Ιατρικά Άρθρα Αλέξανδρος Γ. Σφακιανάκης: 01/10/17

Τρίτη 10 Ιανουαρίου 2017

First-in-Human Evaluation of the Safety and Immunogenicity of an Intranasally Administered Replication-Competent Sendai Virus-Vectored HIV Type 1 Gag Vaccine: Induction of Potent T-Cell or Antibody Responses in Prime-Boost Regimens

Background. We report the first-in-human safety and immunogenicity assessment of a prototype intranasally administered, replication-competent Sendai virus (SeV)–vectored, human immunodeficiency virus type 1 (HIV-1) vaccine.

Methods. Sixty-five HIV-1–uninfected adults in Kenya, Rwanda, and the United Kingdom were assigned to receive 1 of 4 prime-boost regimens (administered at 0 and 4 months, respectively; ratio of vaccine to placebo recipients, 12:4): priming with a lower-dose SeV-Gag given intranasally, followed by boosting with an adenovirus 35–vectored vaccine encoding HIV-1 Gag, reverse transcriptase, integrase, and Nef (Ad35-GRIN) given intramuscularly (S_LA); priming with a higher-dose SeV-Gag given intranasally, followed by boosting with Ad35-GRIN given intramuscularly (S_HA); priming with Ad35-GRIN given intramuscularly, followed by boosting with a higher-dose SeV-Gag given intranasally (AS_H); and priming and boosting with a higher-dose SeV-Gag given intranasally (S_HS_H).

Results. All vaccine regimens were well tolerated. Gag-specific IFN- enzyme-linked immunospot–determined response rates and geometric mean responses were higher (96% and 248 spot-forming units, respectively) in groups primed with SeV-Gag and boosted with Ad35-GRIN (S_LA and S_HA) than those after a single dose of Ad35-GRIN (56% and 54 spot-forming units, respectively) or SeV-Gag (55% and 59 spot-forming units, respectively); responses persisted for ≥8 months after completion of the prime-boost regimen. Functional CD8⁺ T-cell responses with greater breadth, magnitude, and frequency in a viral inhibition assay were also seen in the S_LA and S_HA groups after Ad35-GRIN boost, compared with those who received either vaccine alone. SeV-Gag did not boost T-cell counts in the AS_H group. In contrast, the highest Gag-specific antibody titers were seen in the AS_H group. Mucosal antibody responses were sporadic.

Conclusions. SeV-Gag primed functional, durable HIV-specific T-cell responses and boosted antibody responses. The prime-boost sequence appears to determine which arm of the immune response is stimulated.

Clinical Trials Registration. NCT01705990.

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Vaccines Against Respiratory Syncytial Virus: The Time Has Come

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Reply to Mori

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The Gut Microbiome as Possible Key to Understanding and Improving Rotavirus Vaccine Performance in High-Disease Burden Settings

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Molecular Epidemiology of Ascaris Infection Among Pigs in Iowa

Ascaris is a large roundworm parasite that infects humans and pigs throughout the world. Molecular markers have been used to study parasite transmission in Ascaris-endemic and -nonendemic regions of the world. In the United States, ascariasis still persists in commercial swine and has been designated a neglected disease of poverty in humans. However, relatively few data are available for evaluation of zoonotic transmission. In the present study, we obtained adult worms from abattoirs and characterized each worm on the basis of the gene encoding nuclear internal transcribed sequence (ITS) and mitochondrial cox1. Restriction fragment–length polymorphism analysis of ITS revealed swine, human, and hybrid genotypes. cox1 sequences were compared to all complete sequences available in GenBank, and haplotype analysis demonstrated 92 haplotypes worldwide. Sequences from the parasites in this study represented 10 haplotypes, including 6 new haplotypes that have not been previously described. Our results indicate that anthropozoonotic transmission has occurred in the past, resulting in the presence of human genotypes in pigs and supporting further investigation of zoonotic Ascaris transmission in the United States.

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Redeploying {beta}-Lactams Against Staphylococcus aureus: Repurposing With a Purpose

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The Outpatient Burden of Respiratory Syncytial Virus Infections in Older Children

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Reducing Health Regrets in a Changing Climate

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Monocyte Activation Is Associated With Worse Cognitive Performance in HIV-Infected Women With Virologic Suppression

Background. Cognitive impairment persists despite suppression of plasma human immunodeficiency virus (HIV) RNA. Monocyte-related immune activation is a likely mechanism. We examined immune activation and cognition in a cohort of HIV-infected and uninfected women from the Women's Interagency HIV Study (WIHS).

Methods. Blood levels of activation markers, soluble CD163 (sCD163), soluble CD14 (sCD14), CRP, IL-6, and a gut microbial translocation marker (intestinal fatty acid binding protein (I-FABP)) were measured in 253 women (73% HIV-infected). Markers were compared to concurrent (within ± one semiannual visit) neuropsychological testing performance.

Results. Higher sCD163 levels were associated with worse overall performance and worse verbal learning, verbal memory, executive function, psychomotor speed, and fine motor skills (P < .05 for all comparisons). Higher sCD14 levels were associated with worse verbal learning, verbal memory, executive function, and psychomotor speed (P < .05 for all comparisons). Among women with virological suppression, sCD163 remained associated with overall performance, verbal memory, psychomotor speed, and fine motor skills, and sCD164 remained associated with executive function (P < .05 for all comparisons). CRP, IL-6, and I-FABP were not associated with worse cognitive performance.

Conclusions. Monocyte activation was associated with worse cognitive performance, and associations persisted despite viral suppression. Persistent inflammatory mechanisms related to monocytes correlate to clinically pertinent brain outcomes.

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Clinical and Socioeconomic Burden of Respiratory Syncytial Virus Infection in Children

Background. Vaccines and antivirals against respiratory syncytial virus (RSV) are being developed, but there are scarce data on the full impact of RSV infection on outpatient children.

Methods. We analyzed the burden of RSV illness in a prospective cohort study of children aged ≤13 years during 2 consecutive respiratory seasons in Turku, Finland (2231 child-seasons of follow-up). We examined the children and obtained nasal swabs for the detection of RSV during each respiratory illness. The parents filled out daily symptom diaries throughout the study.

Results. Of 6001 medically attended respiratory infections, 302 (5%) were caused by RSV. Per 1000 children, the average annual RSV infection incidence rates among children aged <3, 3–6, and 7–13 years were 275, 117, and 46 cases, respectively. In children aged <3 years, acute otitis media developed in 58%, and 66% of children in this age group received antibiotics. The mean duration of RSV illness was longest (13.0 days) and the rate of parental work absenteeism was highest (136 days per 100 children with RSV illness) in children aged <3 years.

Conclusions. The burden of RSV is particularly great among outpatient children aged <3 years. Young children are an important target group for the development of RSV vaccines and antivirals.

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The Early Adaptive Immune Response in the Pathophysiological Process of Pneumococcal Meningitis

Background. The adaptive immune system has been considered to play a minimal role in the early host response during bacterial meningitis.

Methods. We investigated the progression and outcome of pneumococcal meningitis in Rag1^–/– mice lacking functional B and T cells by assessing overall and symptom-free survival, bacteriological and histological studies, as well as flow cytometry and measurements of proinflammatory mediators.

