Survival is increasing after early breast cancer revealing frequent relapses and possibility of developing secondary malignancies. The concomitant occurrence of these two events is exceptionally disastrous and...
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Δευτέρα 9 Ιανουαρίου 2017
Acupuncture combined with methylcobalamin for the treatment of chemotherapy-induced peripheral neuropathy in patients with multiple myeloma
Chemotherapy-induced peripheral neuropathy (CIPN) seriously affects the quality of life of patients with multiple myeloma (MM) as well as the response rate to chemotherapy. Acupuncture has a potential role in ...
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Pancreatic neuroendocrine tumor with metastasis to the spleen: a case report
Long-term term survival in patients with pancreatic neuroendocrine tumors has been reported, even in patients with metastatic disease. Metastases to the spleen are extremely rare, but have been reported from a...
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Diversity in the organization of elastin bundles and intramembranous muscles in bat wings
Abstract
Unlike birds and insects, bats fly with wings composed of thin skin that envelops the bones of the forelimb and spans the area between the limbs, digits, and sometimes the tail. This skin is complex and unusual; it is thinner than typical mammalian skin and contains organized bundles of elastin and embedded skeletal muscles. These elements are likely responsible for controlling the shape of the wing during flight and contributing to the aerodynamic capabilities of bats. We examined the arrangement of two macroscopic architectural elements in bat wings, elastin bundles and wing membrane muscles, to assess the diversity in bat wing skin morphology. We characterized the plagiopatagium and dactylopatagium of 130 species from 17 families of bats using cross-polarized light imaging. This method revealed structures with distinctive relative birefringence, heterogeneity of birefringence, variation in size, and degree of branching. We used previously published anatomical studies and tissue histology to identify birefringent structures, and we analyzed their architecture across taxa. Elastin bundles, muscles, neurovasculature, and collagenous fibers are present in all species. Elastin bundles are oriented in a predominantly spanwise or proximodistal direction, and there are five characteristic muscle arrays that occur within the plagiopatagium, far more muscle than typically recognized. These results inform recent functional studies of wing membrane architecture, support the functional hypothesis that elastin bundles aid wing folding and unfolding, and further suggest that all bats may use these architectural elements for flight. All species also possess numerous muscles within the wing membrane, but the architecture of muscle arrays within the plagiopatagium varies among families. To facilitate present and future discussion of these muscle arrays, we refine wing membrane muscle nomenclature in a manner that reflects this morphological diversity. The architecture of the constituents of the skin of the wing likely plays a key role in shaping wings during flight.
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Retningslinje for rehabilitering etter ervervet overekstremitetsamputasjon
Norges første retningslinje for rehabilitering av pasienter med ervervet overekstremitetsamputasjon er nå tilgjengelig på nett. Retningslinjen dekker hele rehabiliteringsforløpet. Mange av anbefalingene er også relevante for pasienter med medfødte mangler på overekstremitetene (dysmeli) og for behandling av amputasjonsrelaterte smerter hos benamputerte.
Personer med ervervet overekstremitetsamputasjon (arm-, hånd/delhånd- og fingeramputasjon) er en pasientgruppe som til nå har hatt et mangelfullt rehabiliteringstilbud i Norge. Det er avdekket store variasjoner i rehabiliteringen og et udekket behov for flere ulike tjenester i kommune- og spesialisthelsetjenesten (1).
Pasientene er i hovedsak unge og ellers friske (2). Amputasjonen påvirker fysisk funksjon, bevegelsesmønster, utseende, arbeidsevne og livskvalitet (1). Gjenopprettelse av optimal funksjon og forebygging av sekundære plager som muskelskjelett-smerter forutsetter tilgang til spesialisert, tverrfaglig rehabilitering. Det kreves også god samhandling mellom spesialisert rehabilitering og andre helsetjenester i første- og annenlinjetjenesten (som ortopedi og smerteklinikk). Overekstremitetsamputerte har normale livsutsikter, og deres behov endres ofte i tråd med ulike ervervsmessige og familiære forpliktelser. Dette er dermed en gruppe som har behov for oppfølging i et livsløpsperspektiv (3, 4).
Derfor er det nå utarbeidet en kunnskapsbasert faglig retningslinje for rehabilitering etter ervervet overekstremitetsamputasjon i Norge (5). Målet er å sikre denne pasientgruppen enhetlig rehabilitering i tråd med beste praksis og redusere uønsket variasjon i rehabiliteringstilbudet.
Arbeidsgruppen
Retningslinjen er utarbeidet av en tverrfaglig sammensatt arbeidsgruppe bestående av representanter fra alle landets fem spesialiserte tverrfaglige armamputasjonsteam, de to ortopediske verkstedene i Norge som lager armproteser (Norsk Teknisk Ortopedi og Sophies Minde Ortopedi), primærhelsetjenesten og pasientgruppen. I tillegg bidro en aktiv referansegruppe bestående av helsepersonell med ulik fagbakgrunn knyttet til både primær- og spesialisthelsetjenesten.
Arbeidet ble finansiert av Helsedirektoratet via tilskuddsmidler (på initiativ fra en av forfatterne av denne artikkelen, K. Østlie) og har fulgt Helsedirektoratets Veileder for utarbeidelse av kunnskapsbaserte retningslinjer samt AGREE II (Appraisal of Guidelines REsearch & Evaluation), et verktøy for utvikling av retningslinjer med vekt på en transparent prosess (6). Litteratur og anbefalinger er kvalitetsvurdert og gradert ved bruk av GRADE (Grading of Recommendations Assessment, Development and Evaluation) (7). Retningslinjen møter dermed standarden for troverdige retningslinjer (8).
Anbefalingene
Den nye retningslinjen er publisert i den elektroniske retningslinjeplattformen MAGICapp i såkalt topplokkformat (9). Det vil si at man på alle elektroniske plattformer kostnadsfritt kan gå inn og lese dem. Man har også full tilgang til bakgrunnsinformasjon, begrunnelse, nøkkelinformasjon om grunnlagsfaktorer og styrken på hver enkelt anbefaling, oppsummering av tilgjengelig kunnskap og kvaliteten på denne samt eventuell praktisk informasjon.
Styrken på de ulike anbefalingene er basert på en balansert vurdering av kvaliteten på kunnskapsgrunnlaget, balansen mellom fordeler og ulemper ved et tiltak, pasientens verdier og preferanser og kostnadsvurderinger/ressurshensyn. En sterk anbefaling innebærer at fordelene klart veier opp for ulempene og at nær sagt alle pasienter vil ønske/bør tilbys den anbefalte intervensjonen. Ved svake anbefalinger er balansen noe mer usikker, og det er forventet større variasjon i individuelle preferanser (10).
Retningslinjen omfatter hele rehabiliteringsforløpet. Det er spesielt viktig å legge merke til de sterke anbefalingene for henvisning til spesialisert rehabilitering og lav terskel for gjentatte tverrfaglige vurderinger. Nyamputerte anbefales henvist til ett av landets fem spesialiserte armamputasjonsteam senest ved utskrivning fra akuttavdelingen. Barn i og under skolealder anbefales regelmessige kontroller for å fange opp nye behov som følge av vekst og utvikling.
Anbefalingene for behandling av amputasjonsrelaterte smerter er i hovedsak svake, blant annet fordi mye av dokumentasjonen er indirekte (f.eks. forskning på andre typer smerte). Dette gjør det ekstra viktig å gjøre kunnskapsgrunnlaget tilgjengelig for å hjelpe klinikere å fatte beslutninger i samråd med pasientene. Det betyr imidlertid også at anbefalingene i hovedsak er relevante og gyldige også for pasienter med benamputasjoner og amputasjonsrelaterte smerter.
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Development and Evaluation of the LittlEARS® Early Speech Production Questionnaire – LEESPQ
Source:International Journal of Pediatric Otorhinolaryngology
Author(s): Bianka Wachtlin, Joanna Brachmaier, Edda Amann, Vanessa Hoffmann, Annerose Keilmann
ObjectiveUniversal Newborn Hearing Screening programs, now instituted throughout the German-speaking countries, allow hearing loss to be detected and treated much earlier than ever before. With this earlier detection, arises the need for tools fit for assessing the very early speech and language production development of today’s younger (0-18 month old) children. We have created the LittlEARS® Early Speech Production Questionnaire, with the aim of meeting this need.Methods600 questionnaires of the pilot version of the LittlEARS® Early Speech Production Questionnaire were distributed to parents via pediatricians’ practices, day care centers, and personal contact. The completed questionnaires were statistically analyzed to determine their reliability, predictive accuracy, internal consistency, and to what extent gender or unilingualism influenced a child’s score. Further, a norm curve was generated to plot the children’s increased expected speech production ability with age.ResultsAnalysis of the data from the 352/600 returned questionnaires revealed that scores on LittlEARS® Early Speech Production Questionnaire correlate positively with a child’s age, with older children scoring higher than do younger children. Further, the questionnaire has a high measuring reliability, high predictability, high unidemensionality of scale, and is not significantly gender or uni-/multilingually biased. A norm curve for expected development with age was created.ConclusionsThe LittlEARS® Early Speech Production Questionnaire (LEESPQ) is a valid tool for assessing the most important milestones in very early development of speech and language production of German language children with normal hearing aged 0-18 months old. The questionnaire is a potentially useful tool for long-term infant screening and follow-up testing and for children with normal hearing and those who would benefit from or use hearing devices.
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Impact of environmental volatile organic compounds on otitis media in children: Correlation between exposure and urinary metabolites
Publication date: February 2017
Source:International Journal of Pediatric Otorhinolaryngology, Volume 93
Author(s): So Young Kim, Bu-Soon Son, Hee-jin Park, Seung Ha Oh, Jun Ho Lee, Myung-Hwan Suh, Moo Kyun Park
IntroductionVolatile organic compounds (VOCs) induce inflammatory responses. Tobacco smoke contains numerous VOCs and is a risk factor for otitis media effusion (OME); however, no previous studies have investigated the association between VOCs and OME.ObjectivesWe used urinary metabolites and exposure to environmental risk factors to investigate the association between VOC and polycyclic aromatic hydrocarbon exposure and recurrent OME in children.MethodsChildren with recurrent OME who visited the Otorhinolaryngology Department of Seoul National University Hospital between November 2014 and June 2015 were prospectively enrolled in the study. Recurrent OME was defined as more than two OME episodes over a 6-month period lasting longer than 2 months. The control group consisted of children without OME in the last year. Demographic information, including age, sex, and previous medical history was obtained, and endoscopic examinations of the tympanic membrane were performed. Urinary concentrations of 1-hydroxypyrene, 2-naphthol, hippuric acid, trans, trans-muconic acid (t,t-MA), mandelic acid, phenyl glyoxylic acid, and methyl hippuric acid were analyzed using high-performance liquid chromatography/tandem mass spectroscopy. Environmental factors assessed included house type, age, renovations, the presence of furniture <6 months old, proximity to a road, and exposure to passive smoking.ResultsWe enrolled 11 children with OME and 39 controls. Age and sex did not differ between groups. Exposure to passive smoking was significantly more common in the OME group than in the controls (P < 0.001). Urinary concentrations of t.t.-MA were significantly higher in the OME group (126.33 μg/g cr) than in controls (52.661 μg/g cr; P = 0.003). Other metabolites including 1-hydroxypyrene, 2-naphthol, hippuric acid, mandelic acid, phenyl glyoxylic acid, and methyl hippuric acid did not demonstrated significant relation with the OME.ConclusionsLevels of t,t-MA, a biomarker of benzene exposure, were significantly higher in the OME group than in controls. Passive smoking was significantly more common in the OME group. Our findings suggest that high t,t-MA levels which were probably originated from passive smoking and other pollutants could be indicative OME in children.
