increasing trend in segmental AADR with improvement in segmental BBPS. There was statistical significant difference between AADR among Group 0 and 2 (3.8% vs 16.7%, P < 0.05), Group 1 and 2 (14.8% vs 16.7%, P < 0.05) and Group 0 and 1 (3.8% vs 14.8%, P < 0.05). χ2 method was used to compute P value for determining statistical significance. CONCLUSION: Segmental AADRs correlate with segmental BBPS. It is thus valuable to report segmental BBPS in colonoscopy reports in clinical practice. PMID:25852286
Coralli, Connie H
Effective case presentations are an important component of the nurse practitioner's skills, yet very little literature exists to guide the development of this skill, and frequently little priority is given to teaching this skill during the education of the nurse practitioner. This report discusses the importance of effective case presentations, describes the organization of the presentation, and outlines the appropriate information to be included. The main components of a case presentation-introduction, history of the present illness, physical examination, diagnostic studies, differential diagnosis, management, and summary of the case-are discussed in detail. Examples of a formal and an informal case presentation are presented and used to illustrate key points in the text. PMID:16681708
Hillgren, K M; Keppler, D; Zur, A A; Giacomini, K M; Stieger, B; Cass, C E; Zhang, L
The International Transporter Consortium (ITC) has recently described seven transporters of particular relevance to drug development. Based on the second ITC transporter workshop in 2012, we have identified additional transporters of emerging importance in pharmacokinetics, interference of drugs with transport of endogenous compounds, and drug-drug interactions (DDIs) in humans. The multidrug and toxin extrusion proteins (MATEs, gene symbol SLC47A) mediate excretion of organic cations into bile and urine. MATEs are important in renal DDIs. Multidrug resistance proteins (MRPs or ABCCs) are drug and conjugate efflux pumps, and impaired activity of MRP2 results in conjugated hyperbilirubinemia. The bile salt export pump (BSEP or ABCB11) prevents accumulation of toxic bile salt concentrations in hepatocytes, and BSEP inhibition or deficiency may cause cholestasis and liver injury. In addition, examples are presented on the roles of nucleoside and peptide transporters in drug targeting and disposition. PMID:23588305
List, Karin; Currie, Brooke; Scharschmidt, Tiffany C; Szabo, Roman; Shireman, Jessica; Molinolo, Alfredo; Cravatt, Benjamin F; Segre, Julia; Bugge, Thomas H
Human autosomal recessive ichthyosis with hypotrichosis (ARIH) is an inherited disorder recently linked to homozygosity for a point mutation in the ST14 gene that causes a G827R mutation in the matriptase serine protease domain (G216 in chymotrypsin numbering). Here we show that human G827R matriptase has strongly reduced proteolytic activity toward small molecule substrates, as well as toward its candidate epidermal target, prostasin. To further investigate the possible contribution of low matriptase activity to ARIH, we generated an ST14 hypomorphic mouse strain that displays a 100-fold reduction in epidermal matriptase mRNA levels. Interestingly, unlike ST14 null mice, ST14 hypomorphic mice were viable and fertile but displayed a spectrum of abnormalities that strikingly resembled ARIH. Thus, ST14 hypomorphic mice developed hyperproliferative and retention ichthyosis with impaired desquamation, hypotrichosis with brittle, thin, uneven, and sparse hair, and tooth defects. Biochemical analysis of ST14 hypomorphic epidermis revealed reduced prostasin proteolytic activation and profilaggrin proteolytic processing, compatible with a primary role of matriptase in this process. This work strongly indicates that reduced activity of a matriptase-prostasin proteolytic cascade is the etiological origin of human ARIH and provides an important mouse model for the exploration of matriptase function in ARIH, as well as multiple other physiological and pathological processes. PMID:17940283
Cheng, Ching-Rong; Sessler, Daniel I.; Apfel, Christian C.
Neostigmine is used to antagonize neoromuscluar blocker-induced residual neuromuscular paralysis. Despite a previous meta-analysis, the effect of neostigmine on postoperative nausea and vomiting (PONV) remains unresolved. We reevaluated the effect of neostigmine on PONV while considering the different anticholinergics as potentially confounding factors. We performed a systematic literature search using Medline, Embase, Cochrane library, reference listings, and hand searching with no language restriction through December 2004 and identified 10 clinical, randomized, controlled trials evaluating neostigmine's effect on PONV. Data on nausea or vomiting from 933 patients were extracted for the early (0-6 h), delayed (6-24 h), and overall postoperative periods (0-24 h) and analyzed with RevMan 4.2 (Cochrane Collaboration, Oxford, UK) and multiple logistic regression analysis. The combination of neostigmine with either atropine or glycopyrrolate did not significantly increase the incidence of overall (0-24 h) vomiting (relative risk (RR) 0.91 [0.70-1.18], P=0.48) or nausea (RR 1.24 [95% CI: 0.98-1.59], P=0.08). Multiple logistic regression analysis indicated that that there was not a significant increase in the risk of vomiting with large compared with small doses of neostigmine. In contrast to a previous analysis, we conclude that there is insufficient evidence to conclude that neostigmine increases the risk of PONV. PMID:16243993
Klietmann, W; Focht, J; Nösner, K
Imipenem is a thienamycin antibiotic of the first generation with broad antibacterial activity. It covers all gram-positive organisms (including Streptococcus faecalis) and gram-negative bacteria (including Pseudomonas aeruginosa and Serratia spp.) as well as Bacteroides fragilis and other Bacteroides species. In this comparative study the antimicrobic effect against 1020 gram-negative, 927 gram-positive and 352 anaerobic strains from fresh clinical isolates was tested and compared with that of other frequently used antibiotics. The minimum inhibitory concentrations (MIC) were determined by means of a serial dilution test with micro standard plates. Within the group of gram-negative strains, imipenem was the most active antibiotic with a MIC90 of less than or equal to 0.25 mg/l for most isolates. Imipenem shows a broad spectrum of activity against gram-negative pathogenic bacteria including Escherichia coli, Klebsiella spp., Proteus spp, Enterobacter spp., Citrobacter spp. and Serratia spp., and also covers resistant strains of Pseudomonas aeruginosa, Acinetobacter spp. and Alcaligenes faecalis. Imipenem also shows high inhibiting activity against gram-positive strains and anaerobic pathogens. PMID:3477332
Lakusic, Nenad; Mahovic, Darija; Cerkez Habek, Jasna; Novak, Miroslav; Cerovec, Dusko
Heart rate variability is a physiological feature indicating the influence of the autonomic nervous system on the heart rate. Association of the reduced heart rate variability due to myocardial infarction and the increased postinfarction mortality was first described more than thirty years ago. Many studies have unequivocally demonstrated that coronary artery bypass grafting surgery generally leads to significant reduction in heart rate variability, which is even more pronounced than after myocardial infarction. Pathophysiologically, however, the mechanisms of heart rate variability reduction associated with acute myocardial infarction and coronary artery bypass grafting are different. Generally, heart rate variability gradually recovers to the preoperative values within six months of the procedure. Unlike the reduced heart rate variability in patients having sustained myocardial infarction, a finding of reduced heart rate variability after coronary artery bypass surgery is not considered relevant in predicting mortality. Current knowledge about changes in heart rate variability in coronary patients and clinical relevance of such a finding in patients undergoing coronary artery bypass grafting are presented. PMID:26078960
Alcocer, Fernando; David, Mariam; Goodman, Rachel; Jain, Sachin Kumar Amruthlal; David, Shukri
Summary Background: Subclavian Steal Syndrome (SSS) is a fascinating vascular phenomenon in which a steno-occlusive lesion of the proximal subclavian artery causes retrograde flow in the vertebral artery away from the brain stem subsequently causing vertebrobasilar insufficiency. SSS can present with a myriad of neurological and vascular signs and symptoms, but most commonly this phenomenon presents as an incidental finding in an asymptomatic patient. Case Report: Our patient is a 73-year-old female sent to the cardiology clinic for surgical clearance in preparation for an elective cholecystectomy. Shortness of breath was her only complaint. Review of systems was remarkable for left arm pain and blurry vision with repetitive movement. Physical examination noticeable for absence of left radial pulse. Percutaneous angiography demonstrated a totally occulted left subclavian artery with collateral circulation form the vertebrobasilar apparatus. Conclusions: Atypical presentation of this unique entity represents a challenge for physicians who require a high index of suspicion to make the diagnosis. We present an atypical case with radiographical evidence of the steal syndrome, followed by an extensive literature review of the most current diagnostic methods as well as latest recommendations for treatment options and secondary prevention. PMID:23569564
Besur, Siddesh; Hou, Wehong; Schmeltzer, Paul; Bonkovsky, Herbert L
Heme, like chlorophyll, is a primordial molecule and is one of the fundamental pigments of life. Disorders of normal heme synthesis may cause human diseases, including certain anemias (X-linked sideroblastic anemias) and porphyrias. Porphyrias are classified as hepatic and erythropoietic porphyrias based on the organ system in which heme precursors (5-aminolevulinic acid (ALA), porphobilinogen and porphyrins) are chiefly overproduced. The hepatic porphyrias are further subdivided into acute porphyrias and chronic hepatic porphyrias. The acute porphyrias include acute intermittent, hereditary copro-, variegate and ALA dehydratase deficiency porphyria. Chronic hepatic porphyrias include porphyria cutanea tarda and hepatoerythropoietic porphyria. The erythropoietic porphyrias include congenital erythropoietic porphyria (Gűnther's disease) and erythropoietic protoporphyria. In this review, we summarize the key features of normal heme synthesis and its differing regulation in liver versus bone marrow. In both organs, principal regulation is exerted at the level of the first and rate-controlling enzyme, but by different molecules (heme in the liver and iron in the bone marrow). We also describe salient clinical, laboratory and genetic features of the eight types of porphyria. PMID:25372274
Besur, Siddesh; Hou, Weihong; Schmeltzer, Paul; Bonkovsky, Herbert L.