Results. The intracerebral injection of S. pneumoniae D39 induced the recruitment of B and T cells (CD4⁺, and natural killer) into the brain of wild-type mice. Mice with no functional B and T cells developed clinical symptoms and succumbed to the infection earlier than the wild-type group. In the CNS, Rag1^–/– mice showed lower levels of interleukin 1β, reduced microglial proliferation, and impaired granulocyte recruitment with an earlier spread of pneumococci into the bloodstream, compared with wild-type mice. Lack of B and T cells resulted in a severe impairment of bacterial clearance in blood, spleen, and liver and an exaggerated systemic inflammatory response.

Conclusions. B and T cells are important effector cells delaying the spread of pneumococci from the brain to the systemic circulation and shaping the immune response, thereby prolonging the survival of the host in the absence of antibiotic treatment.

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A Randomized, Controlled, Observer-Blinded Phase 1 Study of the Safety and Immunogenicity of a Respiratory Syncytial Virus Vaccine With or Without Alum Adjuvant

Background. Respiratory syncytial virus (RSV) is a leading cause of childhood bronchiolitis and pneumonia, particularly in early infancy. Immunization of pregnant women could boost preexisting immune responses, providing passive protection to newborns through placental transfer of anti-RSV antibody.

Methods. In this first-in-humans clinical trial of a purified recombinant RSV protein F vaccine engineered to preferentially maintain prefusion conformation (RSV-PreF), 128 healthy men 18–44 years old were randomized to one dose of a RSV-PreF vaccine containing 10, 30, or 60 µg of RSV-PreF antigen, with or without alum adjuvant, or control, and followed for one year for safety and immunogenicity outcomes.

Results. Injection site pain was the most common adverse event, reported by up to 81.3% of participants. The highest RSV neutralizing antibody responses were in the 30 µg RSV-PreF/alum, 60 µg RSV-PreF/alum, and 60 µg RSV-PreF/nonadjuvant groups. Responses were evident on day 7, and 30 days after vaccination these participants had RSV-A neutralizing antibody titers of ≥1:512, and >70% had titers of 1:1024, with titers increasing by 3.2–4.9 fold. Responses remained high on day 60 but waned on days 180 and 360.

Conclusions. The RSV-PreF vaccine elicited rapid RSV neutralizing antibody responses in healthy young men, with an acceptable adverse event profile.

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Reply to Lagier et al

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Significant Correlation Between the Infant Gut Microbiome and Rotavirus Vaccine Response in Rural Ghana

Background. Rotavirus (RV) is the leading cause of diarrhea-related death in children worldwide and 95% of RV-associated deaths occur in Africa and Asia where RV vaccines (RVVs) have lower efficacy. We hypothesize that differences in intestinal microbiome composition correlate with the decreased RVV efficacy observed in poor settings.

Methods. We conducted a nested, case-control study comparing prevaccination, fecal microbiome compositions between 6-week old, matched RVV responders and nonresponders in rural Ghana. These infants' microbiomes were then compared with 154 age-matched, healthy Dutch infants' microbiomes, assumed to be RVV responders. Fecal microbiome analysis was performed in all groups using the Human Intestinal Tract Chip.

Results. We analyzed findings in 78 Ghanaian infants, including 39 RVV responder and nonresponder pairs. The overall microbiome composition was significantly different between RVV responders and nonresponders (FDR, 0.12), and Ghanaian responders were more similar to Dutch infants than nonresponders (P = .002). RVV response correlated with an increased abundance of Streptococcus bovis and a decreased abundance of the Bacteroidetes phylum in comparisons between both Ghanaian RVV responders and nonresponders (FDR, 0.008 vs 0.003) and Dutch infants and Ghanaian nonresponders (FDR, 0.002 vs 0.009).

Conclusions. The intestinal microbiome composition correlates significantly with RVV immunogenicity and may contribute to the diminished RVV immunogenicity observed in developing countries.

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Malaria Parasitemia and Parasite Density in Antiretroviral-Treated HIV-Infected Adults Following Discontinuation of Cotrimoxazole Prophylaxis

Background. Cotrimoxazole (CTX) discontinuation increases malaria incidence in human immunodeficiency virus (HIV)–infected individuals. Rates, quantity, and timing of parasitemia rebound following CTX remain undefined.

Methods. Serial specimens from a trial of HIV-infected individuals receiving antiretroviral treatment (ART) randomized to continue (the CTX arm) or discontinue (the STOP-CTX arm) were examined for malaria parasites by quantitative reverse transcription polymerase chain reaction (PCR). Specimens obtained at enrollment and then quarterly for 12 months and at sick visits were assessed; multiplicity of infection was evaluated by PCR that targeted the polymorphic msp-1/msp-2 alleles.

Results. Among 500 HIV-infected adults receiving ART (median ART duration, 4.5 years), 5% had detectable parasitemia at baseline. After randomization, parasite prevalence increased over time in the STOP-CTX arm, compared with the CTX arm, with values of 4% and <1%, respectively, at month 3, 8% and 2% at month 6, 14% and 2% at month 9, and 22% and 4% at month 12 (P = .0034). The combined mean parasite density at the various time points was higher in the STOP-CTX arm (4.42 vs 3.13 log₁₀ parasites/mL; P < .001). The parasitemia incidence was 42.0 cases per 100 person-years in the STOP-CTX arm and 9.9 cases per 100 person-years in the CTX arm, with an incidence rate ratio of 4.3 (95% confidence interval, 2.7–7.1; P < .001). After enrollment, mixed infections (multiplicity of infection, >1) were only present in the STOP-CTX arm.

Conclusion. Discontinuation of CTX by HIV-infected adults receiving ART resulted in progressive increases in malaria parasitemia prevalence and burden.

Clinical Trials Registration. NCT01425073.

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Severity of Plasma Leakage Is Associated With High Levels of Interferon {gamma}-Inducible Protein 10, Hepatocyte Growth Factor, Matrix Metalloproteinase 2 (MMP-2), and MMP-9 During Dengue Virus Infection

Background. Dengue virus infection typically causes mild dengue fever, but, in severe cases, life-threatening dengue hemorrhagic fever (DHF) and dengue shock syndrome (DSS) occur. The pathophysiological hallmark of DHF and DSS is plasma leakage that leads to enhanced vascular permeability, likely due to a cytokine storm.

Methods. Ninety patients with dengue during 2010–2012 in Singapore were prospectively recruited and stratified according to their disease phase, primary and secondary infection status, and disease severity, measured by plasma leakage. Clinical parameters were recorded throughout the disease progression. The levels of various immune mediators were quantified using comprehensive multiplex microbead-based immunoassays for 46 immune mediators.

Results. Associations between clinical parameters and immune mediators were analyzed using various statistical methods. Potential immune markers, including interleukin 1 receptor antagonist, interferon –inducible protein 10, hepatocyte growth factor, soluble p75 tumor necrosis factor α receptor, vascular cell adhesion molecule 1, and matrix metalloproteinase 2, were significantly associated with significant plasma leakage. Secondary dengue virus infections were also shown to influence disease outcome in terms of disease severity.

Conclusions. This study identified several key markers for exacerbated dengue pathogenesis, notably plasma leakage. This will allow a better understanding of the molecular mechanisms of DHF and DSS in patients with dengue.