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Source:International Journal of Pediatric Otorhinolaryngology, Volume 93
Author(s): So Young Kim, Bu-Soon Son, Hee-jin Park, Seung Ha Oh, Jun Ho Lee, Myung-Hwan Suh, Moo Kyun Park
IntroductionVolatile organic compounds (VOCs) induce inflammatory responses. Tobacco smoke contains numerous VOCs and is a risk factor for otitis media effusion (OME); however, no previous studies have investigated the association between VOCs and OME.ObjectivesWe used urinary metabolites and exposure to environmental risk factors to investigate the association between VOC and polycyclic aromatic hydrocarbon exposure and recurrent OME in children.MethodsChildren with recurrent OME who visited the Otorhinolaryngology Department of Seoul National University Hospital between November 2014 and June 2015 were prospectively enrolled in the study. Recurrent OME was defined as more than two OME episodes over a 6-month period lasting longer than 2 months. The control group consisted of children without OME in the last year. Demographic information, including age, sex, and previous medical history was obtained, and endoscopic examinations of the tympanic membrane were performed. Urinary concentrations of 1-hydroxypyrene, 2-naphthol, hippuric acid, trans, trans-muconic acid (t,t-MA), mandelic acid, phenyl glyoxylic acid, and methyl hippuric acid were analyzed using high-performance liquid chromatography/tandem mass spectroscopy. Environmental factors assessed included house type, age, renovations, the presence of furniture <6 months old, proximity to a road, and exposure to passive smoking.ResultsWe enrolled 11 children with OME and 39 controls. Age and sex did not differ between groups. Exposure to passive smoking was significantly more common in the OME group than in the controls (P < 0.001). Urinary concentrations of t.t.-MA were significantly higher in the OME group (126.33 μg/g cr) than in controls (52.661 μg/g cr; P = 0.003). Other metabolites including 1-hydroxypyrene, 2-naphthol, hippuric acid, mandelic acid, phenyl glyoxylic acid, and methyl hippuric acid did not demonstrated significant relation with the OME.ConclusionsLevels of t,t-MA, a biomarker of benzene exposure, were significantly higher in the OME group than in controls. Passive smoking was significantly more common in the OME group. Our findings suggest that high t,t-MA levels which were probably originated from passive smoking and other pollutants could be indicative OME in children.
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Acute care revisits after adenotonsillectomy in a pediatric Medicaid population in Ohio
Publication date: Available online 9 January 2017
Source:International Journal of Pediatric Otorhinolaryngology
Author(s): Dmitry Tumin, Hina Walia, Vidya T. Raman, Joseph D. Tobias
IntroductionGuidelines for inpatient admission after pediatric tonsillectomy have been proposed to improve the safety of this procedure. This study examined the association between performing adenotonsillectomy in an inpatient setting and acute care revisits within 30 days among children enrolled in a Medicaid Accountable Care Organization in Ohio.MethodsThe Affordable Care Organization's claims database was queried for adenotonsillectomies performed in children ages 0–18 years in 2008–2014. Procedures associated with an inpatient facility stay were classified as inpatient adenotonsillectomies. The primary outcome was emergency department visit or inpatient re-admission within 30 days. Secondary outcomes were revisits within 7 days and >7 days post-discharge. Logistic regression was used to test for association between inpatient procedure and need for revisits.ResultsAdenotonsillectomies in 8835 girls and 7773 boys (age 6.8 ± 3.8 years) were analyzed, of which 842 (5%) were inpatient procedures. Revisits were required in 2511 (15%) cases and were primarily visits to the emergency department. In multivariable analysis, inpatient and outpatient procedures had comparable need for 30-day revisits (OR = 0.85; 95% CI: 0.69, 1.05; p = 0.124). In sub-analyses, inpatient adenotonsillectomy was associated with lower odds of early (≤7 days post-discharge; OR = 0.76; 95% CI: 0.58, 0.99; p = 0.045) but not later (>7 days) revisits.ConclusionsIn a pediatric Medicaid population, inpatient adenotonsillectomy was not associated with greater odds of acute care revisits, compared to outpatient procedures. Appropriate risk stratification of children undergoing adenotonsillectomy can reduce the need for early acute care revisits by scheduling high-risk patients for prolonged observation.
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Source:International Journal of Pediatric Otorhinolaryngology
Author(s): Dmitry Tumin, Hina Walia, Vidya T. Raman, Joseph D. Tobias
IntroductionGuidelines for inpatient admission after pediatric tonsillectomy have been proposed to improve the safety of this procedure. This study examined the association between performing adenotonsillectomy in an inpatient setting and acute care revisits within 30 days among children enrolled in a Medicaid Accountable Care Organization in Ohio.MethodsThe Affordable Care Organization's claims database was queried for adenotonsillectomies performed in children ages 0–18 years in 2008–2014. Procedures associated with an inpatient facility stay were classified as inpatient adenotonsillectomies. The primary outcome was emergency department visit or inpatient re-admission within 30 days. Secondary outcomes were revisits within 7 days and >7 days post-discharge. Logistic regression was used to test for association between inpatient procedure and need for revisits.ResultsAdenotonsillectomies in 8835 girls and 7773 boys (age 6.8 ± 3.8 years) were analyzed, of which 842 (5%) were inpatient procedures. Revisits were required in 2511 (15%) cases and were primarily visits to the emergency department. In multivariable analysis, inpatient and outpatient procedures had comparable need for 30-day revisits (OR = 0.85; 95% CI: 0.69, 1.05; p = 0.124). In sub-analyses, inpatient adenotonsillectomy was associated with lower odds of early (≤7 days post-discharge; OR = 0.76; 95% CI: 0.58, 0.99; p = 0.045) but not later (>7 days) revisits.ConclusionsIn a pediatric Medicaid population, inpatient adenotonsillectomy was not associated with greater odds of acute care revisits, compared to outpatient procedures. Appropriate risk stratification of children undergoing adenotonsillectomy can reduce the need for early acute care revisits by scheduling high-risk patients for prolonged observation.
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Visual Speech Alters the Discrimination and Identification of Non-Intact Auditory Speech in Children with Hearing Loss
Source:International Journal of Pediatric Otorhinolaryngology
Author(s): Susan Jerger, Markus F. Damian, Rachel P. McAlpine, Hervé Abdi
ObjectivesUnderstanding spoken language is an audiovisual event that depends critically on the ability to discriminate and identify phonemes yet we have little evidence about the role of early auditory experience and visual speech on the development of these fundamental perceptual skills. Objectives of this research were to determine 1) how visual speech influences phoneme discrimination and identification; 2) whether visual speech influences these two processes in a like manner, such that discrimination predicts identification; and 3) how the degree of hearing loss affects this relationship. Such evidence is crucial for developing effective intervention strategies to mitigate the effects of hearing loss on language development.MethodsParticipants were 58 children with early-onset sensorineural hearing loss (CHL, 53% girls, M = 9;4 yrs) and 58 children with normal hearing (CNH, 53% girls, M = 9;4 yrs). Test items were consonant-vowel (CV) syllables and nonwords with intact visual speech coupled to non-intact auditory speech (excised onsets) as, for example, an intact consonant/rhyme in the visual track (Baa or Baz) coupled to non-intact onset/rhyme in the auditory track (/–B/aa or /–B/az). The items started with an easy-to-speechread /B/ or difficult-to-speechread /G/ onset and were presented in the auditory (static face) vs. audiovisual (dynamic face) modes. We assessed discrimination for intact vs. non-intact different pairs (e.g., Baa:/–B/aa). We predicted that visual speech would cause the non-intact onset to be perceived as intact and would therefore generate more same—as opposed to different—responses in the audiovisual than auditory mode. We assessed identification by repetition of nonwords with non-intact onsets (e.g., /–B/az). We predicted that visual speech would cause the non-intact onset to be perceived as intact and would therefore generate more Baz—as opposed to az— responses in the audiovisual than auditory mode.ResultsPerformance in the audiovisual mode showed more same responses for the intact vs. non-intact different pairs (e.g., Baa:/–B/aa) and more intact onset responses for nonword repetition (Baz for /–B/az). Thus visual speech altered both discrimination and identification in the CHL—to a large extent for the /B/ onsets but only minimally for the /G/ onsets. The CHL identified the stimuli similarly to the CNH but did not discriminate the stimuli similarly. A bias-free measure of the children’s discrimination skills (i.e., d́ analysis) revealed that the CHL had greater difficulty discriminating intact from non-intact speech in both modes. As the degree of HL worsened, the ability to discriminate the intact vs. non-intact onsets in the auditory mode worsened. Discrimination ability in CHL significantly predicted their identification of the onsets—even after variation due to the other variables was controlled.ConclusionsThese results clearly established that visual speech can fill in non-intact auditory speech, and this effect, in turn, made the non-intact onsets more difficult to discriminate from intact speech and more likely to be perceived as intact. Such results 1) demonstrate the value of visual speech at multiple levels of linguistic processing and 2) support intervention programs that view visual speech as a powerful asset for developing spoken language in CHL.
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External airway splint to treat tracheomalacia following laryngotracheal reconstruction
Source:International Journal of Pediatric Otorhinolaryngology
Author(s): Wayne D. Hsueh, Lee P. Smith
This observation reports the use of an external airway splint to treat tracheomalacia in a pediatric patient. The patient underwent a double stage laryngotracheal reconstruction however was unable to be decannulated due to severe tracheomalacia. Our purpose is to further support the use of external splinting in the treatment of tracheomalacia in a unique case involving isolated nighttime airway obstruction following laryngotracheal reconstruction.
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Exercising as “weekend warrior” still yields mortality benefit, study finds
Compressing the recommended amount of physical activity into a weekend rather than spreading it over the whole week may be sufficient to reduce all cause, cardiovascular, and cancer mortality, say...
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Norovirus infections in England hit highest rate for five years
The number of people testing positive for norovirus infection, the so called “winter vomiting bug,” has reached its highest level for five years, figures from Public Health England have shown.1The...
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Cancer and Apoptosis: Who Is Built to Last?
Publication date: 9 January 2017
Source:Cancer Cell, Volume 31, Issue 1
Author(s): Douglas R. Green
Effective cancer therapy requires that a cancer be more susceptible to a treatment than are the essential tissues in the body. A paper by Sarosiek et al. in this issue now shows that, unlike those of cancer cells, mitochondria in many tissues in adults are in an apoptosis-resistant state.
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Source:Cancer Cell, Volume 31, Issue 1
Author(s): Douglas R. Green
Effective cancer therapy requires that a cancer be more susceptible to a treatment than are the essential tissues in the body. A paper by Sarosiek et al. in this issue now shows that, unlike those of cancer cells, mitochondria in many tissues in adults are in an apoptosis-resistant state.
Teaser
Effective cancer therapy requires that a cancer be more susceptible to a treatment than are the essential tissues in the body. A paper by Sarosiek et al. in this issue now shows that, unlike those of cancer cells, mitochondria in many tissues in adults are in an apoptosis-resistant state.from #AlexandrosSfakianakis via Alexandros G.Sfakianakis on Inoreader http://ift.tt/2iX3thZ
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Employing Metabolism to Improve the Diagnosis and Treatment of Pancreatic Cancer
Publication date: 9 January 2017
Source:Cancer Cell, Volume 31, Issue 1
Author(s): Christopher J. Halbrook, Costas A. Lyssiotis
Pancreatic ductal adenocarcinoma is on pace to become the second leading cause of cancer-related death. The high mortality rate results from a lack of methods for early detection and the inability to successfully treat patients once diagnosed. Pancreatic cancer cells have extensively reprogrammed metabolism, which is driven by oncogene-mediated cell-autonomous pathways, the unique physiology of the tumor microenvironment, and interactions with non-cancer cells. In this review, we discuss how recent efforts delineating rewired metabolic networks in pancreatic cancer have revealed new in-roads to develop detection and treatment strategies for this dreadful disease.
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Source:Cancer Cell, Volume 31, Issue 1
Author(s): Christopher J. Halbrook, Costas A. Lyssiotis
Pancreatic ductal adenocarcinoma is on pace to become the second leading cause of cancer-related death. The high mortality rate results from a lack of methods for early detection and the inability to successfully treat patients once diagnosed. Pancreatic cancer cells have extensively reprogrammed metabolism, which is driven by oncogene-mediated cell-autonomous pathways, the unique physiology of the tumor microenvironment, and interactions with non-cancer cells. In this review, we discuss how recent efforts delineating rewired metabolic networks in pancreatic cancer have revealed new in-roads to develop detection and treatment strategies for this dreadful disease.