Heme, like chlorophyll, is a primordial molecule and is one of the fundamental pigments of life. Disorders of normal heme synthesis may cause human diseases, including certain anemias (X-linked sideroblastic anemias) and porphyrias. Porphyrias are classified as hepatic and erythropoietic porphyrias based on the organ system in which heme precursors (5-aminolevulinic acid (ALA), porphobilinogen and porphyrins) are chiefly overproduced. The hepatic porphyrias are further subdivided into acute porphyrias and chronic hepatic porphyrias. The acute porphyrias include acute intermittent, hereditary copro-, variegate and ALA dehydratase deficiency porphyria. Chronic hepatic porphyrias include porphyria cutanea tarda and hepatoerythropoietic porphyria. The erythropoietic porphyrias include congenital erythropoietic porphyria (Gűnther’s disease) and erythropoietic protoporphyria. In this review, we summarize the key features of normal heme synthesis and its differing regulation in liver versus bone marrow. In both organs, principal regulation is exerted at the level of the first and rate-controlling enzyme, but by different molecules (heme in the liver and iron in the bone marrow). We also describe salient clinical, laboratory and genetic features of the eight types of porphyria. PMID:25372274
Camacho Rodriguez, Juan Carlos; Stäubert, Sebastian; Löbe, Matthias
Electronic data capture (EDC) tools are designed to simplify data acquisition, improving data quality and managing clinical data electronically. Some data are collected from the laboratory information management system (LIMS), which is an important data source for a study. OpenClinica is an open source clinical data management system (CDMS) for web-based electronic data capture (EDC), which is used widely in academic clinical research. TranSMART is also an open source web-based platform used for the management and analysis of different data types common in clinical and translational research. Many LIMS use the Health Level 7 standard - Version 2.x (HL7) as a message exchange protocol. In this paper, we implement Mirth Connect as a Communication Server (CS) to convert these HL7 messages either to Operational Data Model (ODM) data for the automatic import in OpenClinica or tabular-delimited text format files, whose data is uploaded in tranSMART using the tMDataLoader tool. PMID:27577395
Ohara, Yusuke; Oda, Tatsuya; Sugano, Masato; Hashimoto, Shinji; Enomoto, Tsuyoshi; Yamada, Keiichi; Akashi, Yoshimasa; Miyamoto, Ryoichi; Kobayashi, Akihiko; Fukunaga, Kiyoshi; Morishita, Yukio; Ohkohchi, Nobuhiro
CD44(+) /CD24(+) /EpCAM(+) cells have been reported to be cancer stem cells in pancreatic cancer; however, the histological and clinical importance of these cells has not yet been investigated. Here we clarified the characteristics of CD44(+) /CD24(+) /EpCAM(+) cells in clinical specimens of pancreatic cancer using immunohistochemical assay. We used surgical specimens of pancreatic ductal adenocarcinoma from 101 patients. In view of tumor heterogeneity, we randomly selected 10 high-power fields per case, and triple-positive CD44(+) /CD24(+) /EpCAM(+) expression was identified using our scoring system. The distribution, histological characteristics, and prognostic importance of CD44(+) /CD24(+) /EpCAM(+) cells were then analyzed. As a result, the distribution of CD44(+) /CD24(+) /EpCAM(+) cells varied widely among the 101 cases examined, and CD44(+) /CD24(+) /EpCAM(+) expression was correlated with poor glandular differentiation and high proliferation. Survival analysis showed that CD44(+) /CD24(+) /EpCAM(+) expression was not correlated with patient outcome; however, CD44(+) /CD24(+) expression appeared to be correlated with poor prognosis. In conclusion, CD44(+) /CD24(+) /EpCAM(+) expression overlapped with poorly differentiated cells and possessed high proliferative potential in clinical pancreatic cancer. In particular, the presence of double-positive CD44(+) /CD24(+) expression seemed to have clinical relevance, associating with poor prognosis. PMID:23679813
Gürses, İlke Ali; Gayretli, Özcan; Kale, Ayşin; Öztürk, Adnan; Usta, Ahmet; Şahinoğlu, Kayıhan
Background: Transcatheter arterial chemoembolization is a common treatment for patients with inoperable hepatocellular carcinoma. If the carcinoma is advanced or the main arterial supply, the hepatic artery, is occluded, extrahepatic collateral arteries may develop. Both, right and left inferior phrenic arteries (RIPA and LIPA) are the most frequent and important among these collaterals. However, the topographic anatomy of these arteries has not been described in detail in anatomy textbooks, atlases and most previous reports. Aims: To investigate the anatomy and branching patterns of RIPA and LIPA on cadavers and compare our results with the literature. Study Design: Descriptive study. Methods: We bilaterally dissected 24 male and 2 female cadavers aged between 49 and 88 years for this study. Results: The RIPA and LIPA originated as a common trunk in 5 cadavers. The RIPA originated from the abdominal aorta in 13 sides, the renal artery in 2 sides, the coeliac trunk in 1 side and the left gastric artery in 1 side. The LIPA originated from the abdominal aorta in 9 sides and the coeliac trunk in 6 sides. In 6 cadavers, the ascending and posterior branches of the LIPA had different sources of origin. Conclusion: As both the RIPA and LIPA represent the half of all extrahepatic arterial collaterals to hepatocellular carcinomas, their anatomy gains importance not only for anatomists but interventional radiologists as well. PMID:26167344
de Matos, Leandro Luongo; Trufelli, Damila Cristina; de Matos, Maria Graciela Luongo; da Silva Pinhal, Maria Aparecida
The immunohistochemistry technique is used in the search for cell or tissue antigens that range from amino acids and proteins to infectious agents and specific cellular populations. The technique comprises two phases: (1) slides preparation and stages involved for the reaction; (2) interpretation and quantification of the obtained expression. Immunohistochemistry is an important tool for scientific research and also a complementary technique for the elucidation of differential diagnoses which are not determinable by conventional analysis with hematoxylin and eosin. In the last couple of decades there has been an exponential increase in publications on immunohistochemistry and immunocytochemistry techniques. This review covers the immunohistochemistry technique; its history, applications, importance, limitations, difficulties, problems and some aspects related to results interpretation and quantification. Future developments on the immunohistochemistry technique and its expression quantification should not be disseminated in two languages—that of the pathologist and another of clinician or surgeon. The scientific, diagnostic and prognostic applications of this methodology must be explored in a bid to benefit of patient. In order to achieve this goal a collaboration and pooling of knowledge from both of these valuable medical areas is vital PMID:20212918
Fernández-Ruiz, Javier; Sagredo, Onintza; Pazos, M Ruth; García, Concepción; Pertwee, Roger; Mechoulam, Raphael; Martínez-Orgado, José
Cannabidiol (CBD) is a phytocannabinoid with therapeutic properties for numerous disorders exerted through molecular mechanisms that are yet to be completely identified. CBD acts in some experimental models as an anti-inflammatory, anticonvulsant, anti-oxidant, anti-emetic, anxiolytic and antipsychotic agent, and is therefore a potential medicine for the treatment of neuroinflammation, epilepsy, oxidative injury, vomiting and nausea, anxiety and schizophrenia, respectively. The neuroprotective potential of CBD, based on the combination of its anti-inflammatory and anti-oxidant properties, is of particular interest and is presently under intense preclinical research in numerous neurodegenerative disorders. In fact, CBD combined with Δ9-tetrahydrocannabinol is already under clinical evaluation in patients with Huntington's disease to determine its potential as a disease-modifying therapy. The neuroprotective properties of CBD do not appear to be exerted by the activation of key targets within the endocannabinoid system for plant-derived cannabinoids like Δ9-tetrahydrocannabinol, i.e. CB1 and CB2 receptors, as CBD has negligible activity at these cannabinoid receptors, although certain activity at the CB2 receptor has been documented in specific pathological conditions (i.e. damage of immature brain). Within the endocannabinoid system, CBD has been shown to have an inhibitory effect on the inactivation of endocannabinoids (i.e. inhibition of FAAH enzyme), thereby enhancing the action of these endogenous molecules on cannabinoid receptors, which is also noted in certain pathological conditions. CBD acts not only through the endocannabinoid system, but also causes direct or indirect activation of metabotropic receptors for serotonin or adenosine, and can target nuclear receptors of the PPAR family and also ion channels. PMID:22625422
Fernández-Ruiz, Javier; Sagredo, Onintza; Pazos, M Ruth; García, Concepción; Pertwee, Roger; Mechoulam, Raphael; Martínez-Orgado, José
Cannabidiol (CBD) is a phytocannabinoid with therapeutic properties for numerous disorders exerted through molecular mechanisms that are yet to be completely identified. CBD acts in some experimental models as an anti-inflammatory, anticonvulsant, anti-oxidant, anti-emetic, anxiolytic and antipsychotic agent, and is therefore a potential medicine for the treatment of neuroinflammation, epilepsy, oxidative injury, vomiting and nausea, anxiety and schizophrenia, respectively. The neuroprotective potential of CBD, based on the combination of its anti-inflammatory and anti-oxidant properties, is of particular interest and is presently under intense preclinical research in numerous neurodegenerative disorders. In fact, CBD combined with Δ(9)-tetrahydrocannabinol is already under clinical evaluation in patients with Huntington's disease to determine its potential as a disease-modifying therapy. The neuroprotective properties of CBD do not appear to be exerted by the activation of key targets within the endocannabinoid system for plant-derived cannabinoids like Δ(9)-tetrahydrocannabinol, i.e. CB(1) and CB(2) receptors, as CBD has negligible activity at these cannabinoid receptors, although certain activity at the CB(2) receptor has been documented in specific pathological conditions (i.e. damage of immature brain). Within the endocannabinoid system, CBD has been shown to have an inhibitory effect on the inactivation of endocannabinoids (i.e. inhibition of FAAH enzyme), thereby enhancing the action of these endogenous molecules on cannabinoid receptors, which is also noted in certain pathological conditions. CBD acts not only through the endocannabinoid system, but also causes direct or indirect activation of metabotropic receptors for serotonin or adenosine, and can target nuclear receptors of the PPAR family and also ion channels. PMID:22625422
Slatter, D H; Edwards, M E; Hawkins, C D; Wilcox, G E
A postal survey of cattle producers throughout Australia was conducted to obtain information concerning the occurrence, signs and treatment of infectious bovine keratocojunctivitis, animals breeds, animal numbers and types, environmental conditions under which the animals were kept and management routines and systems of the animals (Slatter et al 1982). The most common clinical signs reported were ocular discharge (43.9%), corneal opacity (9.9%), or both (46.1%). The majority of respondents (54.8%) indicated duration of infections of at least 3 weeks. The condition was predominantly unilateral (74.7%) but 22.3% of respondents reported an equal occurrence of the condition unilaterally and bilaterally. The most frequently used drugs were homidium bromide (26.7%), oxytetracycline hydrochloride (22.8%), chloramphenicol derivatives (13.7%) and penicillin derivatives (13.5%). However, described treatment regimes indicated that therapeutic levels of antibiotics would not be maintained in the eyes of treated animals. Producers considered that 75% of affected animals showed reduced rates of weight gain, and 64% indicated they were more difficult to handle. An approximate figure of +22,000,000 was determined for loss of national production due to the disease, based on producers' estimates. In addition, a further cost of +1,566,500 was estimated for the labour involved in current treatment regimes. Beef and dairy producers spent different amounts on medications and treated for different durations. The economic significance of the disease justifies further studies on production losses due to the disease and cost effective methods of treatment. PMID:7159309