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Prevalence and Correlates of Persistent HIV-1 RNA in Cerebrospinal Fluid During Antiretroviral Therapy

Background. Neurocognitive disorders remain common among human immunodeficiency virus (HIV)–positive adults, perhaps owing to persistent HIV-1 RNA in cerebrospinal fluid (CSF) during antiretroviral therapy (ART).

Methods. Using a single-copy assay, we measured HIV-1 RNA levels in CSF and plasma specimens from 220 HIV-positive adults who were taking suppressive ART. Fifty-five participants were tested twice.

Results. HIV-1 RNA was detected in 42.3% of CSF and 65.2% of plasma samples. Correlates of higher CSF HIV-1 RNA levels included higher nadir and current CD4⁺ T-cell counts, a plasma HIV-1 RNA level of ≥ 1 copy/mL, and a lower central nervous system penetration-effectiveness score (model P < .001). Worse neurocognitive performance was associated with discordance in HIV-1 RNA detection between plasma and CSF, lower overall CSF HIV-1 RNA level, and longer ART duration, among others (model P < .001). In the longitudinal subgroup, CSF HIV-1 RNA persisted in most participants (69%) over 7 months.

Conclusions. Low-level HIV-1 RNA in CSF is common during suppressive ART and is associated with low-level HIV-1 RNA in blood, better immune status, and lower ART drug distribution into CSF. The association between HIV-1 RNA discordance and HIV-associated neurocognitive disorder (HAND) may reflect compartmentalization. The relationship between HAND, lower HIV-1 RNA levels in CSF, and lower CD4⁺ T-cell counts may reflect disturbances in the immune response to HIV-1 in the CNS.

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A Live Attenuated Chimeric West Nile Virus Vaccine, rWN/DEN4{Delta}30, Is Well Tolerated and Immunogenic in Flavivirus-Naive Older Adult Volunteers

West Nile virus (WNV) is a major cause of mosquito-borne illness in the United States. Human disease ranges from mild febrile illness to severe fatal neurologic infection. Adults aged >60 years are more susceptible to neuroinvasive disease accompanied by a high mortality rate or long-lasting neurologic sequelae. A chimeric live attenuated West Nile virus vaccine, rWN/DEN430, was shown to be safe and immunogenic in healthy adults aged 18–50 years. This study evaluated rWN/DEN430 in flavivirus-naive adults aged 50–65 years and found it to be safe and immunogenic. Outbreaks of WNV infection tend to be unpredictable, and a safe and effective vaccine will be an important public health tool.

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Trimethoprim-Sulfamethoxazole Prophylaxis During Live Malaria Sporozoite Immunization Induces Long-Lived, Homologous, and Heterologous Protective Immunity Against Sporozoite Challenge

Trimethoprim-sulfamethoxazole (TMP-SMX) is widely used in malaria-endemic areas in human immunodeficiency virus (HIV)–infected children and HIV-uninfected, HIV-exposed children as opportunistic infection prophylaxis. Despite the known effects that TMP-SMX has in reducing clinical malaria, its impact on development of malaria-specific immunity in these children remains poorly understood. Using rodent malaria models, we previously showed that TMP-SMX, at prophylactic doses, can arrest liver stage development of malaria parasites and speculated that TMP-SMX prophylaxis during repeated malaria exposures would induce protective long-lived sterile immunity targeting pre-erythrocytic stage parasites in mice. Using the same models, we now demonstrate that repeated exposures to malaria parasites during TMP-SMX administration induces stage-specific and long-lived pre-erythrocytic protective anti-malarial immunity, mediated primarily by CD8⁺ T-cells. Given the HIV infection and malaria coepidemic in sub-Saharan Africa, clinical studies aimed at determining the optimum duration of TMP-SMX prophylaxis in HIV-infected or HIV-exposed children must account for the potential anti-infection immunity effect of TMP-SMX prophylaxis.

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2-Year Efficacy, Immunogenicity, and Safety of Vigoo Enterovirus 71 Vaccine in Healthy Chinese Children: A Randomized Open-Label Study

Background. This study evaluated the 2-year efficacy, immunogenicity, and safety of the Vigoo enterovirus 71 (EV71) vaccine.

Method. In an initial phase 3 study, we randomly assigned healthy infants and children aged 6–35 months (ratio, 1:1) to receive 2 doses of either EV71 vaccine (5120 participants) or placebo (5125 participants) at days 0 and 28, and followed them for 12 months after vaccination. In this extended follow-up study, we continued to evaluate the efficacy, immunogenicity, and safety of the EV71 vaccine for up to 2 years.

Results. Overall efficacy was 94.84% (95% confidence interval [CI], 83.53%–98.38%) during the 2-year follow-up period (P < .0001), and the vaccine efficacy during the second year was 100.00% (95% CI, 84.15%–100.00%) against EV71-associated hand-foot-and-mouth disease (HFMD; P < .0001). Geometric mean titers of neutralizing antibody in participants remained high during the 2-year follow-up period, and no vaccine-related serious adverse events were recorded.

Conclusions. Two doses of Vigoo EV71 vaccine could provide sustained protection against EV71-associated HFMD in healthy Chinese children.

Clinical Trials Registration. NCT01508247.

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Sedimentation rate

Sedimentation rate: A blood test that detects and monitors inflammation in the body. Abbreviated sed rate. The sed rate measures the rate at which red blood cells in a test tube separate from blood serum over time, becoming sediment at the bottom of the test tube. The sed rate increases as inflammation increases. The sed rate can also become elevated in diseases that feature the production of abnormal proteins, such as multiple myeloma. Also known as erythrocyte sedimentation rate, or ESR.

MedTerms (TM) is the Medical Dictionary of MedicineNet.com.
We Bring Doctors' Knowledge To You

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Clinical Thyroidology for the Public – Highlighted Article

From Clinical Thyroidology for the Public: Hypothyroidism (underactive thyroid) is very common, especially in women and is diagnosed most of the time by an increased TSH level. Read More….

The post Clinical Thyroidology for the Public – Highlighted Article appeared first on American Thyroid Association.

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Idrett på glattisen?

Idretten har solt seg i glansen av gode resultater. Den senere tids dopinghendelser gjør det imidlertid nødvendig å diskutere skyggesidene også.

Idretten har en solside. Prestasjonene, som vi kan lære noe av. Heltene. Den brusende nasjonalfølelsen som vi alle vil ta del i og som nærer vår narsissisme. Idrettens positive effekter på livskvalitet og helse (1). Samtidig har det vært støy rundt skyggesidene.

Én skyggeside, idrettsskadene, har vi taklet godt i Norge. Vi er i front innen forskning på slike skader, etter at vi erkjente at vi ikke klarte å behandle dem godt nok. Man måtte satse mer på dokumentert forebygging (2). Andre skyggesider, som økt risiko for hjertestans og spiseforstyrrelser, har det vært harde debatter om og intern støy og motstand mot å erkjenne, kanskje fordi dette kan oppfattes som uheldig i den gode saks tjeneste – å få folk til å trene og bevege seg mer.