Teaser
Pancreatic ductal adenocarcinoma is on pace to become the second leading cause of cancer-related death. The high mortality rate results from a lack of methods for early detection and the inability to successfully treat patients once diagnosed. Pancreatic cancer cells have extensively reprogrammed metabolism, which is driven by oncogene-mediated cell-autonomous pathways, the unique physiology of the tumor microenvironment, and interactions with non-cancer cells. In this review, we discuss how recent efforts delineating rewired metabolic networks in pancreatic cancer have revealed new in-roads to develop detection and treatment strategies for this dreadful disease.from #AlexandrosSfakianakis via Alexandros G.Sfakianakis on Inoreader http://ift.tt/2j2tRcO
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Epigenetic siRNA and Chemical Screens Identify SETD8 Inhibition as a Therapeutic Strategy for p53 Activation in High-Risk Neuroblastoma
Publication date: 9 January 2017
Source:Cancer Cell, Volume 31, Issue 1
Author(s): Veronica Veschi, Zhihui Liu, Ty C. Voss, Laurent Ozbun, Berkley Gryder, Chunhua Yan, Ying Hu, Anqi Ma, Jian Jin, Sharlyn J. Mazur, Norris Lam, Barbara K. Souza, Giuseppe Giannini, Gordon L. Hager, Cheryl H. Arrowsmith, Javed Khan, Ettore Appella, Carol J. Thiele
Given the paucity of druggable mutations in high-risk neuroblastoma (NB), we undertook chromatin-focused small interfering RNA and chemical screens to uncover epigenetic regulators critical for the differentiation block in high-risk NB. High-content Opera imaging identified 53 genes whose loss of expression led to a decrease in NB cell proliferation and 16 also induced differentiation. From these, the secondary chemical screen identified SETD8, the H4K20me1 methyltransferase, as a druggable NB target. Functional studies revealed that SETD8 ablation rescued the pro-apoptotic and cell-cycle arrest functions of p53 by decreasing p53K382me1, leading to activation of the p53 canonical pathway. In pre-clinical xenograft NB models, genetic or pharmacological (UNC0379) SETD8 inhibition conferred a significant survival advantage, providing evidence for SETD8 as a therapeutic target in NB.
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Source:Cancer Cell, Volume 31, Issue 1
Author(s): Veronica Veschi, Zhihui Liu, Ty C. Voss, Laurent Ozbun, Berkley Gryder, Chunhua Yan, Ying Hu, Anqi Ma, Jian Jin, Sharlyn J. Mazur, Norris Lam, Barbara K. Souza, Giuseppe Giannini, Gordon L. Hager, Cheryl H. Arrowsmith, Javed Khan, Ettore Appella, Carol J. Thiele
Given the paucity of druggable mutations in high-risk neuroblastoma (NB), we undertook chromatin-focused small interfering RNA and chemical screens to uncover epigenetic regulators critical for the differentiation block in high-risk NB. High-content Opera imaging identified 53 genes whose loss of expression led to a decrease in NB cell proliferation and 16 also induced differentiation. From these, the secondary chemical screen identified SETD8, the H4K20me1 methyltransferase, as a druggable NB target. Functional studies revealed that SETD8 ablation rescued the pro-apoptotic and cell-cycle arrest functions of p53 by decreasing p53K382me1, leading to activation of the p53 canonical pathway. In pre-clinical xenograft NB models, genetic or pharmacological (UNC0379) SETD8 inhibition conferred a significant survival advantage, providing evidence for SETD8 as a therapeutic target in NB.
Graphical abstract
Teaser
Veschi et al. perform both genetic and chemical screening to identify histone methyltransferase SETD8 as a potential target in neuroblastoma (NB). Chemical or genetic inhibition of SETD8 in NB leads to increased p53 activity and reduced tumor cell growth, resulting in prolonged survival in mouse models of NB.from #AlexandrosSfakianakis via Alexandros G.Sfakianakis on Inoreader http://ift.tt/2iXdoE2
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Settling a Nervous Stomach: The Neural Regulation of Enteric Cancer
Publication date: 9 January 2017
Source:Cancer Cell, Volume 31, Issue 1
Author(s): Michelle Monje
The nervous system is emerging as a regulator of malignancy. In this issue of Cancer Cell, Hayakawa et al. demonstrate a feedforward signaling loop in which tumor-derived nerve growth factor promotes enteric tumor innervation, and recruited nerves drive cancer growth through acetylcholine-regulated Wnt signaling and stimulation of further NGF release.
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Source:Cancer Cell, Volume 31, Issue 1
Author(s): Michelle Monje
The nervous system is emerging as a regulator of malignancy. In this issue of Cancer Cell, Hayakawa et al. demonstrate a feedforward signaling loop in which tumor-derived nerve growth factor promotes enteric tumor innervation, and recruited nerves drive cancer growth through acetylcholine-regulated Wnt signaling and stimulation of further NGF release.
Teaser
The nervous system is emerging as a regulator of malignancy. In this issue of Cancer Cell, Hayakawa et al. demonstrate a feedforward signaling loop in which tumor-derived nerve growth factor promotes enteric tumor innervation, and recruited nerves drive cancer growth through acetylcholine-regulated Wnt signaling and stimulation of further NGF release.from #AlexandrosSfakianakis via Alexandros G.Sfakianakis on Inoreader http://ift.tt/2iXf1BP
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Simultaneous Inhibition of PI3Kδ and PI3Kα Induces ABC-DLBCL Regression by Blocking BCR-Dependent and -Independent Activation of NF-κB and AKT
Publication date: 9 January 2017
Source:Cancer Cell, Volume 31, Issue 1
Author(s): Juliane Paul, Maurice Soujon, Antje M. Wengner, Sabine Zitzmann-Kolbe, Andrea Sturz, Katja Haike, Koh Hui Keng Magdalene, Sze Huey Tan, Martin Lange, Soo Yong Tan, Dominik Mumberg, Soon Thye Lim, Karl Ziegelbauer, Ningshu Liu
Compared with follicular lymphoma, high PI3Kα expression was more prevalent in diffuse large B cell lymphoma (DLBCL), although both tumor types expressed substantial PI3Kδ. Simultaneous inhibition of PI3Kα and PI3Kδ dramatically enhanced the anti-tumor profile in ABC-DLBCL models compared with selective inhibition of PI3Kδ, PI3Kα, or BTK. The anti-tumor activity was associated with suppression of p-AKT and a mechanism of blocking nuclear factor-κB activation driven by CD79mut, CARD11mut, TNFAIP3mut, or MYD88mut. Inhibition of PI3Kα/δ resulted in tumor regression in an ibrutinib-resistant CD79BWT/MYD88mut patient-derived ABC-DLBCL model. Furthermore, rebound activation of BTK and AKT was identified as a mechanism limiting CD79Bmut-ABC-DLBCL to show a robust response to PI3K and BTK inhibitor monotherapies. A combination of ibrutinib with the PI3Kα/δ inhibitor copanlisib produced a sustained complete response in vivo in CD79Bmut/MYD88mut ABC-DLBCL models.
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Source:Cancer Cell, Volume 31, Issue 1
Author(s): Juliane Paul, Maurice Soujon, Antje M. Wengner, Sabine Zitzmann-Kolbe, Andrea Sturz, Katja Haike, Koh Hui Keng Magdalene, Sze Huey Tan, Martin Lange, Soo Yong Tan, Dominik Mumberg, Soon Thye Lim, Karl Ziegelbauer, Ningshu Liu
Compared with follicular lymphoma, high PI3Kα expression was more prevalent in diffuse large B cell lymphoma (DLBCL), although both tumor types expressed substantial PI3Kδ. Simultaneous inhibition of PI3Kα and PI3Kδ dramatically enhanced the anti-tumor profile in ABC-DLBCL models compared with selective inhibition of PI3Kδ, PI3Kα, or BTK. The anti-tumor activity was associated with suppression of p-AKT and a mechanism of blocking nuclear factor-κB activation driven by CD79mut, CARD11mut, TNFAIP3mut, or MYD88mut. Inhibition of PI3Kα/δ resulted in tumor regression in an ibrutinib-resistant CD79BWT/MYD88mut patient-derived ABC-DLBCL model. Furthermore, rebound activation of BTK and AKT was identified as a mechanism limiting CD79Bmut-ABC-DLBCL to show a robust response to PI3K and BTK inhibitor monotherapies. A combination of ibrutinib with the PI3Kα/δ inhibitor copanlisib produced a sustained complete response in vivo in CD79Bmut/MYD88mut ABC-DLBCL models.
Graphical abstract
Teaser
Paul et al. reveal that ABC-DLBCL expresses high levels of PI3Kα and PI3Kδ, leading to downstream activation of both NF-κB and AKT signaling. Treatment with the dual PI3Kα/δ inhibitor copanlisib has strong anti-tumor activity and synergizes with the BTK inhibitor ibrutinib, causing tumor remission in DLBCL models.from #AlexandrosSfakianakis via Alexandros G.Sfakianakis on Inoreader http://ift.tt/2j2rPt8
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BCL9L Dysfunction Impairs Caspase-2 Expression Permitting Aneuploidy Tolerance in Colorectal Cancer
Publication date: 9 January 2017
Source:Cancer Cell, Volume 31, Issue 1
Author(s): Carlos López-García, Laurent Sansregret, Enric Domingo, Nicholas McGranahan, Sebastijan Hobor, Nicolai Juul Birkbak, Stuart Horswell, Eva Grönroos, Francesco Favero, Andrew J. Rowan, Nicholas Matthews, Sharmin Begum, Benjamin Phillimore, Rebecca Burrell, Dahmane Oukrif, Bradley Spencer-Dene, Michal Kovac, Gordon Stamp, Aengus Stewart, Havard Danielsen, Marco Novelli, Ian Tomlinson, Charles Swanton
Chromosomal instability (CIN) contributes to cancer evolution, intratumor heterogeneity, and drug resistance. CIN is driven by chromosome segregation errors and a tolerance phenotype that permits the propagation of aneuploid genomes. Through genomic analysis of colorectal cancers and cell lines, we find frequent loss of heterozygosity and mutations in BCL9L in aneuploid tumors. BCL9L deficiency promoted tolerance of chromosome missegregation events, propagation of aneuploidy, and genetic heterogeneity in xenograft models likely through modulation of Wnt signaling. We find that BCL9L dysfunction contributes to aneuploidy tolerance in both TP53-WT and mutant cells by reducing basal caspase-2 levels and preventing cleavage of MDM2 and BID. Efforts to exploit aneuploidy tolerance mechanisms and the BCL9L/caspase-2/BID axis may limit cancer diversity and evolution.
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Source:Cancer Cell, Volume 31, Issue 1
Author(s): Carlos López-García, Laurent Sansregret, Enric Domingo, Nicholas McGranahan, Sebastijan Hobor, Nicolai Juul Birkbak, Stuart Horswell, Eva Grönroos, Francesco Favero, Andrew J. Rowan, Nicholas Matthews, Sharmin Begum, Benjamin Phillimore, Rebecca Burrell, Dahmane Oukrif, Bradley Spencer-Dene, Michal Kovac, Gordon Stamp, Aengus Stewart, Havard Danielsen, Marco Novelli, Ian Tomlinson, Charles Swanton
Chromosomal instability (CIN) contributes to cancer evolution, intratumor heterogeneity, and drug resistance. CIN is driven by chromosome segregation errors and a tolerance phenotype that permits the propagation of aneuploid genomes. Through genomic analysis of colorectal cancers and cell lines, we find frequent loss of heterozygosity and mutations in BCL9L in aneuploid tumors. BCL9L deficiency promoted tolerance of chromosome missegregation events, propagation of aneuploidy, and genetic heterogeneity in xenograft models likely through modulation of Wnt signaling. We find that BCL9L dysfunction contributes to aneuploidy tolerance in both TP53-WT and mutant cells by reducing basal caspase-2 levels and preventing cleavage of MDM2 and BID. Efforts to exploit aneuploidy tolerance mechanisms and the BCL9L/caspase-2/BID axis may limit cancer diversity and evolution.