Del Poeta, M; Schell, W A; Perfect, J R
The in vitro activity of the new antifungal drug pneumocandin L-743,872 against 55 isolates of clinically important molds was examined by an adapted macrobroth dilution method for yeasts. Pneumocandin L-743,872 exhibited in vitro antifungal activity against Alternaria sp., Aspergillus flavus, Aspergillus fumigatus, Curvularia lunata, Exophiala jeanselmei, Fonsecaea pedrosoi, Paecilomyces variotii, and Scedosporium apiospermum. The drug appeared to lack significant in vitro inhibitory activity against Fusarium oxysporum, Fusarium solani, Rhizopus arrhizus, Paecilomyces lilacinus, and Scedosporium prolificans. PMID:9257774
Szücs-Farkas, Z; Vock, P
From conventional radiography to cross-sectional imaging methods, modern radiology offers a wide range of diagnostic tools for investigating patients with fever. To achieve the best results and to yield a correct diagnosis, the radiologist must tailor the diagnostic protocol individually for every patient. The decision on the most suitable imaging method, and the type and timing of contrast media strongly depends on the suspected diagnosis. Based on patient history and laboratory data, some modalities may be contraindicated or the patient may need a premedication. The authors give a short overview of diagnostic strategies in evaluating the most important causes of fever and point to the need of discussion and co-operation between clinicians and radiologists. PMID:17048182
Dhillon, Mandeep Sing; Bali, Kamal; Prabhakar, Sharad
Summary Mechanoreceptors in an intact Anterior Cruciate Ligament (ACL) contribute towards functional stability of the knee joint. Injury to the ACL not only causes mechanical instability, but also leads to a disturbance in the neuromuscular control of the injured knee due to loss or damage to mechanoreceptors. ACL reconstruction restores proprioceptive potential of the knee to some extent, but the results vary. Although the remnant ACL contains residual mechanoreceptors, the number and functionality of these receptors is dependent, to some extent, on the physical characteristics of the remnant and duration of injury. Remnants, especially that adherent to the PCL, may actually act as a possible source of reinnervation of the graft. These remnants are worth preserving during ACL reconstruction and can play an important role in restoration of proprioception of knee following ACL reconstruction. PMID:23738272
Leary, James F.; Szaniszlo, Peter; Prow, Tarl W.; Reece, Lisa M.; Wang, Nan; Asmuth, David M.
be about 100 times more sensitive than they are now to be able to do many biologically and biomedically meaningful experiments and clinical tests.
Mehrle, Andreas H.; Freysinger, Wolfgang; Kikinis, Ron; Gunkel, Andreas; Kral, Florian
The graphical representation of three-dimensional data obtained from tomographic imaging has been the central problem since this technology is available. Neither the representation as a set of two-dimensional slices nor the 2D projection of three-dimensional models yields satisfactory results. In this paper a way is outlined which permits the investigation of volumetric clinical data obtained from standard CT, MR, PET, SPECT or experimental very high resolution CT-scanners in a three dimensional environment within a few worksteps. Volumetric datasets are converted into surface data (segmentation process) using the 3D-Slicer software tool and saved as .vtk files and exported as a collection of primitives in any common file format (.iv, .pfb). Subsequently this files can be displayed and manipulated in the CAVE virtual reality center. The CAVE is a multiuser walkable virtual room consisting of several walls on which stereoscopic images are projected by rear panel beamers. Adequate tracking of the head position and separate image calculation for each eye yields a vivid impression for one or several users. With the use of a seperately tracked 6D joystick manipulations such as rotation, translation, zooming, decomposition or highlighting can be done intuitively. The usage of the CAVE technology opens new possibilities especially in surgical training ("hands-on-effect") and as an educational tool (availability of pathological data). Unlike concurring technologies the CAVE permits a walk-through into the virtual scene but preserves enough physical perception to allow interaction between multiple users, e.g. gestures and movements. By training in a virtual environment on one hand the learning process of students in complex anatomic findings may be improved considerably and on the other hand unaccustomed views such as the one through a microscope or endoscope can be trained in advance. The availability of low-cost PC based CAVE-like systems and the rapidly decreasing price
Taliercio, Jonathan J.; Schold, Jesse D.; Simon, James F.; Arrigain, Susana; Tang, Anne; Saab, Georges; Nally, Joseph V.; Navaneethan, Sankar D.
Background Elevated total serum alkaline phosphatase (ALP) levels have been associated with mortality in the general population and in dialysis patients. Study Design Retrospective cohort study. Setting & Participants 28,678 patients with chronic kidney disease (CKD) stages 3 and 4 (estimated glomerular filtration rate [eGFR], 15–59 ml/min/1.73 m2) were identified using the Cleveland Clinic Chronic Kidney Disease Registry. CKD was defined as two eGFR values <60 ml/min/1.73 m2 drawn >90 days apart using the Chronic Kidney Disease Epidemiology Collaboration creatinine equation. Predictor ALP levels measured using the calorimetric assay was examined as quartiles (quartile 1, <66 U/L; Q2, 66–81 U/L; Q3, 82–101 U/L; and Q4, ≥102 U/L) and as a continuous measure. Outcomes & Measurements All-cause mortality and ESRD were ascertained using the Social Security Death Index and US Renal Data System. Results After a median follow up of 2.2 years, 588 patients progressed to ESRD and 4,755 died. There was a graded increase in the risk for mortality with higher ALP quartiles (Q2, Q3, Q4) when compared to the reference quartile (Q1) after adjusting for demographics, comorbid conditions, use of relevant medications and liver function tests. The highest quartile of ALP was associated with a hazard ratio for ESRD of 1.38 (95% CI, 1.09–1.76). Each 1-standard deviation (42.7 U/L) higher ALP level was associated with 15% (95% CI, 1.09–1.22) and 16% (95% CI, 1.14–1.18) increased risk of ESRD and mortality respectively. Limitations Single center observational study, lack complete data including PTH for all study participants and attrition bias. Conclusions Higher serum ALP levels in CKD stages 3–4 were independently associated with all-cause mortality and ESRD. PMID:23769134
Zammarchi, Lorenzo; Stella, Giulia; Mantella, Antonia; Bartolozzi, Dario; Tappe, Dennis; Günther, Stephan; Oestereich, Lisa; Cadar, Daniel; Muñoz-Fontela, César; Bartoloni, Alessandro; Schmidt-Chanasit, Jonas
We report the first two cases of laboratory confirmed Zika virus (ZIKV) infections imported into Italy from French Polynesia. Both patients presented with low grade fever, malaise, conjunctivitis, myalgia, arthralgia, ankle oedema, and axillary and inguinal lymphadenopathy. One patient showed leukopenia with relative monocytosis and thrombocytopenia. The diagnosis was based on ZIKV seroconversion in both cases and on ZIKV RNA detection in one patient from acute serum sample. Sera from both patients exhibited cross-reactivity with dengue virus antigens. Our immunological analysis demonstrated that recovery from ZIKV infection is associated with restoration of normal numbers of immune cells in the periphery as well as with normal function of antigen-presenting cells. ZIKV is an emerging arbovirus, which has recently spread extensively in tourist destinations on several West Pacific islands. Returning viremic travelers may ignite autochthonous infections in countries like Italy, which are infested by Aedes albopictus, a suitable vector for ZIKV. The role of clinicians is crucial and includes early diagnosis and timely notification of public health authorities in order to quickly implement adequate focal vector control measurements. PMID:25600600
Bhagavath, P; Nayak, B S; Monteiro, N Pf; Kumar, G P
Kidneys are the organs that remove the waste products of the metabolic activities. A smooth blood flow to the kidneys is essential to maintain their function. Abnormalities of the renal vasculature may result not only in impairing the renal function but can lead to conditions like varicocele. During an autopsy of an adult male, we observed renal vascular variations. The left renal vein had a retro-aortic course before its termination into the inferior vena cava. It was joined with the inferior vena cava at the level of inferior mesenteric artery with an acute angle. The left testicular vein joined the left renal vein with an acute angle. The right kidney was supplied by two renal arteries. The knowledge about retro-aortic course of the left renal vein may be important during renal transplantation. The oblique course of left renal vein and the termination of left testicular vein into it with an acute angle may increase the chances of left sided varicocele. PMID:27423291
Evaluation of the renal function is fundamental for the diagnosis and treatment of kidney diseases. It is also important for adjustment of the doses of drugs that are excreted by the kidney. The incidence of contrast-induced nephropathy is high in subjects with a low GFR. Assessment of the renal function is required prior to contrast medium injections. Renal inulin clearance with continuous venous injection is the gold standard for measuring GFR. However, the method is time-consuming. The recent Japanese CKD guide and KDIGO guidelines for CKD management recommended the use of the estimated GFR based on serum creatinine (eGFRcreat) or serum cystatin C (eGFRcys). Because the serum creatinine level is affected by the muscle mass, eGFRcreat is under- or overestimated in subjects with a high or low muscle mass, respectively. The serum cystatin C concentration is less influenced by the muscle mass. Assessment of the renal function by eGFRcys may be useful in subjects with a low or high muscle mass. Recently, it was reported that the association between eGFRcys and the risk of all-cause mortality was much closer compared with eGFRcreat. eGFRcys may be useful for detecting a high risk of complications in a general population and in subjects with CKD. PMID:26529980
Howell, Katherine B; Harvey, A Simon; Archer, John S
The term epileptic encephalopathy (EE) denotes a process by which epileptic activity adversely affects brain function over and above the underlying etiology. Underlying mechanisms are poorly understood, but recent studies demonstrate that seizures and interictal epileptiform discharges can disrupt distributed neural networks that underpin cognitive functions, both temporarily and permanently. EE is just one of a number of factors that can affect development in epilepsy. The presence and relative contribution of EE to cognitive impairment is often difficult to separate from that of the underlying etiology or even effects of antiepileptic medication (AEM). This difficulty has led to the increasing use of the term EE to encapsulate "severe" epileptic syndromes, or etiologies associated with severe epilepsy and intellectual disability (ID), regardless of evidence that the epileptic process has impacted cognition. The use of the term EE in the literature to describe both the process of cognitive impairment by epileptic activity and as a category for severe epilepsy syndromes is creating confusion. We propose that use of the term EE be restricted to the central concept of a pervasive epileptic process disrupting development, and that the use of EE as a classifier be avoided. A different term is needed to encapsulate the broad and heterogenous group of patients with severe epilepsy and ID, for which the mechanisms may be unknown but are often closely related to the underlying genetic, metabolic, or structural etiology. An improved understanding of the mechanisms by which EE develops is of critical importance, potentially leading to identification of biomarkers for early detection and treatment. PMID:26778176
Schüpfer, G; Gfrörer, R; Schleppers, A