Idretten er i sprik. På den ene side ser man periodevis utmerkede resultater, og stadig mer forskning av høy kvalitet dokumenterer viktigheten av å trene, ikke minst for personer med sykdom. Cardiac Exercise Research Group i Trondheim har i så måte vært fremragende. Pasienter med for eksempel hjertesvikt og kols profitterer på trening (3). Innen kardiologien vet vi nå at langvarig kondisjonstrening fører til økt risiko for atrieflimmer (4), en bivirkning vi trenger å forstå bedre. Man arbeider med å finslipe EKG-kriteriene slik at de kan være et troverdig screeningsinstrument for å forebygge idrettsdødsfallene (5). Resultater fra andre studier kan tyde på at moderat trening er bedre for folkehelsen og livslengden enn hardtrening (6). Den internasjonale bevegelsen Exercise is Medicine (Aktivitetsmedisin) (7) er i gang flere steder i Norge.

På den annen side belaster en annen skyggeside, gjentatte dopinghendelser, idrettens renommé. Dopingreglementet kan synes strengt når slurvete bruk av steroidleppekrem uten antatt prestasjonsfremmende hensikt kan føre til sanksjoner. Vanskeligere er det å forstå rasjonalet bak den omfattende bruken av astmamedisin og de svært høye dosene. Hvem er arkitekten bak dette? Likeledes synes praksisen med å få inhalasjoner av ulik karakter før og mellom renn å være i en gråsone. Grenseoppgangen mellom medikamenter brukt som allment akseptert behandling og medikamenter brukt i prestasjonsfremmende hensikt bør trekkes på ny. Det bør være klarere regler for medikamentdosering og administrasjon.

Det har vært en allmenn oppfatning at vi i Norge ikke har en dopingkultur. Den oppfatningen holder fortsatt for meg. Men den siste tids hendelser har vist at det er flere forhold å rydde opp i også i norsk toppidrett.

Man kan diskutere om skattepenger bør brukes til antidopingarbeid i toppidretten. Andre, inkludert helsevesenet, trenger fellesskapets penger mer. Antidopingarbeidet kan en velstående toppidrett finansiere selv. Den har gjentatte ganger over lang tid korrumpert seg med doping og bør selv ta konsekvensene. Fortsatt doping i toppidretten kan undergrave dens privilegerte posisjon. For å synliggjøre at man virkelig vil dopingen til livs, kunne en andel av premiepengene gå til antidopingarbeid. Doping i breddeidretten er et samfunnsproblem, og samfunnets begrensede midler burde kanskje i større grad brukes der.

Flere idrettsmedisinske kolleger har måtte gå av i kjølvannet av dopingsakene. Tradisjonelt har idrettsmedisinere vært spesialister i ortopedi, i fysikalsk medisin eller i allmennmedisin. Bør idrettsmedisinen være flinkere til å bruke flere fagspesifikke spesialister i annenlinjetjenesten, også på grunn av den rivende fagutviklingen i ulike subspesialiteter? Lungemedisinere, gastroenterologer og kardiologer har vært for fraværende, og flere fag, for eksempel infeksjonsmedisin, hvis pasientgruppe utgjør en stor andel av toppidrettsmedisinen (8), burde være representert.

Idretten representerer store verdier. Feil i toppidretten har store konsekvenser og får raskt medienes søkelys på seg. System-, risiko- og kvalitetsanalyser er selvfølgelig i andre bransjer. Man bør se nøyere på organiseringen av idrettsmedisinen – på bruk av spesialister, ansvar og rettigheter for idrettsleger og registrering av reseptforskrivning – for å få et transparent og etterprøvbart system. Idrettens skyggesider bør diskuteres åpent – idretten blir ikke mindre attraktiv av den grunn.

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Structural, Functional and Clinical Characterization of a Novel PTPN11 Mutation Cluster Underlying Noonan Syndrome

ABSTRACT

Germline mutations in PTPN11, the gene encoding the Src-homology 2 (SH2) domain-containing protein tyrosine phosphatase (SHP2), cause Noonan syndrome (NS), a relatively common, clinically variable, multisystem disorder. Here, we report on the identification of five different PTPN11 missense changes affecting residues Leu²⁶¹, Leu²⁶² and Arg²⁶⁵ in 16 unrelated individuals with clinical diagnosis of NS or with features suggestive for this disorder, specifying a novel disease-causing mutation cluster. Expression of the mutant proteins in HEK293T cells documented their activating role on MAPK signaling. Structural data predicted a gain-of-function role of substitutions at residues Leu²⁶² and Arg²⁶⁵ exerted by disruption of the N-SH2/PTP autoinhibitory interaction. Molecular dynamics simulations suggested a more complex behavior for changes affecting Leu²⁶¹, with possible impact on SHP2's catalytic activity/selectivity and proper interaction of the PTP domain with the regulatory SH2 domains. Consistent with that, biochemical data indicated that substitutions at codons 262 and 265 increased the catalytic activity of the phosphatase, while those affecting codon 261 were only moderately activating but impacted substrate specificity. Remarkably, these mutations underlie a relatively mild form of NS characterized by low prevalence of cardiac defects, short stature, and cognitive and behavioral issues, as well as less evident typical facial features.

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Quantification of Phenotype Information Aids the Identification of Novel Disease genes

ABSTRACT

Next generation sequencing led to the identification of many potential novel disease genes. The presence of mutations in the same gene in multiple unrelated patients is, however, a priori insufficient to establish that these genes are truly involved in the respective disease. Here, we show how phenotype information can be incorporated within statistical approaches to provide additional evidence for the causality of mutations. We developed a broadly applicable statistical model that integrates gene-specific mutation rates, cohort size, mutation type and phenotype frequency information to assess the chance of identifying de novo mutations affecting the same gene in multiple patients with shared phenotype features. We demonstrate our approach based on the frequency of phenotype features present in a unique cohort of 6,149 patients with intellectual disability. We show that our combined approach can decrease the number of patients required to identify novel disease genes, especially for patients with combinations of rare phenotypes. In conclusion, we show how integrating genotype-phenotype information can aid significantly in the interpretation of de novo mutations in potential novel disease genes.

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Idrett på glattisen?

Idretten har solt seg i glansen av gode resultater. Den senere tids dopinghendelser gjør det imidlertid nødvendig å diskutere skyggesidene også.

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Wild carrot pentane-based fractions suppress proliferation of human HaCaT keratinocytes and protect against chemically-induced skin cancer

Previous studies in our laboratory showed that the Lebanese Daucus carota ssp. carota (wild carrot) oil extract possesses in vitro and in vivo anticancer activities. The present study aims to examine the cytotoxi...

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Sijunzi Decoction attenuates 2, 4, 6-trinitrobenzene sulfonic acid (TNBS)-induced colitis in rats and ameliorates TNBS-induced claudin-2 damage via NF-κB pathway in Caco2 cells

SijunziDecoction (SJZD) is a traditional Chinese medicine prescription used to treat the diseases of gastrointestinal tract since ancient times. The objective of this study was to investigate the protective ef...