Graphical abstract
Teaser
López-García et al. find that BCL9L is often genetically inactivated in human colorectal cancers with chromosomal instability. BCL9L dysfunction promotes aneuploidy tolerance by reducing basal caspase-2 levels and preventing cleavage of MDM2 and BID independent of TP53 mutation status.from #AlexandrosSfakianakis via Alexandros G.Sfakianakis on Inoreader http://ift.tt/2j2tS0e
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Normalization of Tumor Vessels by Tie2 Activation and Ang2 Inhibition Enhances Drug Delivery and Produces a Favorable Tumor Microenvironment
Publication date: 9 January 2017
Source:Cancer Cell, Volume 31, Issue 1
Author(s): Jin-Sung Park, Il-Kug Kim, Sangyeul Han, Intae Park, Chan Kim, Jeomil Bae, Seung Ja Oh, Seungjoo Lee, Jeong Hoon Kim, Dong-Cheol Woo, Yulong He, Hellmut G. Augustin, Injune Kim, Doheon Lee, Gou Young Koh
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Source:Cancer Cell, Volume 31, Issue 1
Author(s): Jin-Sung Park, Il-Kug Kim, Sangyeul Han, Intae Park, Chan Kim, Jeomil Bae, Seung Ja Oh, Seungjoo Lee, Jeong Hoon Kim, Dong-Cheol Woo, Yulong He, Hellmut G. Augustin, Injune Kim, Doheon Lee, Gou Young Koh
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Free Floating Thrombus in Carotid Artery in a Patient with Recurrent Strokes
We present a case of 72-year-old male with reported past medical history of recurrent transient ischemic attacks (TIAs) presenting with myriad of neurological symptoms. Patient was transferred from outlying hospital with complaints of right sided facial droop and dysarthria. Computed tomography angiography (CTA) showed high grade proximal left internal carotid artery (ICA) stenosis along with interesting finding of a free floating thrombus (FFT) in the left ICA. After discussion with the neurosurgical team, our case was treated conservatively with combination of antiplatelet therapy with Aspirin and anticoagulation with Warfarin without recurrence of TIAs or strokes on six-month follow-up.
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Høy dødelighet ved diabetes i Mexico
Diabetes er vanlig i Mexico, blodsukkerkontrollen er dårlig og prognosen mye dårligere enn i høyinntekstland.
Illustrasjonsfoto: Thinkstock
Mexico er et av landene i verden med høyest forekomst av fedme og type 2-diabetes. I en prospektiv studie med rundt 150 000 voksne i alderen 35 – 84 år ble personer med andre kroniske sykdommer enn diabetes ekskludert (1). Ved studiestart var prevalensen av diabetes 3 % i aldersgruppen 35 – 39 år og opptil 20 % hos deltagere i 60-årsalderen. Til tross for at så mange som rundt 80 % av dem med kjent diabetes fikk medikamentell behandling for å kontrollere blodsukkernivået, var gjennomsnittlig nivå av glykosylert hemoglobin (HbA1c) 9,0 % ved studiestart.
Etter om lag 12 års oppfølging var den relative risikoen for død 5,4 (95 % KI 5,0 – 6,0) for dem med diabetes i aldersgruppen 35 – 59 år, sammenlignet med dem som ikke hadde diabetes ved studiestart. I aldersgruppene 60 – 74 år og 75 – 84 år var den relative risikoen for død henholdsvis 3,1 (95 % KI 2,9 – 3,3) og 1,9 (95 % KI 1,8 – 2,1). Sammenhengen mellom diabetes og død var sterkest for død som følge av nyresykdom, med en relativ risiko på 31,1 (95 % KI 24,3 – 39,8) i aldersgruppen 35 – 59 år. Akutt diabetisk krise lå bak 8 % av dødsfallene hos dem med diabetes. Risikoen for død av hjerte- og karsykdom, infeksjoner og magesår var også økt. Diabetes var derimot ikke assosiert med høyere dødelighet av kols eller kreft.
Forfatterne konkluderer med at diabetes er vanlig i Mexico, at blodsukkerkontrollen er dårlig, og at prognosen er mye dårligere enn i høyinntektsland.
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Cosmetics, Vol. 4, Pages 4: Oxidative Stress and Ageing: The Influence of Environmental Pollution, Sunlight and Diet on Skin
Skin ageing is a complex process that is determined by both intrinsic and extrinsic factors, which leads to a progressive loss of structure and function. There is extensive evidence indicating that oxidative stress induced by reactive oxygen species plays an important role in the process of human skin ageing. Mitochondria are the major source of cellular oxidative stress and are widely implicated in cutaneous ageing. Extrinsic skin ageing is driven to a large extent by environmental factors and external stressors such as ultraviolet radiation (UVR), pollution and lifestyle factors which have been shown to stimulate the production of reactive oxygen species and generate oxidative stress. The oxidative damage from these exogenous sources can impair skin structure and function, leading to the phenotypic features of extrinsic skin ageing. The following review highlights the current evidence surrounding the role of mitochondria and oxidative stress in the ageing process and the influence of environmental factors such as ultraviolet radiation, pollution and diet on skin ageing.
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Høy dødelighet ved diabetes i Mexico
Diabetes er vanlig i Mexico, blodsukkerkontrollen er dårlig og prognosen mye dårligere enn i høyinntekstland.
Illustrasjonsfoto: Thinkstock
Mexico er et av landene i verden med høyest forekomst av fedme og type 2-diabetes. I en prospektiv studie med rundt 150 000 voksne i alderen 35 – 84 år ble personer med andre kroniske sykdommer enn diabetes ekskludert (1). Ved studiestart var prevalensen av diabetes 3 % i aldersgruppen 35 – 39 år og opptil 20 % hos deltagere i 60-årsalderen. Til tross for at så mange som rundt 80 % av dem med kjent diabetes fikk medikamentell behandling for å kontrollere blodsukkernivået, var gjennomsnittlig nivå av glykosylert hemoglobin (HbA1c) 9,0 % ved studiestart.
Etter om lag 12 års oppfølging var den relative risikoen for død 5,4 (95 % KI 5,0 – 6,0) for dem med diabetes i aldersgruppen 35 – 59 år, sammenlignet med dem som ikke hadde diabetes ved studiestart. I aldersgruppene 60 – 74 år og 75 – 84 år var den relative risikoen for død henholdsvis 3,1 (95 % KI 2,9 – 3,3) og 1,9 (95 % KI 1,8 – 2,1). Sammenhengen mellom diabetes og død var sterkest for død som følge av nyresykdom, med en relativ risiko på 31,1 (95 % KI 24,3 – 39,8) i aldersgruppen 35 – 59 år. Akutt diabetisk krise lå bak 8 % av dødsfallene hos dem med diabetes. Risikoen for død av hjerte- og karsykdom, infeksjoner og magesår var også økt. Diabetes var derimot ikke assosiert med høyere dødelighet av kols eller kreft.
Forfatterne konkluderer med at diabetes er vanlig i Mexico, at blodsukkerkontrollen er dårlig, og at prognosen er mye dårligere enn i høyinntektsland.
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Looking forward to new targeted treatments for chronic spontaneous urticaria
The introduction of omalizumab to the management of chronic spontaneous urticaria (CSU) has markedly improved the therapeutic possibilities for both, patients and physicians dealing with this disabling disease...
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Topical and cutaneous delivery using nanosystems
Publication date: 10 February 2017
Source:Journal of Controlled Release, Volume 247
Author(s): MS Roberts, Y Mohammed, MN Pastore, S Namjoshi, S Yousef, A Alinaghi, IN Haridass, E Abd, VR Leite-Silva, HAE Benson, JE Grice
The goal of topical and cutaneous delivery is to deliver therapeutic and other substances to a desired target site in the skin at appropriate doses to achieve a safe and efficacious outcome.Normally, however, when the stratum corneum is intact and the skin barrier is uncompromised, this is limited to molecules that are relatively lipophilic, small and uncharged, thereby excluding many potentially useful therapeutic peptides, proteins, vaccines, gene fragments or drug-carrying particles. In this review we will describe how nanosystems are being increasingly exploited for topical and cutaneous delivery, particularly for these previously difficult substances. This is also being driven by the development of novel technologies, which include minimally invasive delivery systems and more precise fabrication techniques. While there is a vast array of nanosystems under development and many undergoing advanced clinical trials, relatively few have achieved full translation to clinical practice. This slow uptake may be due, in part, to the need for a rigorous demonstration of safety in these new nanotechnologies. Some of the safety aspects associated with nanosystems will be considered in this review.
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Source:Journal of Controlled Release, Volume 247
Author(s): MS Roberts, Y Mohammed, MN Pastore, S Namjoshi, S Yousef, A Alinaghi, IN Haridass, E Abd, VR Leite-Silva, HAE Benson, JE Grice
The goal of topical and cutaneous delivery is to deliver therapeutic and other substances to a desired target site in the skin at appropriate doses to achieve a safe and efficacious outcome.Normally, however, when the stratum corneum is intact and the skin barrier is uncompromised, this is limited to molecules that are relatively lipophilic, small and uncharged, thereby excluding many potentially useful therapeutic peptides, proteins, vaccines, gene fragments or drug-carrying particles. In this review we will describe how nanosystems are being increasingly exploited for topical and cutaneous delivery, particularly for these previously difficult substances. This is also being driven by the development of novel technologies, which include minimally invasive delivery systems and more precise fabrication techniques. While there is a vast array of nanosystems under development and many undergoing advanced clinical trials, relatively few have achieved full translation to clinical practice. This slow uptake may be due, in part, to the need for a rigorous demonstration of safety in these new nanotechnologies. Some of the safety aspects associated with nanosystems will be considered in this review.
Graphical abstract
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IL-1β-induced modulation of gene expression profile in human dermal fibroblasts: the effects of Thai herbal Sahatsatara formula, piperine and gallic acid possessing antioxidant properties
Pain is the main symptom of most musculoskeletal disorders and can be caused by inflammation in association with oxidative stress. Thai herbal Sahatsatara formula (STF), a polyherbal formula, has been traditio...
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Spatiotemporal changes of optical signals in the somatosensory cortex of neuropathic rats after electroacupuncture stimulation
Peripheral nerve injury causes physiological changes in primary afferent neurons. Neuropathic pain associated with peripheral nerve injuries may reflect changes in the excitability of the nervous system, inclu...
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The Benzopyrone Biochanin-A as a reversible, competitive, and selective monoamine oxidase B inhibitor
Monoamine oxidase-B (MAO-B) inhibitors are widely used in the treatment of Parkinson’s disease. They increase vital monoamine neurotransmitters in the brain. However, there is a need for safer natural reversib...
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Høy dødelighet ved diabetes i Mexico
Diabetes er vanlig i Mexico, blodsukkerkontrollen er dårlig og prognosen mye dårligere enn i høyinntekstland.
Illustrasjonsfoto: Thinkstock
Mexico er et av landene i verden med høyest forekomst av fedme og type 2-diabetes. I en prospektiv studie med rundt 150 000 voksne i alderen 35 – 84 år ble personer med andre kroniske sykdommer enn diabetes ekskludert (1). Ved studiestart var prevalensen av diabetes 3 % i aldersgruppen 35 – 39 år og opptil 20 % hos deltagere i 60-årsalderen. Til tross for at så mange som rundt 80 % av dem med kjent diabetes fikk medikamentell behandling for å kontrollere blodsukkernivået, var gjennomsnittlig nivå av glykosylert hemoglobin (HbA1c) 9,0 % ved studiestart.
Etter om lag 12 års oppfølging var den relative risikoen for død 5,4 (95 % KI 5,0 – 6,0) for dem med diabetes i aldersgruppen 35 – 59 år, sammenlignet med dem som ikke hadde diabetes ved studiestart. I aldersgruppene 60 – 74 år og 75 – 84 år var den relative risikoen for død henholdsvis 3,1 (95 % KI 2,9 – 3,3) og 1,9 (95 % KI 1,8 – 2,1). Sammenhengen mellom diabetes og død var sterkest for død som følge av nyresykdom, med en relativ risiko på 31,1 (95 % KI 24,3 – 39,8) i aldersgruppen 35 – 59 år. Akutt diabetisk krise lå bak 8 % av dødsfallene hos dem med diabetes. Risikoen for død av hjerte- og karsykdom, infeksjoner og magesår var også økt. Diabetes var derimot ikke assosiert med høyere dødelighet av kols eller kreft.
Forfatterne konkluderer med at diabetes er vanlig i Mexico, at blodsukkerkontrollen er dårlig, og at prognosen er mye dårligere enn i høyinntektsland.
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Early life socioeconomic environment and mammographic breast density
Early life social environment may influence breast cancer through shaping risk factors operating in early life, adolescence and adulthood, or may be associated with breast cancer risk independent of known risk...
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Swallowing interventions for the treatment of dysphagia after head and neck cancer: a systematic review of behavioural strategies used to promote patient adherence to swallowing exercises
Dysphagia is a significant side-effect following treatment for head and neck cancers, yet poor adherence to swallowing exercises is frequently reported in intervention studies. Behaviour change techniques (BCT...