In only a few contexts is the need for substantial learning more pronounced than in health care. For a health care provider, the ability to learn is essential in a changing environment. Although individual humans are programmed to learn naturally, organisations are not. Learning that is limited to individual professions and traditional approaches to continuing medical education is not sufficient to bring about substantial changes in the learning capacity of an institution. Also, organisational learning is an important issue for anaesthesia departments. Future success of an organisation often depends on new capabilities and competencies. Organisational learning is the capacity or processes within an organisation to maintain or improve performance based on experience. Learning is seen as a system-level phenomenon as it stays in the organisation regardless of the players involved. Experience from other industries shows that learning strategies tend to focus on single loop learning, with relatively little double loop learning and virtually no meta-learning or non-learning. The emphasis on team delivery of health care reinforces the need for team learning. Learning organisations make learning an intrinsic part of their organisations and are a place where people continually learn how to learn together. Organisational learning practice can help to improve existing skills and competencies and to change outdated assumptions, procedures and structures. So far, learning theory has been ignored in medicine, due to a wide variety of complex political, economic, social, organisational culture and medical factors that prevent innovation and resist change. The organisational culture is central to every stage of the learning process. Learning organisations move beyond simple employee training into organisational problem solving, innovation and learning. Therefore, teamwork and leadership are necessary. Successful organisations change the competencies of individuals, the systems
Dyatlov, I A; Mironov, A Yu; Shepelin, A P; Aleshkin, V A
The import substitution becomes one of the strategic tasks of national economy as a result of prolongation of economic sanctions concerning the Russian Federation of part of the USA, EU countries, Japan and number of other countries. It is not proper to be limited in import substitution only by goods because in conditions ofsanctions when access toforeign technologies is complicated Russia is needed to substitute foreign technologies by national designs in faster manner One of directions of effective import substitution is localization of production of laboratory equipment and consumables for clinical and sanitary microbiology on the territory ofthe Russian Federation and countries of Customs union. In Russia, in the field ofdiagnostic of dangerous and socially significant infections, all components for import substitution to implement gene diagnostic, immune diagnostic. bio-sensory and biochip approaches, isolation and storage of live microbial cultures, implementation of high-tech methods of diagnostic are available. At the same time, national diagnostic instrument-making industry for microbiology is factually absent. The few devices of national production more than on 50% consist of import components. The microbiological laboratories are to be equipped only with import devices of open type for applying national components. The most perspective national designs to be implemented are multiplex polimerase chain reaction test-systems and biochips on the basis of national plotters and readers. The modern development of diagnostic equipment and diagnostic instruments requires supplement of national collections of bacterial and viral pathogens and working-through of organizational schemes of supplying collections with strains. The presented data concerning justification of nomenclature of laboratory equipment and consumables permits to satisfy in fill scope the needs of clinical and sanitary microbiology in devices, growth mediums, consumables of national production
Lee, Chang-Ro; Lee, Jung Hun; Park, Kwang Seung; Jeong, Byeong Chul; Lee, Sang Hee
The increase of methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant Enterococcus (VRE) poses a worldwide and serious health threat. Although new antibiotics, such as daptomycin and linezolid, have been developed for the treatment of infections of Gram-positive pathogens, the emergence of daptomycin-resistant and linezolid-resistant strains during therapy has now increased clinical treatment failures. In the past few years, studies using quantitative proteomic methods have provided a considerable progress in understanding antibiotic resistance mechanisms. In this review, to understand the resistance mechanisms to four clinically important antibiotics (methicillin, vancomycin, linezolid, and daptomycin) used in the treatment of Gram-positive pathogens, we summarize recent advances in studies on resistance mechanisms using quantitative proteomic methods, and also examine proteins playing an important role in the bacterial mechanisms of resistance to the four antibiotics. Proteomic researches can identify proteins whose expression levels are changed in the resistance mechanism to only one antibiotic, such as LiaH in daptomycin resistance and PrsA in vancomycin resistance, and many proteins simultaneously involved in resistance mechanisms to various antibiotics. Most of resistance-related proteins, which are simultaneously associated with resistance mechanisms to several antibiotics, play important roles in regulating bacterial envelope biogenesis, or compensating for the fitness cost of antibiotic resistance. Therefore, proteomic data confirm that antibiotic resistance requires the fitness cost and the bacterial envelope is an important factor in antibiotic resistance. PMID:26322035
Li, L; Kalaga, R; Paul, S
Chemical catalysis, an effector mechanism utilized by fully assembled antibodies, can also be mediated by the isolated antibody subunits. Because trace amounts of free light chains (L chains) are present in IgG preparations, a detailed study was undertaken to identify the constituents responsible for the polyreactive proteolytic activity of IgG purified from human sera, determined as the extent of cleavage of the model peptide substrate Pro-Phe-Arg-methylcoumarinamide. Two proteolytic species with approximate mass of 50 kD and 150 kD were separated by repetitive gel filtration in a denaturing solvent (6 m guanidine hydrochloride). The activity of the renatured 50-kD fraction (in fluorescence units/μg protein) was more than 45-fold greater than of the 150-kD fraction. Both fractions lost the activity following immunoadsorption on immobilized anti-IgG antibody. Fab fragments prepared from the 150-kD IgG fraction retained the activity. Reducing and non-reducing SDS-electrophoresis suggested the 50-kD fraction isolated from the IgG preparations to be a mixture of heavy chain (H chain) monomers and disulphide bonded L chain dimers. Electrophoretically homogeneous monomers of 50-kD H chains and 25-kD L chains were prepared by gel filtration of reduced and alkylated IgG from seven human subjects. Each of the alkylated L chain preparations displayed the proteolytic activity. The activity in alkylated H chains was undetectable or only marginally greater than the background values. L chain dimers appear to be the major species responsible for the polyreactive proteolytic activity of serum IgG preparations, with a smaller contribution furnished by tetrameric IgG. PMID:10792374
Munoz-Sanjuan, Ignacio; Bates, Gillian P.
Huntington disease (HD) is a dominantly inherited neurodegenerative disorder that results from expansion of the polyglutamine repeat in the huntingtin (HTT) gene. There are currently no effective treatments for this devastating disease. Given its monogenic nature, disease modification therapies for HD should be theoretically feasible. Currently, pharmacological therapies aimed at disease modification by altering levels of HTT protein are in late-stage preclinical development. Here, we review current efforts to develop new treatments for HD based on our current understanding of HTT function and the main pathological mechanisms. We emphasize the need to enhance translational efforts and highlight the importance of aligning the clinical and basic research communities to validate existing hypotheses in clinical studies. Human and animal therapeutic trials are presented with an emphasis on cellular and molecular mechanisms relevant to disease progression. PMID:21285520
Beganović, Jasna; Kos, Blaženka; Leboš Pavunc, Andreja; Uroić, Ksenija; Džidara, Petra; Šušković, Jagoda
The aim of this research was to investigate the potential of previously defined probiotic strain Lactobacillus helveticus M92 as functional starter culture for fermented dairy products. Therefore, proteolytic activity of L. helveticus M92 was investigated and compared with those of different representatives of probiotic and starter culture strains. Cluster analysis of AFLP fingerprints showed a difference of L. helveticus M92 compared to five other L. helveticus strains, but the percentage of similarity confirmed the identification on species level. Casein hydrolysis by L. helveticus M92 was monitored by agar-well diffusion test, SDS-PAGE and Anson's method. L. helveticus M92 exhibited the highest proteolytic activity among tested probiotic and starter cultures strains with the fastest acidification rate and the highest pH decrease after overnight incubation in skim milk. The presence of prtH2 gene was confirmed by PCR amplification with specific primers, while PCR product was not obtained after amplification with primers specific to prtH. Furthermore, SDS-PAGE LC-MS/MS analysis of insoluble proteome of L. helveticus M92 enabled identification of several proteins involved in proteolytic system of L. helveticus such as protease PrtM as well as proteins involved in Opp peptide transport system and the intracellular peptidases PepE, PepN, and PepQ. PMID:23454496
Igarashi, Yoshinobu; Heureux, Emily; Doctor, Kutbuddin S; Talwar, Priti; Gramatikova, Svetlana; Gramatikoff, Kosi; Zhang, Ying; Blinov, Michael; Ibragimova, Salmaz S; Boyd, Sarah; Ratnikov, Boris; Cieplak, Piotr; Godzik, Adam; Smith, Jeffrey W; Osterman, Andrei L; Eroshkin, Alexey M
The Proteolysis MAP (PMAP, http://www.proteolysis.org) is a user-friendly website intended to aid the scientific community in reasoning about proteolytic networks and pathways. PMAP is comprised of five databases, linked together in one environment. The foundation databases, ProteaseDB and SubstrateDB, are driven by an automated annotation pipeline that generates dynamic 'Molecule Pages', rich in molecular information. PMAP also contains two community annotated databases focused on function; CutDB has information on more than 5000 proteolytic events, and ProfileDB is dedicated to information of the substrate recognition specificity of proteases. Together, the content within these four databases will ultimately feed PathwayDB, which will be comprised of known pathways whose function can be dynamically modeled in a rule-based manner, and hypothetical pathways suggested by semi-automated culling of the literature. A Protease Toolkit is also available for the analysis of proteases and proteolysis. Here, we describe how the databases of PMAP can be used to foster understanding of proteolytic pathways, and equally as significant, to reason about proteolysis. PMID:18842634
Medintz, Igor L.; Clapp, Aaron R.; Brunel, Florence M.; Goldman, Ellen R.; Chang, Eddie L.; Dawson, Phillip E.; Mattoussi, Hedi
We have previously assembled QD-based fluorescence resonance energy transfer (FRET) sensors specific for the sugar nutrient maltose and the explosive TNT. These sensors utilize several inherent benefits of QDs as FRET donors. In this report, we show that QD-FRET based sensors can also function in the monitoring of proteolytic enzyme activity. We utilize a QD with multiple dye-labeled proteins attached to the surface as a substrate for a prototypical protease. We then demonstrate how this strategy can be extended to detect protease activity by utilizing a dye-labeled peptide attached to the QD as a proteolytic substrate. Self-assembly of the peptide-dye on the QD brings the dye in close proximity to the QD and result in efficient FRET. Addition of a proteolytic enzyme that specifically recognizes and cleaves the peptide alters the FRET signature of the sensor in a concentration-dependent manner. Both qualitative and quantitative data can be derived from these sensors. The potential benefits of this type of QD sensing strategy are discussed.