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IJERPH, Vol. 14, Pages 60: Perceptions of E-Cigarettes among Black Youth in California

Research suggests that Black youth are less likely to use e-cigarettes than their white counterparts, yet little is known as to why. We examined perceptions of e-cigarettes among Black young adults (ages 18–25) to explore the meanings these youth ascribe to e-cigarettes and the role that identity plays in how these devices are viewed. Analysis of in-depth interviews with 36 Black smokers and non-smokers in the San Francisco Bay Area suggests that Black youth perceive e-cigarettes as serving distinct, yet overlapping roles: a utilitarian function, in that they are recognized as legitimate smoking cessation tools, and a social function, insofar as they serve to mark social identity, specifically a social identity from which our participants disassociated. Participants described e-cigarette users in highly racialized and classed terms and generally expressed disinterest in using e-cigarettes, due in part perhaps to the fact that use of these devices would signal alignment with a middle class, hipster identity. This analysis is discussed within a highly charged political and public health debate about the benefits and harms associated with e-cigarette use.

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Ikke kluss med naturen

Adhesjon av de små kjønnsleppene hos jenter trenger sjelden behandling.

I dette nummer av Tidsskriftet har S. Knudtzon og medarbeidere en informativ artikkel om diagnostikk og behandling av adhesjon av de små kjønnsleppene (1). Selv om tilstanden er ganske vanlig, er den ikke særlig godt kjent hos foreldre og helsepersonell, kanskje fordi et flertall av jentene ikke har symptomer (1 – 6). Insidensen er i enkelte studier så høy som 20 – 40 %, og én forfatter spør om ikke adhesjon av de små kjønnsleppene bør oppfattes som et normalfunn hos prepubertale jenter (4)? Tilstanden anses å være ervervet, siden den ikke finnes i de tre første levemånedene (6). Ettersom den heller ikke finnes etter puberteten (2 – 6), antas det at sammenloddingen har sammenheng med det naturlig lave østrogennivået i årene mellom nyfødtperioden og fertil alder (2,4 – 6).

Diagnosen stilles enkelt ved inspeksjon. Tilstanden skilles fra vagina som ender blindt, manglende vagina og hymen imperforatum ved at vulva og de små kjønnsleppene her ser normale ut og urinrørsåpningen er synlig (5). Sammenloddingen av de små kjønnsleppene kan på diagnosetidspunktet være ganske fast. Siden tilstandens naturlige forløp er spontan normalisering før puberteten (1 – 6), vil det selvsagt også finnes jenter med svært lettgradige adhesjoner. Ved første legebesøk kan derfor et forsøk på å trekke kjønnsleppene fra hverandre uten anestesi være fristende. Etter min erfaring bør dette frarådes. Barns smerteopplevelse er individuell, og for mange er bare det å bli holdt skremmende. Det bør være lav terskel for anvendelse av lokalbedøvelse og endatil narkose ved slike anledninger.

I sin studie har kollegene ved St. Olavs hospital vist at resultatene ved både lokal applikasjon av østrogen- eller glukokortikoidkrem og kirurgisk behandling er dårlige – ved behandlingsslutt var sammenloddingen løsnet hos kun litt over halvparten (1). Resultatet er imidlertid i samsvar med litteraturen (2, 6). Gitt tilstandens naturlige forløp er det en svakhet ved denne studien at kun åtte av 105 jenter ble observert uten behandling og at kun fire av dem ble fulgt til normalisering. Forfatterne konkluderer likevel med: «Tilstanden går spontant tilbake hos alle, senest i puberteten.» Pasientene ved St. Olavs hospital er ikke fulgt lenge nok til å kunne bekrefte denne påstanden, som imidlertid har solid støtte i litteraturen (2 – 6). Det konkluderes videre med at observasjon alene bør være første behandlingsvalg hos symptomfrie jenter. Denne anbefalingen synes det også å være bred enighet om (2 – 6). Ved ledsagende plager som urinveisinfeksjon, uretritt eller vulvovaginitt, derimot, er det vanlig å anbefale at sammenloddingene løsnes (2 – 4, 6). Slike ledsagende tilstander behøver imidlertid ikke å ha noe med adhesjonen å gjøre. Ved det velrenommerte Hôpital Necker-Enfants malades i Paris, der man årlig ser rundt 40 nye tilfeller av denne tilstanden, løsner man ikke sammenloddingene selv hos dem som blir behandlet for de ovenfornevnte sykdommene. Kjønnsleppene åpnes kun når det er behov for tilgang til urinrørsåpningen (f.eks. for cystografi) eller ved lichen sclerosus (5).

Når adhesjon påvises, blir det viktigste å forsikre foreldrene om at det ikke er noen grunn til bekymring, dernest å informere skikkelig om tilstandens naturlige forløp samt poengtere betydningen av god perineal hygiene. Etter mitt syn er ytterligere oppfølging og kontroller av symptomfrie jenter (med eller uten adhesjon) ikke nødvendig. Hos dem med ledsagende symptomer kan behandling bli aktuelt. Da må informasjonen om behandlingsalternativene inkludere omtale av hyppige tilbakefall, både etter medikamentell og kirurgisk behandling (2 – 4). En forfatter rapporterer tilbakefall hos hele 40 % (6). Det kan også være betenkelig å forskrive en behandling som innebærer at småjenter skal smøres i skrittet to ganger daglig i opptil åtte uker (1). Mange foreldre vil kunne føle seg ubekvemme med denne oppgaven. Alt dette og fordi behandling kan være ubehagelig og ha sidevirkninger (1) taler for å anbefale observasjon som eneste tiltak. Selv om jeg har stor sans for behandlingsprinsippene ved Hôpital Necker (5), har jeg ikke problemer med å akseptere at en del foreldre ser annerledes på saken. Deres ønske om å løsne sammenloddingen, kirurgisk eller medikamentelt, bør da etterkommes, det er tross alt ingen stor sak.

Sammenfatningsvis har Knudtzon og medarbeidere gitt et viktig bidrag til å informere alle som arbeider med småbarn om en vanlig tilstand som affiserer jenters kjønnsorgan og som av og til krever behandling. Men som regel er altså det beste tiltaket å vente på at naturen ordner opp selv.

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UbE2E1/UBCH6 is a critical in vivo E2 for the PRC1 catalyzed ubiquitination of H2A at K119 [Gene Regulation]

UbE2E1/UbcH6 is an E2 ubiquitin conjugating enzyme that is regulated by USP7. We identified UbE2E1 as a novel component of Polycomb Repressive Complex 1 (PRC1), the E3 ligase complex responsible for histone H2A ubiquitination and gene silencing. We demonstrate that UbE2E1 is critical for the mono-ubiquitination of H2A at residue K119 (uH2AK119) through its association with the PRC1 complex. UbE2E1 interacts with PRC1 subunits including Ring1A and Ring1B. Overexpression of UbE2E1 results in increased levels of uH2AK119 whereas overexpression of catalytically inactive UbE2E1C131A or UbE2E1 knockdown results in decreased levels of uH2AK119. The down-regulation of H2A ubiquitination by loss of function of UbE2E1 is correlated with alleviated p16INK4a promoter repression and induced growth inhibition in HCT116 cells. These results are specific to UbE2E1 as knockdown of UbE2D E2s does not show any effect on uH2AK119. We extended the UbE2E1 regulation of ubiquitinated H2AK119 to USP7 and showed that USP7 is also a key regulator for mono-ubiquitination at H2AK119 as both knockdown and deletion of USP7 results in decreased levels of uH2AK119. This study reveals that UbE2E1 is an in vivo E2 for the PRC1 ligase complex and thus plays an important role in the regulation of H2AK119 mono-ubiquitination.