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The efficacy and roles of combining temozolomide with whole brain radiotherapy in protection neurocognitive function and improvement quality of life of non-small-cell lung cancer patients with brain metastases
Brain metastasis (BM) is a poor prognostic factor for non-small-cell lung cancer (NSCLC). The efficacy and roles of combining temozolomide (TMZ) with whole brain radiotherapy (WBRT) in protection neurocognitiv...
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Concordance between PIK3CA mutations in endoscopic biopsy and surgically resected specimens of esophageal squamous cell carcinoma
PIK3CA mutations are expected to be potential therapeutic targets for esophageal squamous cell carcinoma (ESCC). We aimed to clarify the concordance between PIK3CA mutations detected i...
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The acceleration of glucose accumulation in renal cell carcinoma assessed by FDG PET/CT demonstrated acquisition of resistance to tyrosine kinase inhibitor therapy
Tyrosine-kinase inhibitor (TKI) targeting angiogenesis improves the prognosis of patients with metastatic renal cell carcinoma (RCC), but its effect is temporary. In order to understand the mechanism by which ...
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Ear wax
Ear wax: A natural wax-like substance secreted by special glands in the skin on the outer part of the ear canal. It repels water, and traps material such as dust and sand particles. Usually a small amount of wax accumulates, and then dries up and falls out of the ear canal carrying with it unwanted particles. Ear wax is helpful in normal amounts and serves to coat the skin of the ear canal where it acts as a temporary water repellent. The absence of ear wax may result in dry, itchy ears, and even infection.
There are two types of ear wax: wet and dry.
MedTerms (TM) is the Medical Dictionary of MedicineNet.com.
We Bring Doctors' Knowledge To You
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Høy dødelighet ved diabetes i Mexico
Diabetes er vanlig i Mexico, blodsukkerkontrollen er dårlig og prognosen mye dårligere enn i høyinntekstland.
Illustrasjonsfoto: Thinkstock
Mexico er et av landene i verden med høyest forekomst av fedme og type 2-diabetes. I en prospektiv studie med rundt 150 000 voksne i alderen 35 – 84 år ble personer med andre kroniske sykdommer enn diabetes ekskludert (1). Ved studiestart var prevalensen av diabetes 3 % i aldersgruppen 35 – 39 år og opptil 20 % hos deltagere i 60-årsalderen. Til tross for at så mange som rundt 80 % av dem med kjent diabetes fikk medikamentell behandling for å kontrollere blodsukkernivået, var gjennomsnittlig nivå av glykosylert hemoglobin (HbA1c) 9,0 % ved studiestart.
Etter om lag 12 års oppfølging var den relative risikoen for død 5,4 (95 % KI 5,0 – 6,0) for dem med diabetes i aldersgruppen 35 – 59 år, sammenlignet med dem som ikke hadde diabetes ved studiestart. I aldersgruppene 60 – 74 år og 75 – 84 år var den relative risikoen for død henholdsvis 3,1 (95 % KI 2,9 – 3,3) og 1,9 (95 % KI 1,8 – 2,1). Sammenhengen mellom diabetes og død var sterkest for død som følge av nyresykdom, med en relativ risiko på 31,1 (95 % KI 24,3 – 39,8) i aldersgruppen 35 – 59 år. Akutt diabetisk krise lå bak 8 % av dødsfallene hos dem med diabetes. Risikoen for død av hjerte- og karsykdom, infeksjoner og magesår var også økt. Diabetes var derimot ikke assosiert med høyere dødelighet av kols eller kreft.
Forfatterne konkluderer med at diabetes er vanlig i Mexico, at blodsukkerkontrollen er dårlig, og at prognosen er mye dårligere enn i høyinntektsland.
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Efficacy and Safety of Vedolizumab in Ulcerative Colitis and Crohn’s Disease Patients Stratified by Age
Abstract
Introduction
The efficacy and safety of vedolizumab, a gut-selective α4β7 integrin antibody, were demonstrated in the GEMINI 1 and GEMINI 2 clinical trials of adults aged 18–80 years. We investigated the efficacy and safety of vedolizumab in patients stratified by age from the GEMINI trials.
Methods
Safety and efficacy, including clinical response, clinical remission, and corticosteroid-free remission, at week 6 and/or 52 were determined post hoc in patients aged <35, 35 to <55, and ≥55 years.
Results
At baseline, 353, 412, and 130 ulcerative colitis (UC) and 582, 443, and 90 Crohn’s disease (CD) patients were aged <35, 35 to <55, and ≥55. Of these patients, 56 were aged ≥65 years (UC: 33, CD: 23). Trends favoring vedolizumab over placebo were observed for most efficacy endpoints irrespective of patient age; some variability between subgroups was observed. Safety profiles of vedolizumab and placebo were similar in all age groups. Vedolizumab-treated patients aged ≥55 had the lowest incidence of serious infections (0.9 per 100 person–years) and adverse events leading to hospitalization (14.8 per 100 person–years). There were no age-related differences in the incidence of adverse hematological events, malignancy, or death.
Conclusions
The safety and efficacy of vedolizumab in patients with UC or CD were similar for all age groups. The number of patients in the oldest age group in these analyses was small; thus further studies of vedolizumab in larger cohorts of elderly patients are warranted.
Funding
Millennium Pharmaceuticals, Inc. (d/b/a Takeda Pharmaceuticals International Co.).
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Pharmacokinetic Evaluation of Once-Weekly and Once-Monthly Buprenorphine Subcutaneous Injection Depots (CAM2038) Versus Intravenous and Sublingual Buprenorphine in Healthy Volunteers Under Naltrexone Blockade: An Open-Label Phase 1 Study
Abstract
Introduction
CAM2038 q1w (once weekly) and q4w (once monthly) are investigational buprenorphine subcutaneous (SC) formulations based on FluidCrystal® injection depot technology. These two drug products are being developed for opioid dependence treatment, with a target for once-weekly and once-monthly SC dosing. The rationale for developing two products with different dosing frequencies is that treatment strategies/routines, and hence different treatment preferences, can vary between patients, different stages of opioid maintenance treatment, and countries. This study evaluated the pharmacokinetics and safety of buprenorphine and norbuprenorphine following administration of CAM2038 q1w or q4w versus active controls.
Methods
Healthy volunteers were randomized to five treatment groups. All received a single intravenous dose of buprenorphine 600 µg, followed post-washout by a single dose of CAM2038 q4w 96 mg, a single dose of CAM2038 q4w 192 mg, or sublingual buprenorphine 8, 16, or 24 mg daily for 7 days, followed post-washout by a single dose of CAM2038 q4w 64 or 128 mg or four repeated weekly doses of CAM2038 q1w 16 mg. All subjects received daily naltrexone.
Results
Eighty-seven subjects were randomized. Median buprenorphine t max after CAM2038 q4w was 4–10 h (24 h for CAM2038 q1w); mean terminal half-life was 19–25 days (5 days for CAM2038 q1w). CAM2038 q4w showed dose-proportional buprenorphine release, with similar exposure to repeat-dose CAM2038 q1w at comparable monthly dose level. Both CAM2038 formulations showed complete absolute bioavailability of buprenorphine and 5.7- to 7.7-fold greater buprenorphine bioavailability versus sublingual buprenorphine. CAM2038 q1w and q4w were well tolerated; subjects’ acceptance was higher for CAM2038 than for sublingual buprenorphine 1 h post-dose.
Conclusions
The pharmacokinetic profiles of CAM2038 q1w and q4w versus sublingual buprenorphine support expected treatment efficacy with once-weekly and once-monthly dosing, respectively. CAM2038 formulations were safe and showed good local tolerability.
Trial registration: ISRCTN24987553.
Funding: Camurus AB.
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Optimizing the effects of Persian gum and carrot pomace powder for development of low-fat donut with high fibre content
Publication date: Available online 10 January 2017
Source:Bioactive Carbohydrates and Dietary Fibre
Author(s): Mehran Nouri, Behzad Nasehi, Vahid Samavati, Saman Abdanan Mehdizadeh
The objective of present study was to develop and optimize a low-fat high fibre donut formulation using response surface methodology. A 5-level-3-factor central composite rotatable design was employed, where the independent variables were Persian gum (0–1.5g/100g), carrot pomace powder (0–15g/100g) and water (38–53g/100g), while the dependent variables were physicochemical properties of donuts. It was found that Persian gum and carrot pomace powder both effectively contributed to retention of donuts moisture content which in turn led to significant reduction of fat uptake during frying process (p < 0.05). Persian gum decreased the donuts firmness while carrot pomace powder adversely affected the textural properties as well as specific volume (p < 0.05). Image analysis revealed that carrot pomace powder influenced all the image analysis parameters investigated negatively. Response surface methodology described that donuts with optimum formulation of 1.20g/100gPersian gum, 6.45g/100gcarrot pomace powder and 48.16g/100g water had considerably lower fat uptake and acceptable sensory attributes compared to control sample.
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Source:Bioactive Carbohydrates and Dietary Fibre
Author(s): Mehran Nouri, Behzad Nasehi, Vahid Samavati, Saman Abdanan Mehdizadeh
The objective of present study was to develop and optimize a low-fat high fibre donut formulation using response surface methodology. A 5-level-3-factor central composite rotatable design was employed, where the independent variables were Persian gum (0–1.5g/100g), carrot pomace powder (0–15g/100g) and water (38–53g/100g), while the dependent variables were physicochemical properties of donuts. It was found that Persian gum and carrot pomace powder both effectively contributed to retention of donuts moisture content which in turn led to significant reduction of fat uptake during frying process (p < 0.05). Persian gum decreased the donuts firmness while carrot pomace powder adversely affected the textural properties as well as specific volume (p < 0.05). Image analysis revealed that carrot pomace powder influenced all the image analysis parameters investigated negatively. Response surface methodology described that donuts with optimum formulation of 1.20g/100gPersian gum, 6.45g/100gcarrot pomace powder and 48.16g/100g water had considerably lower fat uptake and acceptable sensory attributes compared to control sample.
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Oligomeric state of hypoxanthine−guanine phosphoribosyltransferase from Mycobacterium tuberculosis
Publication date: Available online 9 January 2017
Source:Biochimie
Author(s): Wai Soon Eng, Dianne T. Keough, Dana Hockova, Donald J. Winzor, Luke W. Guddat
Sedimentation equilibrium and size-exclusion chromatography experiments on Mycobacterium tuberculosis hypoxanthine-guanine phosphoribosyltransferase (MtHGPRT) have established the existence of this enzyme as a reversibly associating mixture of dimeric and tetrameric species in 0.1 M Tris-HCl−0.012 M MgCl2, pH 7.4. Displacement of the equilibrium position towards the larger oligomer by phosphate signifies the probable existence of MtHGPRT as a tetramer in the biological environment. These data thus add credibility to the relevance of considering enzyme function in the light of a published tetrameric structure deduced from X-ray crystallography. Failure of 5-phospho-α-D-ribosyl-1-pyrophosphate (PRib-PP) to perturb the dimer−tetramer equilibrium position indicates the equivalence and independence of binding for this substrate (the first to bind in an ordered sequential mechanism) to the two oligomers. By virtue of the displacement of the equilibrium position towards dimer that is affected by removing MgCl2 from the Tris-HCl buffer, it can be concluded that divalent metal ions, as well as phosphate, can affect the oligomerization. These characteristics of MtHGPRT in solution are correlated with published crystal structures of four enzyme−ligand complexes.
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Source:Biochimie
Author(s): Wai Soon Eng, Dianne T. Keough, Dana Hockova, Donald J. Winzor, Luke W. Guddat
Sedimentation equilibrium and size-exclusion chromatography experiments on Mycobacterium tuberculosis hypoxanthine-guanine phosphoribosyltransferase (MtHGPRT) have established the existence of this enzyme as a reversibly associating mixture of dimeric and tetrameric species in 0.1 M Tris-HCl−0.012 M MgCl2, pH 7.4. Displacement of the equilibrium position towards the larger oligomer by phosphate signifies the probable existence of MtHGPRT as a tetramer in the biological environment. These data thus add credibility to the relevance of considering enzyme function in the light of a published tetrameric structure deduced from X-ray crystallography. Failure of 5-phospho-α-D-ribosyl-1-pyrophosphate (PRib-PP) to perturb the dimer−tetramer equilibrium position indicates the equivalence and independence of binding for this substrate (the first to bind in an ordered sequential mechanism) to the two oligomers. By virtue of the displacement of the equilibrium position towards dimer that is affected by removing MgCl2 from the Tris-HCl buffer, it can be concluded that divalent metal ions, as well as phosphate, can affect the oligomerization. These characteristics of MtHGPRT in solution are correlated with published crystal structures of four enzyme−ligand complexes.