Bui, Hung M.; Enis, David; Robciuc, Marius R.; Nurmi, Harri J.; Cohen, Jennifer; Chen, Mei; Yang, Yiqing; Dhillon, Veerpal; Johnson, Kathy; Zhang, Hong; Kirkpatrick, Robert; Traxler, Elizabeth; Alitalo, Kari
Lymphangiogenesis is supported by 2 homologous VEGFR3 ligands, VEGFC and VEGFD. VEGFC is required for lymphatic development, while VEGFD is not. VEGFC and VEGFD are proteolytically cleaved after cell secretion in vitro, and recent studies have implicated the protease a disintegrin and metalloproteinase with thrombospondin motifs 3 (ADAMTS3) and the secreted factor collagen and calcium binding EGF domains 1 (CCBE1) in this process. It is not well understood how ligand proteolysis is controlled at the molecular level or how this process regulates lymphangiogenesis, because these complex molecular interactions have been difficult to follow ex vivo and test in vivo. Here, we have developed and used biochemical and cellular tools to demonstrate that an ADAMTS3-CCBE1 complex can form independently of VEGFR3 and is required to convert VEGFC, but not VEGFD, into an active ligand. Consistent with these ex vivo findings, mouse genetic studies revealed that ADAMTS3 is required for lymphatic development in a manner that is identical to the requirement of VEGFC and CCBE1 for lymphatic development. Moreover, CCBE1 was required for in vivo lymphangiogenesis stimulated by VEGFC but not VEGFD. Together, these studies reveal that lymphangiogenesis is regulated by two distinct proteolytic mechanisms of ligand activation: one in which VEGFC activation by ADAMTS3 and CCBE1 spatially and temporally patterns developing lymphatics, and one in which VEGFD activation by a distinct proteolytic mechanism may be stimulated during inflammatory lymphatic growth. PMID:27159393
Igarashi, Yoshinobu; Heureux, Emily; Doctor, Kutbuddin S.; Talwar, Priti; Gramatikova, Svetlana; Gramatikoff, Kosi; Zhang, Ying; Blinov, Michael; Ibragimova, Salmaz S.; Boyd, Sarah; Ratnikov, Boris; Cieplak, Piotr; Godzik, Adam; Smith, Jeffrey W.; Osterman, Andrei L.; Eroshkin, Alexey M.
The Proteolysis MAP (PMAP, http://www.proteolysis.org) is a user-friendly website intended to aid the scientific community in reasoning about proteolytic networks and pathways. PMAP is comprised of five databases, linked together in one environment. The foundation databases, ProteaseDB and SubstrateDB, are driven by an automated annotation pipeline that generates dynamic ‘Molecule Pages’, rich in molecular information. PMAP also contains two community annotated databases focused on function; CutDB has information on more than 5000 proteolytic events, and ProfileDB is dedicated to information of the substrate recognition specificity of proteases. Together, the content within these four databases will ultimately feed PathwayDB, which will be comprised of known pathways whose function can be dynamically modeled in a rule-based manner, and hypothetical pathways suggested by semi-automated culling of the literature. A Protease Toolkit is also available for the analysis of proteases and proteolysis. Here, we describe how the databases of PMAP can be used to foster understanding of proteolytic pathways, and equally as significant, to reason about proteolysis. PMID:18842634
Sinha, Siddhartha S; Cameron, Jody; Brooks, James C; Leifer, Cynthia A
TLR9 is an innate immune receptor important for recognizing DNA of host and foreign origin. A mechanism proposed to prevent excessive response to host DNA is the requirement for proteolytic cleavage of TLR9 in endosomes to generate a mature form of the receptor (TLR9(471-1032)). We previously described another cleavage event in the juxtamembrane region of the ectodomain that generated a dominant-negative form of TLR9. Thus, there are at least two independent cleavage events that regulate TLR9. In this study, we investigated whether an N-terminal fragment of TLR9 could be responsible for regulation of the mature or negative-regulatory form. We show that TLR9(471-1032), corresponding to the proteolytically cleaved form, does not function on its own. Furthermore, activity is not rescued by coexpression of the N-terminal fragment (TLR9(1-440)), inclusion of the hinge region (TLR9(441-1032)), or overexpression of UNC93B1, the last of which is critical for trafficking and cleavage of TLR9. TLR9(1-440) coimmunoprecipitates with full-length TLR9 and TLR9(471-1032) but does not rescue the native glycosylation pattern; thus, inappropriate trafficking likely explains why TLR9(471-1032) is nonfunctional. Lastly, we show that TLR9(471-1032) is also a dominant-negative regulator of TLR9 signaling. Together, these data provide a new perspective on the complexity of TLR9 regulation by proteolytic cleavage and offer potential ways to inhibit activity through this receptor, which may dampen autoimmune inflammation. PMID:27421483
Alfakry, Hatem; Malle, Ernst; Koyani, Chintan N; Pussinen, Pirkko J; Sorsa, Timo
Cardiovascular diseases are chronic inflammatory diseases that affect a large segment of society. Coronary heart disease (CHD), the most common cardiovascular disease, progresses over several years and affects millions of people worldwide. Chronic infections may contribute to the systemic inflammation and enhance the risk for CHD. Periodontitis is one of the most common chronic infections that affects up to 50% of the adult population. Under inflammatory conditions the activation of endogenous degradation pathways mediated by immune responses leads to the release of destructive cellular molecules from both resident and immigrant cells. Matrix metalloproteinases (MMPs) and their regulators can activate each other and play an important role in immune response via degrading extracellular matrix components and modulating cytokines and chemokines. The action of MMPs is required for immigrant cell recruitment at the site of inflammation. Stimulated neutrophils represent the major pathogen-fighting immune cells that upregulate expression of several proteinases and oxidative enzymes, which can degrade extracellular matrix components (e.g. MMP-8, MMP-9 and neutrophil elastase). The activity of MMPs is regulated by endogenous inhibitors and/or candidate MMPs (e.g. MMP-7). The balance between MMPs and their inhibitors is thought to mirror the proteolytic burden. Thus, neutrophil-derived biomarkers, including myeloperoxidase, may activate proteolytic destructive cascades that are involved in subsequent immune-pathological events associated with both periodontitis and CHD. Here, we review the existing studies on the contribution of MMPs and their regulators to the infection-related pathology. Also, we discuss the possible proteolytic involvement and role of neutrophil-derived enzymes as an etiological link between chronic periodontitis and CHD. PMID:26608308
Pepper, M S; Vassalli, J D; Wilks, J W; Schweigerer, L; Orci, L; Montesano, R
A tightly controlled increase in extracellular proteolysis, restricted both in time and space, is an important component of the angiogenic process, while anti-proteolysis is effective in inhibiting angiogenesis. By focussing on the plasminogen activator (PA)-plasmin system, the objective of the present studies was to assess whether previously described inhibitors of angiogenesis modify bovine microvascular endothelial cell proteolytic properties. We demonstrate that although synthetic angiostatic steroids (U-24067 and U-42129), heparin, suramin, interferon alpha-2a, and retinoic acid are all inhibitors of in vitro angiogenesis, each of these agents has distinct effects on the plasminogen-dependent proteolytic system. Specifically, angiostatic steroids and interferon alpha-2a reduce urokinase-type PA (u-PA) and PA inhibitor-1 activity, while heparin and retinoic acid increase u-PA activity. Suramin reduces cell-associated u-PA activity and greatly increases PAI-1 production at doses which induce monolayer disruption. These findings demonstrate that a spectrum of alterations in extracellular proteolysis is associated with anti-angiogenesis, and that anti-angiogenesis and anti-proteolysis are not necessarily correlated. A reduction in extracellular proteolysis would be expected to reduce invasion, whereas an increase in proteolysis might modulate the activity of inhibitory cytokines, which in turn could reduce endothelial cell proliferation and migration and inhibit angiogenesis. The spectrum of effects on different elements of the PA system observed in response to the agents assessed suggests that the role of modulations in extracellular proteolytic activity in anti-angiogenesis is likely to be varied and complex. PMID:7525617
Higgins, H.M.; Dryden, I.L.; Green, M.J.
