Background The genetic determinants of the human innate immune response are poorly understood. Apolipoprotein (Apo) E, a lipid-trafficking protein that affects inflammation, has well-described ...wild-type (ε3) and disease-associated (ε2 and ε4) alleles, but its connection to human innate immunity is undefined. Objective We sought to define the relationship of APOε4 to the human innate immune response. Methods We evaluated APOε4 in several functional models of the human innate immune response, including intravenous LPS challenge in human subjects, and assessed APOε4 association to organ injury in patients with severe sepsis, a disease driven by dysregulated innate immunity. Results Whole blood from healthy APOε3 / APOε4 volunteers induced higher cytokine levels on ex vivo stimulation with Toll-like receptor (TLR) 2, TLR4, or TLR5 ligands than blood from APOε3 / APOε3 patients, whereas TLR7/8 responses were similar. This was associated with increased lipid rafts in APOε3/APOε4 monocytes. By contrast, APOε3 / APOε3 and APOε3 / APOε4 serum neutralized LPS equivalently and supported similar LPS responses in Apoe -deficient macrophages, arguing against a differential role for secretory APOE4 protein. After intravenous LPS, APOε3/APOε4 patients had higher hyperthermia and plasma TNF-α levels and earlier plasma IL-6 than APOε3/APOε3 patients. APOE4-targeted replacement mice displayed enhanced hypothermia, plasma cytokines, and hepatic injury and altered splenic lymphocyte apoptosis after systemic LPS compared with APOE3 counterparts. In a cohort of 828 patients with severe sepsis, APOε4 was associated with increased coagulation system failure among European American patients. Conclusions APOε4 is a determinant of the human innate immune response to multiple TLR ligands and associates with altered patterns of organ injury in human sepsis.
Summary Background In preclinical studies, davunetide promoted microtubule stability and reduced tau phosphorylation. Because progressive supranuclear palsy (PSP) is linked to tau pathology, ...davunetide could be a treatment for PSP. We assessed the safety and efficacy of davunetide in patients with PSP. Methods In a double-blind, parallel group, phase 2/3 trial, participants were randomly assigned with permuted blocks in a 1:1 ratio to davunetide (30 mg twice daily, intranasally) or placebo for 52 weeks at 48 centres in Australia, Canada, France, Germany, the UK, and the USA. Participants met the modified Neuroprotection and Natural History in Parkinson Plus Syndrome study criteria for PSP. Primary endpoints were the change from baseline in PSP Rating Scale (PSPRS) and Schwab and England Activities of Daily Living (SEADL) scale at up to 52 weeks. All participants and study personnel were masked to treatment assignment. Analysis was by intention to treat. The trial is registered with Clinicaltrials.gov , number NCT01110720. Findings 313 participants were randomly assigned to davunetide (n=157) or to placebo (n=156), and 241 (77%) completed the study (118 and 156 in the davunetide and placebo groups, respectively). There were no differences in the davunetide and placebo groups in the baseline PSPRS and SEADL. The davunetide and placebo groups did not differ in the change from baseline in PSPRS (median 11·8 95% CI 10·5 to 13·0 vs 11·8 10·5 to 13·0, respectively, p=0·41) or SEADL (−0·20 −0·20 to −0·17 vs −0·20 −0·22 to −0·17, respectively, p=0·92). 54 serious adverse events were reported in each of the treatment groups, including 11 deaths in the davunetide group and ten in the placebo group. The frequency of nasal adverse events was greater in the davunetide group than in the placebo group (epistaxis 18 12% of 156 vs 13 8% of 156, rhinorrhoea 15 10% vs eight 5%, and nasal discomfort 15 10% vs one <1%). Interpretation Davunetide is not an effective treatment for PSP. Clinical trials of disease-modifying treatment are feasible in patients with PSP and should be pursued with other promising tau-directed treatments. Funding Allon Therapeutics.