Graphical abstract
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Høy dødelighet ved diabetes i Mexico
Diabetes er vanlig i Mexico, blodsukkerkontrollen er dårlig og prognosen mye dårligere enn i høyinntekstland.
Illustrasjonsfoto: Thinkstock
Mexico er et av landene i verden med høyest forekomst av fedme og type 2-diabetes. I en prospektiv studie med rundt 150 000 voksne i alderen 35 – 84 år ble personer med andre kroniske sykdommer enn diabetes ekskludert (1). Ved studiestart var prevalensen av diabetes 3 % i aldersgruppen 35 – 39 år og opptil 20 % hos deltagere i 60-årsalderen. Til tross for at så mange som rundt 80 % av dem med kjent diabetes fikk medikamentell behandling for å kontrollere blodsukkernivået, var gjennomsnittlig nivå av glykosylert hemoglobin (HbA1c) 9,0 % ved studiestart.
Etter om lag 12 års oppfølging var den relative risikoen for død 5,4 (95 % KI 5,0 – 6,0) for dem med diabetes i aldersgruppen 35 – 59 år, sammenlignet med dem som ikke hadde diabetes ved studiestart. I aldersgruppene 60 – 74 år og 75 – 84 år var den relative risikoen for død henholdsvis 3,1 (95 % KI 2,9 – 3,3) og 1,9 (95 % KI 1,8 – 2,1). Sammenhengen mellom diabetes og død var sterkest for død som følge av nyresykdom, med en relativ risiko på 31,1 (95 % KI 24,3 – 39,8) i aldersgruppen 35 – 59 år. Akutt diabetisk krise lå bak 8 % av dødsfallene hos dem med diabetes. Risikoen for død av hjerte- og karsykdom, infeksjoner og magesår var også økt. Diabetes var derimot ikke assosiert med høyere dødelighet av kols eller kreft.
Forfatterne konkluderer med at diabetes er vanlig i Mexico, at blodsukkerkontrollen er dårlig, og at prognosen er mye dårligere enn i høyinntektsland.
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Sensitive Versatile Fluorogenic Transmembrane Peptide Substrates for Rhomboid Intramembrane Proteases [Membrane Biology]
Rhomboid proteases are increasingly being explored as potential drug targets, but their potent and specific inhibitors are not available, and strategies for inhibitor development are hampered by the lack of widely usable and easily modifiable in vitro activity assays. Here we address this bottleneck and report on the development of new fluorogenic transmembrane peptide substrates, which are cleaved by several unrelated rhomboid proteases, can be used both in detergent micelles and in liposomes, and contain red-shifted fluorophores that are suitable for high-throughput screening of compound libraries. We show that nearly the entire transmembrane domain of the substrate is important for efficient cleavage, implying that it extensively interacts with the enzyme. Importantly, we demonstrate that in the detergent micelle system, commonly used for the enzymatic analyses of intramembrane proteolysis, the cleavage rate strongly depends on detergent concentration, since the reaction proceeds only in the micelles. Furthermore, we show that the catalytic efficiency and selectivity towards a rhomboid substrate can be dramatically improved by targeted modification of the sequence of its P5 to P1 region. The fluorogenic substrates that we describe and their sequence variants should find wide use in the detection of activity and development of inhibitors of rhomboid proteases.
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Kinetic Modeling and Analysis of the Akt/Mechanistic Target of Rapamycin Complex 1 (mTORC1) Signaling Axis Reveals Cooperative, Feedforward Regulation [Computational Biology]
Mechanistic target of rapamycin complex 1 (mTORC1) controls biosynthesis and has been implicated in uncontrolled cell growth in cancer. Although many details of mTORC1 regulation are well understood, a systems-level, predictive framework synthesizing those details is currently lacking. We constructed various mathematical models of mTORC1 activation mediated by Akt and aligned the model outputs to kinetic data acquired for growth factor-stimulated cells. A model based on a putative feedforward loop orchestrated by Akt consistently predicted how the pathway was altered by depletion of key regulatory proteins. Analysis of the successful model also elucidates two dynamical motifs: neutralization of a negative regulator, which characterizes how Akt indirectly activates mTORC1, and seesaw enzyme regulation, which describes how activated and inhibited states of mTORC1 are controlled in concert to produce a nonlinear, ultrasensitive response. Such insights lend quantitative understanding of signaling networks and their precise manipulation in various contexts.
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The Receptor-Interacting Serine/Threonine Protein Kinase 1 (Ripk1) Regulates Progranulin Levels [Molecular Bases of Disease]
Progranulin (PGRN), a secreted growth factor, is a key regulator of inflammation and is genetically linked to two common and devastating neurodegenerative diseases. Haploinsufficiency mutations in GRN, the gene encoding PGRN, cause frontotemporal dementia (FTD) and a GRN SNP confers significantly increased risk for Alzheimer's disease (AD). Because cellular and animal data indicate that increasing PGRN can reverse phenotypes of both FTD and AD, modulating PGRN level has been proposed as a therapeutic strategy for both diseases. However, little is known about the regulation of PGRN levels. In this study, we performed an siRNA-based screen of the kinome to identify genetic regulators of Pgrn levels in a rodent cell-based model system. We found that knocking down receptor-interacting serine/threonine protein kinase 1 (Ripk1) increased both intracellular and extracellular Pgrn protein levels by increasing the translation rate of Pgrn without affecting mRNA levels. We observed this effect in neuro2a cells, wild-type primary mouse neurons, and Grn-haploinsufficient primary neurons from an FTD mouse model. We found that the effect of Ripk1 on Pgrn is independent of Ripk1's kinase activity and occurs through a novel signaling pathway. These data suggest that targeting Ripk1 may be a therapeutic strategy in both AD and FTD.
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Cooperative substrate-cofactor interactions and membrane localization of the bacterial PLA2 enzyme, ExoU [Protein Structure and Folding]
The ExoU type III secretion enzyme is a potent phospholipase A2 secreted by the Gram-negative opportunistic pathogen, Pseudomonas aeruginosa. Activation of phospholipase activity is induced by protein-protein interactions with ubiquitin in the cytosol of a targeted eukaryotic cell, leading to destruction of host cell membranes. Previous work in our laboratory suggested that conformational changes within a C-terminal domain of the toxin might be involved in the activation mechanism. In this study, we use site-directed spin labeling electron paramagnetic resonance spectroscopy to investigate conformational changes in a C-terminal four-helical bundle region of ExoU as it interacts with lipid substrates and ubiquitin, and to examine the localization of this domain with respect to the lipid bilayer. In the absence of ubiquitin or substrate liposomes, the overall structure of the C-terminal domain is in good agreement with crystallographic models derived from ExoU in complex with its chaperone, SpcU. Significant conformational changes are observed throughout the domain in the presence of ubiquitin and liposomes combined that are not observed with either liposomes or ubiquitin alone. In the presence of ubiquitin, two interhelical loops of the C-terminal four-helix bundle appear to penetrate the membrane bilayer, stabilizing ExoU-membrane association. Thus, ubiquitin and the substrate lipid bilayer act synergistically to induce a conformational rearrangement in the C-terminal domain of ExoU.
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Residues in the RecQ C-terminal Domain of the Human Werner Syndrome Helicase are Involved in Unwinding G-quadruplex DNA [Enzymology]
The structural and biophysical properties typically associated with G-quadruplex (G4) structures renders them a significant block for DNA replication, which must be overcome for cell division to occur. The Werner syndrome protein (WRN) is a RecQ-family helicase that has been implicated in the efficient processing of G4 DNA structures. The aim of the current study was to identify the residues of WRN involved in the binding and ATPase-driven unwinding of G4 DNA. Using a c-Myc G4 DNA model sequence and recombinant WRN, we have determined that the RecQ-C-terminal (RQC) domain of WRN imparts a 2-fold preference for binding to G4 DNA relative to non-G4 DNA substrates. NMR studies identified residues involved specifically in interactions with G4 DNA. Three of the amino acids in the WRN RQC domain that exhibited the largest G4-specific changes in NMR signal were then mutated alone or in combination. Mutating individual residues implicated in G4 binding had a modest effect on WRN binding to DNA, decreasing the preference for G4 substrates by ~25%. Mutating two G4-interacting residues (T1024G and T1086G) abrogated preferential binding of WRN to G4 DNA. Very modest decreases in G4 DNA-stimulated ATPase activity were observed for the mutant enzymes. Most strikingly, G4 unwinding by WRN was inhibited ~50% for all three point mutants and >90% for the WRN double mutant (T1024G/T1086G) relative to normal B-form dsDNA substrates. Our work has helped to identify residues in the WRN RQC domain that are involved specifically in the interaction with G4 DNA.
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TGF-{beta}1/Smad3 pathway targets PP2A-AMPK-FoxO1 to regulate hepatic gluconeogenesis [Molecular Bases of Disease]
Maintenance of glucose homeostasis is essential for normal physiology. Deviation from normal glucose levels, in either direction, increases susceptibility to serious medical complications such as hypoglycemia or diabetes. Maintenance of glucose homeostasis is achieved via functional interactions amongst various organs, liver, skeletal muscle, adipose tissue, brain and the endocrine pancreas. The liver is the primary site for endogenous glucose production, especially during states of prolonged fasting. However, enhanced gluconeogenesis is also a signature feature of type 2 diabetes (T2D). Thus, elucidating the signaling pathways that regulate hepatic gluconeogenesis would allow better insight into the process of normal endogenous glucose production as well as how this process is impaired in T2D. Here we demonstrate that the TGF-β1/Smad3 signaling pathway promotes hepatic gluconeogenesis, both upon prolonged fasting and during T2D. In contrast, genetic and pharmacological inhibition of TGF-β1/Smad3 signals suppressed endogenous glucose production. TGF-β1 and Smad3 signals achieve this effect via targeting key regulators of hepatic gluconeogenesis, the protein phosphatase 2A (PP2A), AMPK and FoxO1 proteins. Specifically, TGF-β1 signaling suppressed the LKB1-AMPK axis thereby facilitating the nuclear translocation of FoxO1 and activation of key gluconeogenic genes, glucose-6-phosphatase and phosphoenol-pyruvate carboxy kinase. These findings underscore an important role of TGF-β1/Smad3 signaling in hepatic gluconeogenesis, both in normal physiology and in the pathophysiology of metabolic diseases such as diabetes, and are thus of significant medical relevance.
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Sporadic cases of adult measles: a research article
Measles caused by a paramyxovirus, characterized by fever, malaise, cough, coryza conjunctivitis, a maculopapular rash is known to result in pneumonia, encephalitis and death. Fatal cases of measles in Sri Lan...
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Occurrence of Emery-Dreifuss muscular dystrophy in a rural setting of Cameroon: a case report and review of the literature
Emery-Dreifuss muscular dystrophy is a rare genetic muscular disease, presenting mainly with contractures, weakness and cardiac conduction abnormalities. Its clinical and laboratory similarities to other muscu...
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Association between physical activity and sleep-disordered breathing in male Japanese workers: a cross-sectional study
Whether physical activity reduces the risk of sleep-disordered breathing (SDB) for non-obese people remains unclear. The present cross-sectional study examined the association between physical activity and SDB...
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MOD-4023, a long-acting carboxy-terminal peptide-modified human growth hormone: results of a Phase 2 study in growth hormone-deficient adults
Objective
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Growth hormone (GH) replacement therapy currently requires daily injections, which may cause distress and low compliance. C-terminal peptide (CTP)-modified growth hormone (MOD-4023) is being developed as a once-weekly dosing regimen in patients with GH deficiency (GHD). This study’s objective is to evaluate the safety, pharmacokinetics (PK), pharmacodynamics (PD) and efficacy of MOD-4023 administered once-weekly in GHD adults.