The two key aims of this research were: (i) to conduct a probabilistic elicitation to quantify the variation in veterinarians’ beliefs regarding the efficacy of systemic antibiotics when used as an adjunct to intra-mammary dry cow therapy and (ii) to investigate (in a Bayesian statistical framework) the strength of future research evidence required (in theory) to change the beliefs of practising veterinary surgeons regarding the efficacy of systemic antibiotics, given their current clinical beliefs. The beliefs of 24 veterinarians in 5 practices in England were quantified as probability density functions. Classic multidimensional scaling revealed major variations in beliefs both within and between veterinary practices which included: confident optimism, confident pessimism and considerable uncertainty. Of the 9 veterinarians interviewed holding further cattle qualifications, 6 shared a confidently pessimistic belief in the efficacy of systemic therapy and whilst 2 were more optimistic, they were also more uncertain. A Bayesian model based on a synthetic dataset from a randomised clinical trial (showing no benefit with systemic therapy) predicted how each of the 24 veterinarians’ prior beliefs would alter as the size of the clinical trial increased, assuming that practitioners would update their beliefs rationally in accordance with Bayes’ theorem. The study demonstrated the usefulness of probabilistic elicitation for evaluating the diversity and strength of practitioners’ beliefs. The major variation in beliefs observed raises interest in the veterinary profession's approach to prescribing essential medicines. Results illustrate the importance of eliciting prior beliefs when designing clinical trials in order to increase the chance that trial data are of sufficient strength to alter the clinical beliefs of practitioners and do not merely serve to satisfy researchers. PMID:22336321
McDonald, L C; Fune, J; Gaido, L B; Weinstein, M P; Reimer, L G; Flynn, T M; Wilson, M L; Mirrett, S; Reller, L B
Two recent multicenter blood culture studies found that BacT/Alert FAN (FAN) bottles (Organon Teknika, Durham, N.C.) had increased yields in detecting bacteremia and fungemia compared with standard BacT/Alert (STD) bottles. Because the clinical importance of this increase in microbial recovery is unknown, we performed a retrospective analysis to determine the frequency with which FAN bottles were the sole means of detecting an episode of bacteremia. There were 1,047 positive blood cultures in which both study bottles were adequately filled and the organism isolated was judged to be the cause of sepsis: 240 (23%) were positive only in FAN bottles and 73 (7%) were positive only in STD bottles. Of a total of 664 episodes of bacteremia, 126 (19%) were identified only by FAN bottles and 43 (7%) were identified only by STD bottles (P < 0.0001). Episodes detected only by FAN bottles more often were recurrent events (23 of 126, or 18%) than episodes detected only by STD bottles (2 of 43, or 5%) (P < 0.05) and more commonly occurred in patients receiving theoretically effective antibiotic therapy (33 of 126 [26%] versus 4 of 43 [9%]) (P < 0.05). The medical records for patients with 127 of these episodes (92 FAN bottles only; 35 STD bottles only) were available for review. More than half of both FAN bottle-only (60 of 92, or 65%) and STD bottle-only (20 of 35, or 57%) episodes were judged to be clinically important. We conclude that FAN bottles improve the detection of bacteremia and that the majority of the additional episodes detected are clinically important. The benefits of the greater yield in specific patient populations must be balanced against the higher costs of FAN bottles. PMID:8862581
Orlandelli, Ravely Casarotti; de Almeida, Tiago Tognolli; Alberto, Raiani Nascimento; Polonio, Julio Cesar; Azevedo, João Lúcio; Pamphile, João Alencar
Endophytes are being considered for use in biological control, and the enzymes they secrete might facilitate their initial colonization of internal plant tissues and direct interactions with microbial pathogens. Microbial proteases are also biotechnologically important products employed in bioremediation processes, cosmetics, and the pharmaceutical, photographic and food industries. In the present study, we evaluated antagonism and competitive interactions between 98 fungal endophytes and Alternaria alternata, Colletotrichum sp., Phyllosticta citricarpa and Moniliophthora perniciosa. We also examined the proteolytic activities of endophytes grown in liquid medium and conducted cup plate assays. The results showed that certain strains in the assemblage of P. hispidum endophytes are important sources of antifungal properties, primarily Lasiodiplodia theobromae JF766989, which reduced phytopathogen growth by approximately 54 to 65%. We detected 28 endophytes producing enzymatic halos of up to 16.40 mm in diameter. The results obtained in the present study highlight the proteolytic activity of the endophytes Phoma herbarum JF766995 and Schizophyllum commune JF766994, which presented the highest enzymatic halo diameters under at least one culture condition tested. The increased activities of certain isolates in the presence of rice or soy flour as a substrate (with halos up to 17.67 mm in diameter) suggests that these endophytes have the potential to produce enzymes using agricultural wastes. PMID:26273250
Orlandelli, Ravely Casarotti; de Almeida, Tiago Tognolli; Alberto, Raiani Nascimento; Polonio, Julio Cesar; Azevedo, João Lúcio; Pamphile, João Alencar
Endophytes are being considered for use in biological control, and the enzymes they secrete might facilitate their initial colonization of internal plant tissues and direct interactions with microbial pathogens. Microbial proteases are also biotechnologically important products employed in bioremediation processes, cosmetics, and the pharmaceutical, photographic and food industries. In the present study, we evaluated antagonism and competitive interactions between 98 fungal endophytes and Alternaria alternata, Colletotrichum sp., Phyllosticta citricarpa and Moniliophthora perniciosa. We also examined the proteolytic activities of endophytes grown in liquid medium and conducted cup plate assays. The results showed that certain strains in the assemblage of P. hispidum endophytes are important sources of antifungal properties, primarily Lasiodiplodia theobromae JF766989, which reduced phytopathogen growth by approximately 54 to 65%. We detected 28 endophytes producing enzymatic halos of up to 16.40 mm in diameter. The results obtained in the present study highlight the proteolytic activity of the endophytes Phoma herbarum JF766995 and Schizophyllum commune JF766994, which presented the highest enzymatic halo diameters under at least one culture condition tested. The increased activities of certain isolates in the presence of rice or soy flour as a substrate (with halos up to 17.67 mm in diameter) suggests that these endophytes have the potential to produce enzymes using agricultural wastes. PMID:26273250
McDonald, Craig M; Henricson, Erik K; Abresch, R Ted; Florence, Julaine; Eagle, Michelle; Gappmaier, Eduard; Glanzman, Allan M; Spiegel, Robert; Barth, Jay; Elfring, Gary; Reha, Allen; Peltz, Stuart W
Introduction: An international clinical trial enrolled 174 ambulatory males ≥5 years old with nonsense mutation Duchenne muscular dystrophy (nmDMD). Pretreatment data provide insight into reliability, concurrent validity, and minimal clinically important differences (MCIDs) of the 6-minute walk test (6MWT) and other endpoints. Methods: Screening and baseline evaluations included the 6-minute walk distance (6MWD), timed function tests (TFTs), quantitative strength by myometry, the PedsQL, heart rate–determined energy expenditure index, and other exploratory endpoints. Results: The 6MWT proved feasible and reliable in a multicenter context. Concurrent validity with other endpoints was excellent. The MCID for 6MWD was 28.5 and 31.7 meters based on 2 statistical distribution methods. Conclusions: The ratio of MCID to baseline mean is lower for 6MWD than for other endpoints. The 6MWD is an optimal primary endpoint for Duchenne muscular dystrophy (DMD) clinical trials that are focused therapeutically on preservation of ambulation and slowing of disease progression. Muscle Nerve 48: 357–368, 2013 PMID:23674289
Background Translational research typically aims to identify and functionally validate individual, disease-specific genes. However, reaching this aim is complicated by the involvement of thousands of genes in common diseases, and that many of those genes are pleiotropic, that is, shared by several diseases. Methods We integrated genomic meta-analyses with prospective clinical studies to systematically investigate the pathogenic, diagnostic and therapeutic roles of pleiotropic genes. In a novel approach, we first used pathway analysis of all published genome-wide association studies (GWAS) to find a cell type common to many diseases. Results The analysis showed over-representation of the T helper cell differentiation pathway, which is expressed in T cells. This led us to focus on expression profiling of CD4+ T cells from highly diverse inflammatory and malignant diseases. We found that pleiotropic genes were highly interconnected and formed a pleiotropic module, which was enriched for inflammatory, metabolic and proliferative pathways. The general relevance of this module was supported by highly significant enrichment of genetic variants identified by all GWAS and cancer studies, as well as known diagnostic and therapeutic targets. Prospective clinical studies of multiple sclerosis and allergy showed the importance of both pleiotropic and disease specific modules for clinical stratification. Conclusions In summary, this translational genomics study identified a pleiotropic module, which has key pathogenic, diagnostic and therapeutic roles. PMID:24571673
Na, Young Ju; Chai, Jong-Yil; Jung, Bong-Kwang; Lee, Hyun Jung; Song, Ji Young; Je, Ji Hye; Seo, Ji Hye; Park, Sung Hun; Choi, Ji Seon
While imported falciparum malaria has been increasingly reported in recent years in Korea, clinicians have difficulties in making a clinical diagnosis as well as in having accessibility to effective anti-malarial agents. Here we describe an unusual case of imported falciparum malaria with severe hemolytic anemia lasting over 2 weeks, clinically mimicking a coinfection with babesiosis. A 48-year old Korean man was diagnosed with severe falciparum malaria in France after traveling to the Republic of Benin, West Africa. He received a 1-day course of intravenous artesunate and a 7-day course of Malarone (atovaquone/proguanil) with supportive hemodialysis. Coming back to Korea 5 days after discharge, he was readmitted due to recurrent fever, and further treated with Malarone for 3 days. Both the peripheral blood smears and PCR test were positive for Plasmodium falciparum. However, he had prolonged severe hemolytic anemia (Hb 5.6 g/dl). Therefore, 10 days after the hospitalization, Babesia was considered to be potentially coinfected. A 7-day course of Malarone and azithromycin was empirically started. He became afebrile within 3 days of this babesiosis treatment, and hemolytic anemia profiles began to improve at the completion of the treatment. He has remained stable since his discharge. Unexpectedly, the PCR assays failed to detect DNA of Babesia spp. from blood. In addition, during the retrospective review of the case, the artesunate-induced delayed hemolytic anemia was considered as an alternative cause of the unexplained hemolytic anemia. PMID:25548419
Background Health-related quality of life (QoL) has become a crucial outcome in medical care. However, few studies have assessed physician knowledge of QoL and rate of physicians adopting QoL measures in clinical practice. The present study aimed at assessing the level of knowledge of QoL and the perceived importance of incorporating QoL assessment in clinical practice among physicians of a tertiary level academic hospital in Rome, Italy. Materials and methods A survey study performed through the distribution of a questionnaire assessing knowledge of QoL studies that used the SF-36 scale, participation in studies evaluating QoL as well as knowledge of journals publishing articles on QoL Physicians and residents at the hospital Policlinico Gemelli, Catholic University of Rome. Results Three-hundred nine physicians completed the questionnaire. Thirty-eight percent % reported knowing studies on QoL and using their results in clinical practice or for research purposes; 29% reported knowing the SF-36 questionnaire; 30% stated that at least one study assessing QoL had been conducted in their department. Fourty-six percent % stated that QoL must influence much or very much diagnostic choices and an even higher percentage reported that QoL must influence much or very much therapeutic and palliative strategies (70.8% and 91.3%, respectively). Reported barriers to the use of QoL measures in clinical practice were related to time constraints (8.7%) but also to doubts on methodological issues of QoL (30.7%). The large majority of physicians (94.3%) would have used more expensive drugs if these could improve QoL. Conclusions The present study shows that in a tertiary level academic italian hospital one third of the physicians, reported to know QoL measures and that more than 80% of them would like to use QoL in their daily clinical practice. Future studies are needed to identify the best strategies to implement the use of QoL measures in clinical practice. PMID:20416062
Lowther, Chelsea; Speevak, Marsha; Armour, Christine M.; Goh, Elaine S.; Graham, Gail E.; Li, Chumei; Zeesman, Susan; Nowaczyk, Malgorzata J.M.; Schultz, Lee-Anne; Morra, Antonella; Nicolson, Rob; Bikangaga, Peter; Samdup, Dawa; Zaazou, Mostafa; Boyd, Kerry; Jung, Jack H.; Siu, Victoria; Rajguru, Manjulata; Goobie, Sharan; Tarnopolsky, Mark A.; Prasad, Chitra; Dick, Paul T.; Hussain, Asmaa S.; Walinga, Margreet; Reijenga, Renske G.; Gazzellone, Matthew; Lionel, Anath C.; Marshall, Christian R.; Scherer, Stephen W.; Stavropoulos, Dimitri J.; McCready, Elizabeth; Bassett, Anne S.