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Serine/threonine Kinase Unc-51 Like Kinase-1 (Ulk1) Phosphorylates the Co-chaperone Cdc37 and Thereby Disrupts the Stability of Cdc37 Client Proteins [Protein Synthesis and Degradation]

The serine/threonine kinase Unc-51 like kinase-1 (Ulk1) is thought to be essential for induction of autophagy, an intracellular bulk degradation process that is activated by various stresses. Although several proteins have been suggested as Ulk1 substrates during autophagic process, it still remains largely unknown about Ulk1's physiological substrates. Here, by performing in vitro and in vivo phosphorylation assay, we report that the co-chaperone cell division cycle protein 37 (Cdc37) is an Ulk1 substrate. Ulk1-mediated phosphorylation of Ser339 in Cdc37 compromised the recruitment of client kinases to a complex comprising Cdc37 and heat shock protein 90 (Hsp90), but only modestly affected Cdc37 binding to Hsp90. Since the recruitment of protein kinase clients to the Hsp90 complex is essential for their stability and functions, Ser339 phosphorylation of Cdc37 disrupts its ability as a co-chaperone to coordinate Hsp90. Hsp90 inhibitors are cancer chemotherapeutic agents by inducing depletion of clients, many of which are oncogenes. Upon treatment with an Hsp90 inhibitor in cancer cells, Ulk1 promoted the degradation of Hsp90-Cdc37 client kinases, resulting in increased cellular sensitivity to Hsp90 inhibitors. Thus, our study provides evidence for an anti-proliferative role of Ulk1 in response to Hsp90 inhibition in cancer cells.

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Raf Kinases are Essential for Phosphate Induction of Erk1/2 Phosphorylation in Hypertrophic Chondrocytes and Normal Endochondral Bone Development [Developmental Biology]

Hypophosphatemia causes rickets by impairing hypertrophic chondrocyte apoptosis. Phosphate induction of Mek1/2;Erk1/2 phosphorylation in hypertrophic chondrocytes is required for phosphate-mediated apoptosis and growth plate maturation. Mek1/2 can be activated by numerous molecules including Raf isoforms. A- and B-Raf ablation in chondrocytes does not alter skeletal development while ablation of C-Raf decreases hypertrophic chondrocyte apoptosis and impairs vascularization of the growth plate. However, ablation of C-Raf does not impair phosphate-induced Erk1/2 phosphorylation in vitro, but leads to rickets by decreasing VEGF protein stability. To determine if Raf isoforms are required for phosphate-induced hypertrophic chondrocyte apoptosis, mice lacking all three Raf isoforms in chondrocytes were generated. Raf deletion caused neonatal death and a significant expansion of the hypertrophic chondrocyte layer of the growth plate, accompanied by decreased cleaved caspase-9. This was associated with decreased pErk1/2 immunoreactivity in the hypertrophic chondrocyte layer and impaired vascular invasion. These data further demonstrated that Raf Kinases are required for phosphate-induced Erk1/2 phosphorylation in cultured hypertrophic chondrocytes and perform essential, but partially redundant roles in growth plate maturation.

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Auxiliary metabolic genes- Distinct Features of Cyanophage-encoded T-type Phycobiliprotein Lyase {theta}CpeT [Protein Structure and Folding]

Auxiliary metabolic genes (AMG) are commonly found in the genomes of phages that infect cyanobacteria and increase cyanophage′s fitness. AMGs are often homologs of host genes, and also typically related to photosynthesis. For example, the θcpeT gene in the cyanophage P-HM1 encodes a putative phycobiliprotein lyase related to cyanobacterial T-type lyases, which facilitate attachment of linear tetrapyrrole chromophores to Cys-155 of phycobiliprotein β-subunits, suggesting that θCpeT may also help assemble light-harvesting phycobiliproteins during infection. In order to investigate this possibility, we structurally and biochemically characterized recombinant θCpeT. The solved crystal structure of θCpeT at 1.8 Å resolution revealed that the protein adopts a similar fold as the cyanobacterial T-type lyase CpcT from Nostoc sp. PCC7120 but overall is more compact and smaller. θCpeT specifically binds phycoerythrobilin (PEB) in vitro leading to a tight complex that can also be formed in Escherichia coli when it is co-expressed with genes encoding PEB biosynthesis (i.e. ho1 and pebS). The formed θCpeT:PEB complex was very stable as the chromophore was not lost during chromatography and displayed a strong red fluorescence with a fluorescence quantum yield of θF=0.3. This complex was not directly able to transfer PEB to the host phycobiliprotein β-subunit. However, it could assist the host lyase CpeS in its function by providing a pool of readily available PEB, a feature that might be important for fast phycobiliprotein assembly during phage infection.

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Ceramide-CD300f binding inhibits lipopolysaccharide-induced skin inflammation [Signal Transduction]

Lipopolysaccharide (LPS) triggers inflammatory responses; however, the negative regulation of LPS responses in vivo remains poorly understood. CD300f is an inhibitory receptor among the CD300 family of paired activating and inhibitory receptors. We have previously identified ceramide as a ligand for CD300f and shown that the binding of ceramide to CD300f inhibits IgE-mediated mast cell activation and allergic responses in mouse models. Here we identify the critical role of CD300f in inhibiting LPS-induced skin inflammation. CD300f deficiency remarkably enhanced LPS-induced skin edema and neutrophil recruitment in mice. Higher levels of factors that increase vascular permeability and of factors that induce neutrophil recruitment were detected in LPS-injected skin pouch exudates of CD300f-/- mice compared to wild-type mice. CD300f was highly expressed in mast cells and recruited neutrophils, but not in macrophages, among skin myeloid cells. CD300f deficiency failed to influence the intrinsic migratory ability of neutrophils. Ceramide-CD300f binding suppressed the release of chemical mediators from mast cells and from neutrophils in response to LPS. Adoptive transfer experiments indicated that mast cells mediated enhanced edema in LPS-stimulated skin of CD300f-/- mice, whereas mast cells together with recruited neutrophils mediated robust neutrophil accumulation. Importantly, administering a ceramide antibody or ceramide-containing vesicles enhanced or suppressed LPS-induced skin inflammation of wild-type mice, respectively. Thus, ceramide-CD300f binding inhibits LPS-induced skin inflammation, implicating CD300f as a negative regulator of Toll-like receptor 4 (TLR4) signaling in vivo.

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A Truncated G-CSFR Inhibits Apoptosis Induced by Neutrophil Elastase G185R Mutant: Implication for Understanding CSF3R Mutations in Severe Congenital Neutropenia [Signal Transduction]

Mutations in ELANE encoding neutrophil elastase (NE) have been identified in the majority of patients with severe congenital neutropenia (SCN). The NE mutants have been shown to activate unfolded protein response (UPR) and induce premature apoptosis in myeloid cells. Patients with SCN are predisposed to acute myeloid leukemia (AML), and progression from SCN to AML is accompanied by mutations in CSF3R encoding the G-CSF receptor (G-CSFR) in approximately 80% patients. The mutations result in the expression of C-terminally truncated G-CSFRs that promote strong cell proliferation and survival. It is unknown why the CSF3R mutations, which are rare in de novo AML, are so prevalent in SCN/AML. We show here that a G-CSFR mutant, d715, derived from an SCN patient inhibited G-CSF-induced expression of NE in a dominant negative (DN) manner. Furthermore, G-CSFR d715 suppressed UPR and apoptosis induced by an SCN-derived NE mutant, which was associated with sustained activation of Akt and Stat5, and augmented expression of Bcl-xL. Thus, the truncated G-CSFRs associated with SCN/AML may protect myeloid precursor cells from apoptosis induced by the NE mutants. We propose that acquisition of CSF3R mutations may represent a mechanism by which myeloid precursor cells carrying the ELANE mutations evade the pro-apoptotic activity of the NE mutants in SCN patients.