Design54 adults with GHD currently treated with daily GH were normalized and randomized into 4 weekly dosing cohorts of MOD-4023 at 18.5%, 37%, 55.5% or 123.4% of individual cumulative weekly molar hGH dose. The study included 2 stages: Stage A assessed the effectiveness and PK/PD profiles of the 4 dosing regimens of MOD-4023. Stage B was an extension period of once-weekly MOD-4023 administration (61.7% molar hGH content) to collect further safety data and confirm the results from Stage A.
ResultsDose-dependent response was observed for both PK and PD data of weekly MOD-4023 treatment. Insulin-like growth factor I (IGF-I) SDS levels were maintained within normal range. The 18.5% cohort was discontinued due to low efficacy. MOD-4023 was well tolerated and exhibited favorable safety profile in all dose cohorts. The reported adverse events were consistent with known GH-related side effects.
ConclusionsOnce-weekly MOD-4023 administration in GHD adults was found to be clinically effective while maintaining a favorable safety profile and may obviate the need for daily injections. Weekly GH injections may improve compliance and overall outcome. The promising results achieved in this Phase 2 study led to a pivotal Phase 3 trial, which is currently ongoing.
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Cabergoline for Cushings disease: a large retrospective multicenter study
Objective
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The efficacy of cabergoline in Cushing’s disease (CD) is controversial. The aim of this study was to assess the efficacy and tolerability of cabergoline in a large contemporary cohort of patients with CD.
DesignWe conducted a retrospective multicenter study from thirteen French and Belgian university hospitals.
MethodsSixty-two patients with CD received cabergoline monotherapy or add-on therapy. Symptom score, biological markers of hypercortisolism and adverse effects were recorded.
ResultsTwenty-one (40%) of 53 patients who received cabergoline monotherapy had normal urinary free cortisol (UFC) values within 12 months (complete responders), and five of these patients developed corticotropic insufficiency. The fall in UFC was associated with significant reductions in midnight cortisol and plasma ACTH, and with clinical improvement. Compared to other patients, complete responders had similar median baseline UFC (2.0 vs 2.5xULN) and plasma prolactin concentrations but received lower doses of cabergoline (1.5 vs 3.5 mg/week, P < 0.05). During long-term treatment (>12 months), cabergoline was withdrawn in 28% of complete responders because of treatment escape or intolerance. Overall, sustained control of hypercortisolism was obtained in 23% of patients for 32.5 months (19–105). Nine patients on steroidogenesis inhibitors received cabergoline add-on therapy for 19 months (1–240). Hypercortisolism was controlled in 56% of these patients during the first year of treatment with cabergoline at 1.0 mg/week (0.5–3.5).
ConclusionsAbout 20–25% of CD patients are good responders to cabergoline therapy allowing long-term control of hypercortisolism at relatively low dosages and with acceptable tolerability. No single parameter, including the baseline UFC and prolactin levels, predicted the response to cabergoline.
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Clinical characteristics and management of growth hormone excess in patients with McCune-Albright syndrome
Objective
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McCune–Albright syndrome (MAS) is a sporadic, postzygotic disease presenting with fibrous dysplasia, cafe-au-lait spots and multiple endocrinopathies. Growth hormone (GH) excess is an uncommon but potentially severe complication of MAS. This study aims to describe the clinical manifestations of GH excess in the context of MAS and analyze the responses of these patients to treatments.
DesignRetrospective clinical study.
MethodsClinical data from 52 MAS patients were analyzed. Serum GH and IGF1 levels, as well as nadir GH levels after an oral glucose tolerance test and alkaline phosphatase (ALP) levels were determined before and after the treatment.
ResultsIn total, 13 MAS patients (25%) had the complication of GH excess, including 10 males (76.9%). Among them, all had FD, and 6 patients had sphenoidal bone involvement. Visual deficits were present in 8 patients, and hearing deficits were present in 5. Olfactory dysfunction was observed in 3 patients. Evident pituitary adenomas were confirmed in 9 patients by MRI. These patients underwent surgery with or without pretreatment of long-acting somatostatin analogue octreotide, and 6 achieved complete remission. The serum ALP levels decreased significantly after treatment for GH excess.
ConclusionsMAS with GH excess is more common in male patients. GH excess can lead to more severe skeletal lesions in MAS patients involving more of the craniofacial bones. Complete trans-sphenoidal complete tumor excision with neuronavigational guidance is effective and could lower ALP levels. LAR is recommended as a preoperative treatment and when patients fail to achieve complete remission after surgery.
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Høy dødelighet ved diabetes i Mexico
Diabetes er vanlig i Mexico, blodsukkerkontrollen er dårlig og prognosen mye dårligere enn i høyinntekstland.
Illustrasjonsfoto: Thinkstock
Mexico er et av landene i verden med høyest forekomst av fedme og type 2-diabetes. I en prospektiv studie med rundt 150 000 voksne i alderen 35 – 84 år ble personer med andre kroniske sykdommer enn diabetes ekskludert (1). Ved studiestart var prevalensen av diabetes 3 % i aldersgruppen 35 – 39 år og opptil 20 % hos deltagere i 60-årsalderen. Til tross for at så mange som rundt 80 % av dem med kjent diabetes fikk medikamentell behandling for å kontrollere blodsukkernivået, var gjennomsnittlig nivå av glykosylert hemoglobin (HbA1c) 9,0 % ved studiestart.
Etter om lag 12 års oppfølging var den relative risikoen for død 5,4 (95 % KI 5,0 – 6,0) for dem med diabetes i aldersgruppen 35 – 59 år, sammenlignet med dem som ikke hadde diabetes ved studiestart. I aldersgruppene 60 – 74 år og 75 – 84 år var den relative risikoen for død henholdsvis 3,1 (95 % KI 2,9 – 3,3) og 1,9 (95 % KI 1,8 – 2,1). Sammenhengen mellom diabetes og død var sterkest for død som følge av nyresykdom, med en relativ risiko på 31,1 (95 % KI 24,3 – 39,8) i aldersgruppen 35 – 59 år. Akutt diabetisk krise lå bak 8 % av dødsfallene hos dem med diabetes. Risikoen for død av hjerte- og karsykdom, infeksjoner og magesår var også økt. Diabetes var derimot ikke assosiert med høyere dødelighet av kols eller kreft.
Forfatterne konkluderer med at diabetes er vanlig i Mexico, at blodsukkerkontrollen er dårlig, og at prognosen er mye dårligere enn i høyinntektsland.
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Genomic Profiling of a Large Set of Diverse Pediatric Cancers Identifies Known and Novel Mutations across Tumor Spectra
Pediatric cancers are generally characterized by low mutational burden and few recurrently mutated genes. Recent studies suggest that genomic alterations may help guide treatment decisions and clinical trial selection. Here, we describe genomic profiles from 1,215 pediatric tumors representing sarcomas, extracranial embryonal tumors, brain tumors, hematologic malignancies, carcinomas, and gonadal tumors. Comparable published datasets identified similar frequencies of clinically relevant alterations, validating this dataset as biologically relevant. We identified novel ALK fusions in a neuroblastoma (BEND5–ALK) and an astrocytoma (PPP1CB–ALK), novel BRAF fusions in an astrocytoma (BCAS1–BRAF) and a ganglioglioma (TMEM106B–BRAF), and a novel PAX3–GLI2 fusion in a rhabdomyosarcoma. Previously characterized ALK, NTRK1, and PAX3 fusions were observed in unexpected malignancies, challenging the "disease-specific" alterations paradigm. Finally, we identified recurrent variants of unknown significance in MLL3 and PRSS1 predicted to have functional impact. Data from these 1,215 tumors are publicly available for discovery and validation. Cancer Res; 77(2); 1–11. ©2017 AACR.
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IKBKE Is Required during KRAS-Induced Pancreatic Tumorigenesis
Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest malignancies lacking effective therapeutic strategies. Here, we show that the noncanonical IκB-related kinase, IKBKE, is a critical oncogenic effector during KRAS-induced pancreatic transformation. Loss of IKBKE inhibits the initiation and progression of pancreatic tumors in mice carrying pancreatic-specific KRAS activation. Mechanistically, we demonstrate that this protumoral effect of IKBKE involves the activation of GLI1 and AKT signaling and is independent of the levels of activity of the NF-κB pathway. Further analysis reveals that IKBKE regulates GLI1 nuclear translocation and promotes the reactivation of AKT post-inhibition of mTOR in PDAC cells. Interestingly, combined inhibition of IKBKE and mTOR synergistically blocks pancreatic tumor growth. Together, our findings highlight the functional importance of IKBKE in pancreatic cancer, support the evaluation of IKBKE as a therapeutic target in PDAC, and suggest IKBKE inhibition as a strategy to improve efficacy of mTOR inhibitors in the clinic. Cancer Res; 77(2); 1–10. ©2017 AACR.
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Predicting Severity of Disease-Causing Variants
ABSTRACT
Most diseases, including those of genetic origin, express a continuum of severity. Clinical interventions for numerous diseases are based on the severity of the phenotype. Predicting severity due to genetic variants could facilitate diagnosis and choice of therapy. Although computational predictions have been used as evidence for classifying the disease-relevance of genetic variants, special tools for predicting disease severity in large scale are missing. Here, we manually curated a dataset containing variants leading to severe and less severe phenotypes and studied the abilities of variation impact predictors to distinguish between them. We found that these tools cannot separate the two groups of variants. Then, we developed a novel machine learning-based method, PON-PS (http://ift.tt/2j2b8xP), for classification of amino acid substitutions associated with benign, severe, and less severe phenotypes. We tested the method using an independent test dataset and variants in four additional proteins. For distinguishing severe and non-severe variants, PON-PS showed an accuracy of 61% in the test dataset which is higher than for existing tolerance prediction methods. PON-PS is the first generic tool developed for this task. The tool can be used together with other evidence for improving diagnosis and prognosis and for prioritization of preventive interventions, clinical monitoring, and molecular tests.
This article is protected by copyright. All rights reserved
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Høy dødelighet ved diabetes i Mexico
Diabetes er vanlig i Mexico, blodsukkerkontrollen er dårlig og prognosen mye dårligere enn i høyinntekstland.
Illustrasjonsfoto: Thinkstock
Mexico er et av landene i verden med høyest forekomst av fedme og type 2-diabetes. I en prospektiv studie med rundt 150 000 voksne i alderen 35 – 84 år ble personer med andre kroniske sykdommer enn diabetes ekskludert (1). Ved studiestart var prevalensen av diabetes 3 % i aldersgruppen 35 – 39 år og opptil 20 % hos deltagere i 60-årsalderen. Til tross for at så mange som rundt 80 % av dem med kjent diabetes fikk medikamentell behandling for å kontrollere blodsukkernivået, var gjennomsnittlig nivå av glykosylert hemoglobin (HbA1c) 9,0 % ved studiestart.
Etter om lag 12 års oppfølging var den relative risikoen for død 5,4 (95 % KI 5,0 – 6,0) for dem med diabetes i aldersgruppen 35 – 59 år, sammenlignet med dem som ikke hadde diabetes ved studiestart. I aldersgruppene 60 – 74 år og 75 – 84 år var den relative risikoen for død henholdsvis 3,1 (95 % KI 2,9 – 3,3) og 1,9 (95 % KI 1,8 – 2,1). Sammenhengen mellom diabetes og død var sterkest for død som følge av nyresykdom, med en relativ risiko på 31,1 (95 % KI 24,3 – 39,8) i aldersgruppen 35 – 59 år. Akutt diabetisk krise lå bak 8 % av dødsfallene hos dem med diabetes. Risikoen for død av hjerte- og karsykdom, infeksjoner og magesår var også økt. Diabetes var derimot ikke assosiert med høyere dødelighet av kols eller kreft.
Forfatterne konkluderer med at diabetes er vanlig i Mexico, at blodsukkerkontrollen er dårlig, og at prognosen er mye dårligere enn i høyinntektsland.
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Effect of tualang honey against KA-induced oxidative stress and neurodegeneration in the cortex of rats
Administration of KA on rodents has resulted in seizures, behavioral changes, oxidative stress, and neuronal degeneration on selective population of neurons in the brain. The present study was undertaken to in...
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Enterolactone alters FAK-Src signaling and suppresses migration and invasion of lung cancer cell lines
Systemic toxicity of chemotherapeutic agents and the challenges associated with targeting metastatic tumors are limiting factors for current lung cancer therapeutic approaches. To address these issues, plant-d...