Purpose The purpose of the current study was to assess the penetrance of NRXN1 deletions. Methods We compared the prevalence and genomic extent of NRXN1 deletions identified among 19,263 clinically referred cases to that of 15,264 controls. The burden of additional clinically relevant CNVs was used as a proxy to estimate the relative penetrance of NRXN1 deletions. Results We identified 41 (0.21%) previously unreported exonic NRXN1 deletions ascertained for developmental delay/intellectual disability, significantly greater than in controls [OR=8.14 (95% CI 2.91–22.72), p< 0.0001)]. Ten (22.7%) of these had a second clinically relevant CNV. Subjects with a deletion near the 3′ end of NRXN1 were significantly more likely to have a second rare CNV than subjects with a 5′ NRXN1 deletion [OR=7.47 (95% CI 2.36–23.61), p=0.0006]. The prevalence of intronic NRXN1 deletions was not statistically different between cases and controls (p=0.618). The majority (63.2%) of intronic NRXN1 deletion cases had a second rare CNV, a two-fold greater prevalence than for exonic NRXN1 deletion cases (p=0.0035). Conclusions The results support the importance of exons near the 5′ end of NRXN1 in the expression of neurodevelopmental disorders. Intronic NRXN1 deletions do not appear to substantially increase the risk for clinical phenotypes. PMID:27195815
Tryggvesson, Anders; Ståhlberg, Frida M; Mogk, Axel; Zeth, Kornelius; Clarke, Adrian K
The Clp protease is conserved among eubacteria and most eukaryotes, and uses ATP to drive protein substrate unfolding and translocation into a chamber of sequestered proteolytic active sites. In plant chloroplasts and cyanobacteria, the essential constitutive Clp protease consists of the Hsp100/ClpC chaperone partnering a proteolytic core of catalytic ClpP and noncatalytic ClpR subunits. In the present study, we have examined putative determinants conferring the highly specific association between ClpC and the ClpP3/R core from the model cyanobacterium Synechococcus elongatus. Two conserved sequences in the N-terminus of ClpR (tyrosine and proline motifs) and one in the N-terminus of ClpP3 (MPIG motif) were identified as being crucial for the ClpC-ClpP3/R association. These N-terminal domains also influence the stability of the ClpP3/R core complex itself. A unique C-terminal sequence was also found in plant and cyanobacterial ClpC orthologues just downstream of the P-loop region previously shown in Escherichia coli to be important for Hsp100 association to ClpP. This R motif in Synechococcus ClpC confers specificity for the ClpP3/R core and prevents association with E. coli ClpP; its removal from ClpC reverses this core specificity. PMID:22657732
Khan, A. R.; James, M. N.
Proteolytic enzymes are synthesized as inactive precursors, or "zymogens," to prevent unwanted protein degradation, and to enable spatial and temporal regulation of proteolytic activity. Upon sorting or appropriate compartmentalization, zymogen conversion to the active enzyme typically involves limited proteolysis and removal of an "activation segment." The sizes of activation segments range from dipeptide units to independently folding domains comprising more than 100 residues. A common form of the activation segment is an N-terminal extension of the mature enzyme, or "prosegment," that sterically blocks the active site, and thereby prevents binding of substrates. In addition to their inhibitory role, prosegments are frequently important for the folding, stability, and/or intracellular sorting of the zymogen. The mechanisms of conversion to active enzymes are diverse in nature, ranging from enzymatic or nonenzymatic cofactors that trigger activation, to a simple change in pH that results in conversion by an autocatalytic mechanism. Recent X-ray crystallographic studies of zymogens and comparisons with their active counterparts have identified the structural changes that accompany conversion. This review will focus upon the structural basis for inhibition by activation segments, as well as the molecular events that lead to the conversion of zymogens to active enzymes. PMID:9568890
Chambers, R C; Dabbagh, K; McAnulty, R J; Gray, A J; Blanc-Brude, O P; Laurent, G J
Thrombin is a multifunctional serine protease that has a crucial role in blood coagulation. It is also a potent mesenchymal cell mitogen and chemoattractant and might therefore have an important role in the recruitment and local proliferation of mesenchymal cells at sites of tissue injury. We hypothesized that thrombin might also affect the deposition of connective tissue proteins at these sites by directly stimulating fibroblast procollagen production. To address this hypothesis, the effect of thrombin on procollagen production and gene expression by human foetal lung fibroblasts was assessed over 48 h. Thrombin stimulated procollagen production at concentrations of 1 nM and above, with maximal increases of between 60% and 117% at 10 nM thrombin. These effects of thrombin were, at least in part, due to increased steady-state levels of alpha1(I) procollagen mRNA. They could furthermore be reproduced with thrombin receptor-activating peptides for the protease-activated receptor 1 (PAR-1) and were completely abolished when thrombin was rendered proteolytically inactive with the specific inhibitors d-Phe-Pro-ArgCH2Cl and hirudin, indicating that thrombin is mediating these effects via the proteolytic activation of PAR-1. These results suggest that thrombin might influence the deposition of connective tissue proteins during normal wound healing and the development of tissue fibrosis by stimulating fibroblast procollagen production. PMID:9639571
Houston, Simon; Hof, Rebecca; Honeyman, Lisa; Hassler, Julia; Cameron, Caroline E.