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Comparison of characteristics and outcomes of percutaneous coronary intervention in military and non-military men

Objectives

Living in a military environment, as a unique job and lifestyle, may affect the physical and mental status of military personnel. Coronary artery disease (CAD) status and outcomes of percutaneous coronary intervention (PCI) in military personnel as a unique part of each society are less investigated.

Method

In a registry-based study, data of 338 military men and 1954 non-military men who underwent successful PCI from March 2012 to March 2013 were analysed. The primary endpoint was major adverse cardiac events (MACE) after hospital discharge during 1-year follow-up.

Results

Military men were significantly younger and had a higher frequency of hypertension, familial history of CAD and cigarette smoking. Other risk factors were more prevalent in non-military men. PCI for ST-segment elevation myocardial infarction and lower left ventricular ejection fraction were also more prevalent in soldiers. After mean follow-up duration of 12.3 months, MACE that was defined as the composite endpoint of all-cause mortality, non-fatal myocardial infarction or target vessel revascularisation was similar in both groups (HR=1.01 (95% CI 0.88 to 1.16); p=0.872). By adjustment for confounding factors, results were unchanged.

Conclusions

Although there are a number of differences in basic and procedural characteristics between military and non-military men who underwent PCI, 1-year clinical outcomes of this procedure are not different in these patient groups.

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Issue Information

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Idrett på glattisen?

Idretten har solt seg i glansen av gode resultater. Den senere tids dopinghendelser gjør det imidlertid nødvendig å diskutere skyggesidene også.

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Kolibri på MR-bilde

En mann med antatt Parkinsons sykdom ble innlagt i slagavdelingen grunnet økende ustøhet. Foruten parkinsonistiske symptomer hadde han balanseproblemer, kognitiv svekkelse og vertikal blikkparese.

MR-undersøkelse av hjernen viste en uttalt atrofi av mesencephalon som i sagittalsnitt får hjernestammen til å ligne en fugl i profil, gjerne omtalt som kolibritegn eller pingvintegn (pil). Dette er et typisk bildefunn ved den sjeldne nevrodegenerative tilstanden progredierende supranukleær parese (1).

Tilstanden inngår i fellesbetegnelsen atypisk parkinsonisme, en gruppe sjeldne nevrodegenerative tilstander som bør vurderes dersom parkinsonisme opptrer med uvanlige trekk og/eller tilleggssymptomer. Flere av sykdommene har karakteristiske MR-funn som ofte er nøkkelen til at diagnosen stilles (2).

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Idrett på glattisen?

Idretten har solt seg i glansen av gode resultater. Den senere tids dopinghendelser gjør det imidlertid nødvendig å diskutere skyggesidene også.

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Molecular biomarkers to predict response to neoadjuvant chemotherapy for bladder cancer

Bladder cancer (BC) is usually diagnosed at a surgically resectable stage, and early radical cystectomy with pelvic node dissection remains the cornerstone of therapy of muscle-invasive disease. However, cancer-specific survival after cystectomy is relatively low, ranging from 72% at 5 years for patients with organ-confined disease, to 48-25% at 5 years in patients with extravescical extension or lymph node metastases. Nearly half of patients diagnosed with stages T2b-T4a develop metastatic disease within two years [1].

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Migraine and risk of perioperative ischemic stroke and hospital readmission: hospital based registry study

Objective To evaluate whether patients with migraine are at increased risk of perioperative ischemic stroke and whether this may lead to an increased hospital readmission rate.Design Prospective...

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Genomics, proteomics and evolution of dengue virus

The genome of a pathogenic organism possesses a specific order of nucleotides that contains not only information about the synthesis and expression of proteomes, which are required for its growth and survival, but also about its evolution. Inhibition of any particular protein, which is required for the survival of that pathogenic organism, can be used as a potential therapeutic target for the development of effective drugs to treat its infections. In this review, the genomics, proteomics and evolution of dengue virus have been discussed, which will be helpful in better understanding of its origin, growth, survival and evolution, and may contribute toward development of new efficient anti-dengue drugs.

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IgE cross-linking impairs monocyte antiviral responses and inhibits influenza-driven Th1 differentiation

Capsule Summary: IgE-mediated allergic activation impairs the virus-induced Th1 lymphocyte priming capacity of human monocytes in response to influenza exposure. These findings represent one potential mechanism contributing to the link between viral infections and allergic disease.

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Does size really matter- relationship of particle size to lung deposition and exhaled fraction

Capsule summary: We demonstrate that extra-fine particles are not associated with an appreciably higher exhaled fraction, hence explaining their efficacy profile in asthma.

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Autoimmune lymphoproliferative syndrome caused by homozygous FAS mutations with normal or residual protein expression

Capsule summary: The identification of homozygous FAS mutations with normal or residual protein expression expands the spectrum of autoimmune lymphoproliferative syndrome types and should prompt clinicians to search for such patients particularly in highly endogamous populations.

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Identification of drug- and drug-metabolite immune responses originating from both naïve and memory T-cells

Summary: Both naïve and memory T-cells from drug-naive donors can be stimulated by parent drug and drug haptens. Thus, drug-derived antigens can stimulate naïve T-cells alongside pre-existing memory T-cells through proposed heterologous immunity with an as yet undetermined peptide antigen.

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The perfusion code of DIEP and ms-TRAM flaps is a hard nut to crack

We read with interest the article by Ludolph et al. entitled “Cracking the perfusion code?: Laser-assisted Indocyanine Green angiography and combined laser Doppler spectrophotometry for intraoperative evaluation of tissue perfusion in autologous breast reconstruction with DIEP or ms-TRAM flaps”.1 We completely agree with the authors that intraoperative evaluation of flap perfusion can still be challenging. Such is especially true in those cases where flaps are composed of several angiosomes as is usually the case with the DIEP and ms-TRAM flaps.

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The miR-34a-5p promotes the multi-chemoresistance of osteosarcoma via repression of the AGTR1 gene

Chemoresistance hinders the curative cancer chemotherapy. MicroRNAs (miRNAs) are key players in diverse biological processes including the chemoresistance of cancers.

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Lack of MRE11-RAD50-NBS1 (MRN) complex detection occurs frequently in low-grade epithelial ovarian cancer

BRCA1/2-deficient ovarian carcinomas are recognized as target for Poly (ADP-ribose) polymerase (PARP) inhibitors. BRCA1 and BRCA2 proteins are involved in homologous recombination repair of double-strand DNA b...

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Idrett på glattisen?

Idretten har solt seg i glansen av gode resultater. Den senere tids dopinghendelser gjør det imidlertid nødvendig å diskutere skyggesidene også.