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Høy dødelighet ved diabetes i Mexico
Diabetes er vanlig i Mexico, blodsukkerkontrollen er dårlig og prognosen mye dårligere enn i høyinntekstland.
Illustrasjonsfoto: Thinkstock
Mexico er et av landene i verden med høyest forekomst av fedme og type 2-diabetes. I en prospektiv studie med rundt 150 000 voksne i alderen 35 – 84 år ble personer med andre kroniske sykdommer enn diabetes ekskludert (1). Ved studiestart var prevalensen av diabetes 3 % i aldersgruppen 35 – 39 år og opptil 20 % hos deltagere i 60-årsalderen. Til tross for at så mange som rundt 80 % av dem med kjent diabetes fikk medikamentell behandling for å kontrollere blodsukkernivået, var gjennomsnittlig nivå av glykosylert hemoglobin (HbA1c) 9,0 % ved studiestart.
Etter om lag 12 års oppfølging var den relative risikoen for død 5,4 (95 % KI 5,0 – 6,0) for dem med diabetes i aldersgruppen 35 – 59 år, sammenlignet med dem som ikke hadde diabetes ved studiestart. I aldersgruppene 60 – 74 år og 75 – 84 år var den relative risikoen for død henholdsvis 3,1 (95 % KI 2,9 – 3,3) og 1,9 (95 % KI 1,8 – 2,1). Sammenhengen mellom diabetes og død var sterkest for død som følge av nyresykdom, med en relativ risiko på 31,1 (95 % KI 24,3 – 39,8) i aldersgruppen 35 – 59 år. Akutt diabetisk krise lå bak 8 % av dødsfallene hos dem med diabetes. Risikoen for død av hjerte- og karsykdom, infeksjoner og magesår var også økt. Diabetes var derimot ikke assosiert med høyere dødelighet av kols eller kreft.
Forfatterne konkluderer med at diabetes er vanlig i Mexico, at blodsukkerkontrollen er dårlig, og at prognosen er mye dårligere enn i høyinntektsland.
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Høy dødelighet ved diabetes i Mexico
Diabetes er vanlig i Mexico, blodsukkerkontrollen er dårlig og prognosen mye dårligere enn i høyinntekstland.
Illustrasjonsfoto: Thinkstock
Mexico er et av landene i verden med høyest forekomst av fedme og type 2-diabetes. I en prospektiv studie med rundt 150 000 voksne i alderen 35 – 84 år ble personer med andre kroniske sykdommer enn diabetes ekskludert (1). Ved studiestart var prevalensen av diabetes 3 % i aldersgruppen 35 – 39 år og opptil 20 % hos deltagere i 60-årsalderen. Til tross for at så mange som rundt 80 % av dem med kjent diabetes fikk medikamentell behandling for å kontrollere blodsukkernivået, var gjennomsnittlig nivå av glykosylert hemoglobin (HbA1c) 9,0 % ved studiestart.
Etter om lag 12 års oppfølging var den relative risikoen for død 5,4 (95 % KI 5,0 – 6,0) for dem med diabetes i aldersgruppen 35 – 59 år, sammenlignet med dem som ikke hadde diabetes ved studiestart. I aldersgruppene 60 – 74 år og 75 – 84 år var den relative risikoen for død henholdsvis 3,1 (95 % KI 2,9 – 3,3) og 1,9 (95 % KI 1,8 – 2,1). Sammenhengen mellom diabetes og død var sterkest for død som følge av nyresykdom, med en relativ risiko på 31,1 (95 % KI 24,3 – 39,8) i aldersgruppen 35 – 59 år. Akutt diabetisk krise lå bak 8 % av dødsfallene hos dem med diabetes. Risikoen for død av hjerte- og karsykdom, infeksjoner og magesår var også økt. Diabetes var derimot ikke assosiert med høyere dødelighet av kols eller kreft.
Forfatterne konkluderer med at diabetes er vanlig i Mexico, at blodsukkerkontrollen er dårlig, og at prognosen er mye dårligere enn i høyinntektsland.
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Høy dødelighet ved diabetes i Mexico
Diabetes er vanlig i Mexico, blodsukkerkontrollen er dårlig og prognosen mye dårligere enn i høyinntekstland.
Illustrasjonsfoto: Thinkstock
Mexico er et av landene i verden med høyest forekomst av fedme og type 2-diabetes. I en prospektiv studie med rundt 150 000 voksne i alderen 35 – 84 år ble personer med andre kroniske sykdommer enn diabetes ekskludert (1). Ved studiestart var prevalensen av diabetes 3 % i aldersgruppen 35 – 39 år og opptil 20 % hos deltagere i 60-årsalderen. Til tross for at så mange som rundt 80 % av dem med kjent diabetes fikk medikamentell behandling for å kontrollere blodsukkernivået, var gjennomsnittlig nivå av glykosylert hemoglobin (HbA1c) 9,0 % ved studiestart.
Etter om lag 12 års oppfølging var den relative risikoen for død 5,4 (95 % KI 5,0 – 6,0) for dem med diabetes i aldersgruppen 35 – 59 år, sammenlignet med dem som ikke hadde diabetes ved studiestart. I aldersgruppene 60 – 74 år og 75 – 84 år var den relative risikoen for død henholdsvis 3,1 (95 % KI 2,9 – 3,3) og 1,9 (95 % KI 1,8 – 2,1). Sammenhengen mellom diabetes og død var sterkest for død som følge av nyresykdom, med en relativ risiko på 31,1 (95 % KI 24,3 – 39,8) i aldersgruppen 35 – 59 år. Akutt diabetisk krise lå bak 8 % av dødsfallene hos dem med diabetes. Risikoen for død av hjerte- og karsykdom, infeksjoner og magesår var også økt. Diabetes var derimot ikke assosiert med høyere dødelighet av kols eller kreft.
Forfatterne konkluderer med at diabetes er vanlig i Mexico, at blodsukkerkontrollen er dårlig, og at prognosen er mye dårligere enn i høyinntektsland.
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Constitutive high expression of protein arginine methyltransferase 1 in asthmatic airway smooth muscle cells is caused by reduced microRNA-19a expression and leads to enhanced remodeling
In asthma remodeling airway smooth muscle cells (ASMCs) contribute to airway wall thickness through increased proliferation, migration, and extracellular matrix deposition. Previously, we described that protein arginine methyltransferase 1 (PRMT1) participates in airway remodeling in pulmonary inflammation in E3 rats.
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Mechanisms and Barriers in Cancer Nanomedicine: Addressing Challenges, Looking for Solutions
ACS Nano
DOI: 10.1021/acsnano.6b08244
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Self-Sterilized Flexible Single-Electrode Triboelectric Nanogenerator for Energy Harvesting and Dynamic Force Sensing
ACS Nano
DOI: 10.1021/acsnano.6b07389
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Høy dødelighet ved diabetes i Mexico
Diabetes er vanlig i Mexico, blodsukkerkontrollen er dårlig og prognosen mye dårligere enn i høyinntekstland.
Illustrasjonsfoto: Thinkstock
Mexico er et av landene i verden med høyest forekomst av fedme og type 2-diabetes. I en prospektiv studie med rundt 150 000 voksne i alderen 35 – 84 år ble personer med andre kroniske sykdommer enn diabetes ekskludert (1). Ved studiestart var prevalensen av diabetes 3 % i aldersgruppen 35 – 39 år og opptil 20 % hos deltagere i 60-årsalderen. Til tross for at så mange som rundt 80 % av dem med kjent diabetes fikk medikamentell behandling for å kontrollere blodsukkernivået, var gjennomsnittlig nivå av glykosylert hemoglobin (HbA1c) 9,0 % ved studiestart.
Etter om lag 12 års oppfølging var den relative risikoen for død 5,4 (95 % KI 5,0 – 6,0) for dem med diabetes i aldersgruppen 35 – 59 år, sammenlignet med dem som ikke hadde diabetes ved studiestart. I aldersgruppene 60 – 74 år og 75 – 84 år var den relative risikoen for død henholdsvis 3,1 (95 % KI 2,9 – 3,3) og 1,9 (95 % KI 1,8 – 2,1). Sammenhengen mellom diabetes og død var sterkest for død som følge av nyresykdom, med en relativ risiko på 31,1 (95 % KI 24,3 – 39,8) i aldersgruppen 35 – 59 år. Akutt diabetisk krise lå bak 8 % av dødsfallene hos dem med diabetes. Risikoen for død av hjerte- og karsykdom, infeksjoner og magesår var også økt. Diabetes var derimot ikke assosiert med høyere dødelighet av kols eller kreft.
Forfatterne konkluderer med at diabetes er vanlig i Mexico, at blodsukkerkontrollen er dårlig, og at prognosen er mye dårligere enn i høyinntektsland.
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Tarmkreftscreening hos eldre?
Koloskopiscreening gir lavere forekomst av kolorektal kreft hos mennesker opp til 75 års alder. Det viser en ny studie.
Illustrasjon: Science Photo Library
Nasjonalt råd for prioritering i helsetjenesten har nylig anbefalt innføring av screening for kolorektal kreft i Norge (1). Koloskopi er en av metodene som vurderes. I de fleste europeiske land der man har innført screening, stopper man ved 75 år, mens man i USA ikke har noen øvre aldersgrense. Nylig ble den hittil største studien av koloskopiscreening i aldersgruppen 70 – 79 år publisert i Annals of Internal Medicine (2).
Studien er et amerikansk-norsk samarbeidsprosjekt med data fra 1,3 millioner amerikanere forsikret i Medicare. Det ble brukt avanserte statistiske metoder, såkalt kausal inferens, der man simulerte 520 randomiserte studier i datasettet. Insidens av kolorektal kreft ble sammenlignet hos friske individer som var blitt screenet med koloskopi og personer som ikke var blitt screenet. Oppfølgingstiden var på opptil åtte år. For aldersgruppen 70 – 74 år var insidensen av kolorektal kreft 2,62 % hos ikke-screenede og 2,19 % hos screenede (forskjell 0,42 %; 95 % KI – 0,24 – – 0,63). For aldersgruppen 75 – 79 år var tallene 2,97 % for ikke-screenede og 2,84 % for dem som ble screenet (forskjell 0,14 %; 95 % KI – 0,41 – 0,16).
30-dagerskomplikasjonsraten etter koloskopi var dobbelt så høy hos 75 – 79-åringer (10,3 hendelser per 1 000 screenede) som hos personer i alderen 7l – 74 år (5,6 hendelser per 1 000 screenede).
– Denne store studien viser at koloskopiscreening har liten effekt hos dem som er over 74 år og innebærer betydelig større bivirkninger og komplikasjoner. Dette bekrefter vår nåværende anbefaling i Norge om tilby kolorektalscreening for mennesker opp til 74 års alder, sier den norske medforfatteren Michael Bretthauer.
Forskningsgruppe for klinisk effektforskning
Studien er del av et større samarbeid mellom forskningsgruppen for klinisk effektforskning ved Universitetet i Oslo og Oslo universitetssykehus og forskningsgruppen for kausal inferens ved Harvard TH Chan School of Public Health i Boston. Samarbeidet har ført til flere store epidemiologiske studier innen kolorektal kreft og metodeutvikling innenfor kausal inferens. Kausal inferens er et nytt felt innen medisinsk statistikk og får for tiden stor oppmerksomhet i mange land.
Artikkelen ble e-publisert 26.9.2016 i Annals of Internal Medicine, ett av verdens mest velrenommerte medisinske tidsskrifter
Ordforklaringer
Koloskopiscreening: Screening for kolorektal kreft med bøyelig tarmkikkert etter oral tømming av tarmen med tømmingsvæske. Koloskopiscreening gjøres i USA og noen land i Europa.
Kausal inferens: Fagfelt innenfor statistikk og epidemiologi der man utvikler nye metoder for å forstå årsakssammenhenger.
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Erratum: Naphthoquinones from Onosma paniculatum with Potential Anti-inflammatory Activity
Planta Med
DOI: 10.1055/s-0043-100122
Georg Thieme Verlag KG Stuttgart · New York
Article in Thieme eJournals:
Table of contents | Full text
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Big Effect of Small Nanoparticles: A Shift in Paradigm for Polymer Nanocomposites
ACS Nano
DOI: 10.1021/acsnano.6b07172
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