Treponema pallidum is a highly invasive pathogen that undergoes rapid dissemination to establish widespread infection. Previous investigations identified the T. pallidum adhesin, pallilysin, as an HEXXH-containing metalloprotease that undergoes autocatalytic cleavage and degrades laminin and fibrinogen. In the current study we characterized pallilysin's active site, activation requirements, cellular location, and fibrin clot degradation capacity through both in vitro assays and heterologous treponemal expression and degradation studies. Site-directed mutagenesis showed the pallilysin HEXXH motif comprises at least part of the active site, as introduction of three independent mutations (AEXXH [H198A], HAXXH [E199A], and HEXXA [H202A]) abolished pallilysin-mediated fibrinogenolysis but did not adversely affect host component binding. Attainment of full pallilysin proteolytic activity was dependent upon autocatalytic cleavage of an N-terminal pro-domain, a process which could not occur in the HEXXH mutants. Pallilysin was shown to possess a thrombin cleavage site within its N-terminal pro-domain, and in vitro studies confirmed cleavage of pallilysin with thrombin generates a truncated pallilysin fragment that has enhanced proteolytic activity, suggesting pallilysin can also exploit the host coagulation process to facilitate protease activation. Opsonophagocytosis assays performed with viable T. pallidum demonstrated pallilysin is a target of opsonic antibodies, consistent with a host component-interacting, surface-exposed cellular location. Wild-type pallilysin, but not the HEXXA mutant, degraded fibrin clots, and similarly heterologous expression of pallilysin in the non-invasive spirochete Treponema phagedenis facilitated fibrin clot degradation. Collectively these results identify pallilysin as a surface-exposed metalloprotease within T. pallidum that possesses an HEXXH active site motif and requires autocatalytic or host-mediated cleavage of a pro-domain to attain
Hecker, Kent G; Adams, Cindy L; Coe, Jason B
Communication skills are considered to be a core clinical skill in veterinary medicine and essential for practice success, including outcomes of care for patients and clients. While veterinary schools include communication skills training in their programs, there is minimal knowledge on how best to assess communication competence throughout the undergraduate program. The purpose of this study was to further our understanding of the reliability, utility, and suitability of a communication skills Objective Structured Clinical Examination (OSCE). Specifically we wanted to (1) identify the greatest source of variability (student, rater, station, and track) within a first-year, four station OSCE using exam scores and scores from videotape review by two trained raters, and (2) determine the effect of different stations on students' communication skills performance. Reliability of the scores from both the exam data and the two expert raters was 0.50 and 0.46 respectively, with the greatest amount of variance attributable to student by station. The percentage of variance due to raters in the exam data was 16.35%, whereas the percentage of variance for the two expert raters was 0%. These results have three important implications. First, the results reinforce the need for communication educators to emphasize that use of communication skills is moderated by the context of the clinical interaction. Second, by increasing rater training the amount of error in the scores due to raters can be reduced and inter-rater reliability increases. Third, the communication assessment method (in this case the OSCE checklist) should be built purposefully, taking into consideration the context of the case. PMID:22951466
Falissard, Bruno; Sapin, Christophe; Loze, Jean-Yves; Landsberg, Wally; Hansen, Karina
To determine the Minimal Clinically Important Difference (MCID) of the Heinrichs-Carpenter Quality of Life Scale (QLS). Data from the "Schizophrenia Trial of Aripiprazole" (STAR) study were used in this analysis. The MCID value of the QLS total score was estimated using the anchor-based method. These findings were substantiated/validated by comparing the MCID estimate to other measurements collected in the study. Half of the patients (49%) showed improvement in Clinical Global Impressions of Severity (CGI-S) during the trial. The estimated MCID of the QLS total score was 5.30 (standard error: 2.60; 95% confidence interval: [0.16; 10.43]; p < 0.05). Patients were divided into two groups: "QLS improvers" (QLS total score increased ≥ six points) and "non-improvers". The QLS improvers had significantly better effectiveness and reported significantly higher levels of preference for their current medications. There was a statistically significant difference between the two groups in the change in two of the four domains of QLS; "Interpersonal relations" and "Intrapsychic foundations" domains during the study. These findings support the value of the estimated MCID for the QLS and may be a useful tool in evaluating antipsychotic treatment effects and improving long-term patient outcomes in schizophrenia. Copyright © 2015 John Wiley & Sons, Ltd. PMID:26238598
Costello, Leslie C; Franklin, Renty B
Liver cancer (hepatocellular carcinoma, HCC) is increasing worldwide. About 75% of HCC cases result in death generally within one year. The factors responsible for the initiation and progression of HCC remain largely unknown and speculative, thereby impeding advancements in the development of effective therapeutic agents and biomarkers for early detection of HCC. A consistent marked decrease in zinc in HCC tumors compared with normal liver is an established clinical relationship, which occurs in virtually all cases of HCC. However, this relationship has been largely ignored by the contemporary clinical and research community. Consequently, the factors and mechanisms involved in this relationship have not been addressed. Thus, the opportunity and potential for its employment as biomarkers for early identification of malignancy, and for development of a chemotherapeutic approach have been lacking. This presentation includes a review of the literature and the description of important recent and new data, which provide the basis for a concept of the role of zinc in the development of HCC. The basis is presented for characterizing HCC malignancy as ZIP14-deficient tumors, and its requirement to prevent zinc cytotoxic effects on the malignant cells. The potential for an efficacious zinc treatment approach for HCC is described. The involvement of zinc in the predisposition for HCC by chronic liver disease/cirrhosis is presented. Hopefully, this presentation will raise the awareness, interest, and support for the much needed research in the implications of zinc in the development and progression of HCC. PMID:24448510
Salekin, Randall T; Ziegler, Tracey A; Larrea, Maria A; Anthony, Virginia Lee; Bennett, Allyson D
Psychopathy in youth has received increased recognition as a critical clinical construct for the evaluation and management of adolescents who have come into contact with the law (e.g., Forth, Hare, & Hart, 1990; Frick, 1998; Lynam, 1996, 1998). Although considerable attention has been devoted to the adult construct of psychopathy and its relation to recidivism, psychopathy in adolescents has been less thoroughly researched. Recently, a psychopathy scale (Murrie and Cornell Psychopathy Scale; Murrie & Cornell, 2000) was developed from items of the Millon Adolescent Clinical Inventory (MACI; Millon, 1993). This scale was found to be highly related to the Psychopathy Checklist-Revised (Hare, 1991) and was judged to have demonstrated good criterion validity. A necessary step in the validation process of any psychopathy scale is establishing its predictive validity. With this in mind, we investigated the ability of the MACI Psychopathy Scale to predict recidivism with 55 adolescent offenders 2 years after they had been evaluated at a juvenile court evaluation unit. In addition, we devised a psychopathy scale from MACI items that aligned more closely with Cooke and Michie (2001) and Frick, Bodin, and Barry's (2001) recommendations for the refinement of psychopathy and tested its predictive validity. Results indicate that both scales had predictive utility. Interpersonal and affective components of the revised scale were particularly important in the prediction of both general and violent reoffending. PMID:12700018
Cerqueira, Carla; Samperio Ventayol, Pilar; Vogeley, Christian
ABSTRACT The entry of human papillomaviruses into host cells is a complex process. It involves conformational changes at the cell surface, receptor switching, internalization by a novel endocytic mechanism, uncoating in endosomes, trafficking of a subviral complex to the Golgi complex, and nuclear entry during mitosis. Here, we addressed how the stabilizing contacts in the capsid of human papillomavirus 16 (HPV16) may be reversed to allow uncoating of the viral genome. Using biochemical and cell-biological analyses, we determined that the major capsid protein L1 underwent proteolytic cleavage during entry. In addition to a dispensable cathepsin-mediated proteolysis that occurred likely after removal of capsomers from the subviral complex in endosomes, at least two further proteolytic cleavages of L1 were observed, one of which was independent of the low-pH environment of endosomes. This cleavage occurred extracellularly. Further analysis showed that the responsible protease was the secreted trypsin-like serine protease kallikrein-8 (KLK8) involved in epidermal homeostasis and wound healing. Required for infection, the cleavage was facilitated by prior interaction of viral particles with heparan sulfate proteoglycans. KLK8-mediated cleavage was crucial for further conformational changes exposing an important epitope of the minor capsid protein L2. Occurring independently of cyclophilins and of furin that mediate L2 exposure, KLK8-mediated cleavage of L1 likely facilitated access to L2, located in the capsid lumen, and potentially uncoating. Since HPV6 and HPV18 also required KLK8 for entry, we propose that the KLK8-dependent entry step is conserved. IMPORTANCE Our analysis of the proteolytic processing of incoming HPV16, an etiological agent of cervical cancer, demonstrated that the capsid is cleaved extracellularly by a serine protease active during wound healing and that this cleavage was crucial for infection. The cleavage of L1 is one of at least four structural
Raynes, Rachel; Pomatto, Laura C D; Davies, Kelvin J A
The proteasome is a ubiquitous and highly plastic multi-subunit protease with multi-catalytic activity that is conserved in all eukaryotes. The most widely known function of the proteasome is protein degradation through the 26S ubiquitin-proteasome system, responsible for the vast majority of protein degradation during homeostasis. However, the proteasome also plays an important role in adaptive immune responses and adaptation to oxidative stress. The unbound 20S proteasome, the core common to all proteasome conformations, is the main protease responsible for degrading oxidized proteins. During periods of acute stress, the 19S regulatory cap of the 26S proteasome disassociates from the proteolytic core, allowing for immediate ATP/ubiquitin-independent protein degradation by the 20S proteasome. Despite the abundance of unbound 20S proteasome compared to other proteasomal conformations, many publications fail to distinguish between the two proteolytic systems and often regard the 26S proteasome as the dominant protease. Further confounding the issue are the differential roles these two proteolytic systems have in adaptation and aging. In this review, we will summarize the increasing evidence that the 20S core proteasome constitutes the major conformation of the proteasome system and that it is far from a latent protease requiring activation by binding regulators. PMID:27155164
Tulini, Fabricio L; Hymery, Nolwenn; Haertlé, Thomas; Le Blay, Gwenaelle; De Martinis, Elaine C P
Lactic acid bacteria (LAB) can be isolated from different sources such as milk and cheese, and the lipolytic, proteolytic and glycolytic enzymes of LAB are important in cheese preservation and in flavour production. Moreover, LAB produce several antimicrobial compounds which make these bacteria interesting for food biopreservation. These characteristics stimulate the search of new strains with technological potential. From 156 milk and cheese samples from cow, buffalo and goat, 815 isolates were obtained on selective agars for LAB. Pure cultures were evaluated for antimicrobial activities by agar antagonism tests and for proteolytic activity on milk proteins by cultivation on agar plates. The most proteolytic isolates were also tested by cultivation in skim milk followed by sodium dodecyl sulphate polyacrylamide gel electrophoresis (SDS-PAGE) analysis of the fermented milk. Among the 815 tested isolates, three of them identified as Streptococcus uberis (strains FT86, FT126 and FT190) were bacteriocin producers, whereas four other ones identified as Weissella confusa FT424, W. hellenica FT476, Leuconostoc citreum FT671 and Lactobacillus plantarum FT723 showed high antifungal activity in preliminary assays. Complementary analyses showed that the most antifungal strain was L. plantarum FT723 that inhibited Penicillium expansum in modified MRS agar (De Man, Rogosa, Sharpe, without acetate) and fermented milk model, however no inhibition was observed against Yarrowia lipolytica. The proteolytic capacities of three highly proteolytic isolates identified as Enterococcus faecalis (strains FT132 and FT522) and Lactobacillus paracasei FT700 were confirmed by SDS-PAGE, as visualized by the digestion of caseins and whey proteins (β-lactoglobulin and α-lactalbumin). These results suggest potential applications of these isolates or their activities (proteolytic activity or production of antimicrobials) in dairy foods production. PMID:26608755
Bochniarz, M; Wawron, W
The aim of the present study was to assess the haemolytic and proteolytic activity of coagulase-negative staphylococci (CNS) isolated from cows with mastitis. The study was conducted on 100 CNS strains: S. xylosus (n=28), S. chromogenes (n=26), S. haemolyticus (n=25), S. sciuri (n=14), S. warneri (n=4), S. hominis (n=2), S. saprophyticus (n=1); 22 CNS were isolated from cows with clinical mastitis and 78 from those with subclinical mastitis. The CNS studied showed the ability to produce only alpha-haemolysin and belonged to one strain - S. haemolyticus (21.0% of isolated CNS strains). Haemolysin-positive CNS were responsible for both clinical and subclinical mastitis (22.7% and 20.5%, respectively). The ability to produce protease was found in 31.0% of CNS belonging to two strains: S. chromogenes and S. sciuri. Protease-positive CNS were the etiological factor of both clinical and subclinical mastitis (31.8% and 30.8%, respectively). All S. xylosus, S. warneri, S. hominis, and S. saprophyticus strains were found protease-negative and haemolysin-negative, irrespective of whether they caused clinical or subclinical mastitis in cows. PMID:22708359