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Forensic assignment to geographic origin, a useful tool in seafood fraud control

Seafood fraud is an important problem for many reasons and, unfortunately, has becoming widely spread in the last decades, especially in fish [1]. Economic reasons underlie seafood fraud in most cases: species of low commercial values are sold for others more expensive in order to increase benefits [2]. However, this economically motivated adulteration can encompass drastic consequences affecting public health [3] and species conservation [4]. For all these reasons, seafood forensics helps to combat mislabelling and fraud, being DNA-based technology essential on it [5].

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Molecular biomarkers to predict response to neoadjuvant chemotherapy for bladder cancer

Characterisation of Early-Life Fecal Microbiota in Susceptible and Healthy Pigs to Post-Weaning Diarrhoea

by Samir Dou, Pascale Gadonna-Widehem, Véronique Rome, Dounia Hamoudi, Larbi Rhazi, Lyes Lakhal, Thibaut Larcher, Narges Bahi-Jaber, Arturo Pinon-Quintana, Alain Guyonvarch, Isabelle L. E. Huërou-Luron, Latifa Abdennebi-Najar

Early-life microbial exposure is of particular importance to growth, immune system development and long-lasting health. Hence, early microbiota composition is a promising predictive biomarker for health and disease but still remains poorly characterized in regards to susceptibility to diarrhoea. In the present study, we aimed to assess if gut bacterial community diversity and composition during the suckling period were associated with differences in susceptibility of pigs to post-weaning diarrhoea. Twenty piglets from 5 sows (4 piglets / litter) were weaned in poor housing conditions to challenge their susceptibility to post-weaning diarrhoea. Two weeks after weaning, 13 pigs exhibited liquid faeces during 2 or 3 days and were defined as diarrhoeic (D) pigs. The other 7 pigs did not have diarrhea during the whole post-weaning experimental periodand were defined as healthy (H) pigs. Using a molecular characterisation of fecal microbiota with CE-SSCP fingerprint, Next Generation Sequencing and qPCR, we show that D and H pigs were mainly discriminated as early as postnatal day (PND) 7, i.e. 4 weeks before post-weaning diarrhoea occurence. At PND 7 H pigs displayed a lower evenness and a higher abundance of Prevotellaceae, Lachnospiraceae, Ruminocacaceae and Lactobacillaceae compared to D pigs. The sPLS regression method indicates that these bacterial families were strongly correlated to a higher Bacteroidetes abundance observed in PND 30 H pigs one week before diarrhoea. These results emphasize the potential of early microbiota diversity and composition as being an indicator of susceptibility to post-weaning diarrhoea. Furthermore, they support the health promoting strategies of pig herds through gut microbiota engineering.

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VideoEndocrinology™ High-Impact Videos

FREE ACCESS through January 24, 2017.

Thyroidectomy with Wu Gaosong’s Procedure
Gaosong Wu, Deguang Kong

Transoral Endoscopic Thyroidectomy Vestibular Approach
Angkoon Anuwong, Thanyawat Sasanakietkul, Pornpeera Jitpratoom

Transoral Robotic Thyroidectomy
Jeremy D. Richmon, Ralph P. Tufano, Jon Russell, Andrew Day, Hamad M. Chaudhary, Salem I. Noureldine

Novel Experience with Neuromonitoring in Robotic Thyroidectomy Using a Gasless Transaxillary Approach
Eun Jeong Ban, Changro Lee, Seul Gi Lee, Cho Rok Lee, Min Jhi Kim, Jung Bum Choi, Taehyung Kim, Sang Wook Kang, Jandee Lee, Jong Ju Jeong, Kee-Hyun Nam, Woong Youn Chung

A New Method for Direct Evaluation of Incisional Swelling After Thyroidectomy
Jenny Y. Yoo, Kelly L. McCoy, Linwah Yip, Michael T. Stang, Sally E. Carty

Indocyanine Green Fluorescence to Enhance Visual Contrast During Robotic Transaxillary Total Thyroidectomy
Pinar Yazici, Ryaz Chagpar, Sara Sound, Alexis Okoh, Eren Berber

Identification of the External Branch of the Superior Laryngeal Nerve During Thyroidectomy
Jonathan M. Bernstein, Jeremy L. Freeman

Robotic Thyroidectomy: Facelift Approach
Jeremy Richmon, Jason Prescott, Ralph Tufano, Martha Zeiger, Alan Dackiw,Heather Starmer

The post VideoEndocrinology™ High-Impact Videos appeared first on American Thyroid Association.

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Idrett på glattisen?

Idretten har solt seg i glansen av gode resultater. Den senere tids dopinghendelser gjør det imidlertid nødvendig å diskutere skyggesidene også.

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Glucose-ABL1-TOR Signaling Modulates Cell Cycle Tuning to Control Terminal Appressorial Cell Differentiation

journal.pgen.1006557.g001

by Margarita Marroquin-Guzman, Guangchao Sun, Richard A. Wilson

The conserved target of rapamycin (TOR) pathway integrates growth and development with available nutrients, but how cellular glucose controls TOR function and signaling is poorly understood. Here, we provide functional evidence from the devastating rice blast fungus Magnaporthe oryzae that glucose can mediate TOR activity via the product of a novel carbon-responsive gene, ABL1, in order to tune cell cycle progression during infection-related development. Under nutrient-free conditions, wild type (WT) M. oryzae strains form terminal plant-infecting cells (appressoria) at the tips of germ tubes emerging from three-celled spores (conidia). WT appressorial development is accompanied by one round of mitosis followed by autophagic cell death of the conidium. In contrast, Δabl1 mutant strains undergo multiple rounds of accelerated mitosis in elongated germ tubes, produce few appressoria, and are abolished for autophagy. Treating WT spores with glucose or 2-deoxyglucose phenocopied Δabl1. Inactivating TOR in Δabl1 mutants or glucose-treated WT strains restored appressorium formation by promoting mitotic arrest at G1/G0 via an appressorium- and autophagy-inducing cell cycle delay at G2/M. Collectively, this work uncovers a novel glucose-ABL1-TOR signaling axis and shows it engages two metabolic checkpoints in order to modulate cell cycle tuning and mediate terminal appressorial cell differentiation. We thus provide new molecular insights into TOR regulation and cell development in response to glucose.

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Idrett på glattisen?

Idretten har solt seg i glansen av gode resultater. Den senere tids dopinghendelser gjør det imidlertid nødvendig å diskutere skyggesidene også.

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Conversational Entrainment of Vocal Fry in Young Adult Female American English Speakers

Conversational entrainment, the natural tendency for people to modify their behaviors to more closely match their communication partner, is examined as one possible mechanism modulating the prevalence of vocal fry in the speech of young American women engaged in spoken dialogue.

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The Acoustic Breathiness Index (ABI): A Multivariate Acoustic Model for Breathiness

The evaluation of voice quality is a major component of voice assessment. The aim of the present study was to develop a new multivariate acoustic model for the evaluation of breathiness.

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Idrett på glattisen?

Idretten har solt seg i glansen av gode resultater. Den senere tids dopinghendelser gjør det imidlertid nødvendig å diskutere skyggesidene også.

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Πληροφορίες

Τρίτη 10 Ιανουαρίου 2017

ABSTRACT

ABSTRACT

Δημοφιλείς αναρτήσεις