Abstract Background This study aimed at identifying preoperative predictors of patient-reported outcomes after total knee arthroplasty (TKA) and at investigating their association with the outcomes ...over time. Methods We used data from 2080 patients from the Knee Arthroplasty Trial who received primary TKA in the United Kingdom between July 1999 and January 2003. The primary outcome measure was the Oxford knee score (OKS) collected annually over 10 years after TKA. Preoperative predictors included a range of patient characteristics and clinical conditions. Mixed-effects linear regression model analysis of repeated measurements was used to identify predictors of overall OKS, and pain and function subscale scores over 10 years, separately. Results Worse preoperative OKS, worse mental well-being, body mass index greater than 35 kg/m2 , living in the most deprived areas, higher American Society of Anesthesiologists grade, presence of comorbidities, and history of previous knee surgery were associated with worse overall OKS over 10 years after surgery. The same predictors were identified for pain and function subscale scores, and for both long-term (10 years) and short-to-medium-term outcomes (1 and 5 years). However, fitted models explained more variations in function and shorter-term outcomes than in pain and longer-term outcomes, respectively. Conclusion The same predictors were identified for pain and functional outcomes over both short-to-medium term and long term after TKA. Within the factors identified, functional and shorter-term outcomes were more predictable than pain and longer-term outcomes, respectively. Regardless of their preoperative characteristics, on average, patients achieved substantial improvement in pain over time, although improvement for function was less prominent.
Corneal dystrophies are a genetically heterogeneous group of disorders. We previously described a family with an autosomal dominant epithelial recurrent erosion dystrophy (ERED). We aimed to identify ...the underlying genetic cause of ERED in this family and 3 additional ERED families. We sought to characterize the potential function of the candidate genes using the human and zebrafish cornea.
Case series study of 4 white families with a similar ERED. An experimental study was performed on human and zebrafish tissue to examine the putative biological function of candidate genes.
Four ERED families, including 28 affected and 17 unaffected individuals.
HumanLinkage-12 arrays (Illumina, San Diego, CA) were used to genotype 17 family members. Next-generation exome sequencing was performed on an uncle–niece pair. Segregation of potential causative mutations was confirmed using Sanger sequencing. Protein expression was determined using immunohistochemistry in human and zebrafish cornea. Gene expression in zebrafish was assessed using whole-mount in situ hybridization. Morpholino-induced transient gene knockdown was performed in zebrafish embryos.
Linkage microarray, exome analysis, DNA sequence analysis, immunohistochemistry, in situ hybridization, and morpholino-induced genetic knockdown results.
Linkage microarray analysis identified a candidate region on chromosome chr10:12,576,562–112,763,135, and exploration of exome sequencing data identified 8 putative pathogenic variants in this linkage region. Two variants segregated in 06NZ–TRB1 with ERED: COL17A1 c.3156C→T and DNAJC9 c.334G→A. The COL17A1 c.3156C→T variant segregated in all 4 ERED families. We showed biologically relevant expression of these proteins in human cornea. Both proteins are expressed in the cornea of zebrafish embryos and adults. Zebrafish lacking Col17a1a and Dnajc9 during development show no gross corneal phenotype.
The COL17A1 c.3156C→T variant is the likely causative mutation in our recurrent corneal erosion families, and its presence in 4 independent families suggests that it is prevalent in ERED. This same COL17A1 c.3156C→T variant recently was identified in a separate pedigree with ERED. Our study expands the phenotypic spectrum of COL17A1 disease from autosomal recessive epidermolysis bullosa to autosomal dominant ERED and identifies COL17A1 as a key protein in maintaining integrity of the corneal epithelium.
Longer-Lived Parents and Cardiovascular Outcomes Atkins, Janice L., PhD; Pilling, Luke C., PhD; Ble, Alessandro, MD ...
Journal of the American College of Cardiology,
08/2016, Letnik:
68, Številka:
8
Journal Article
Objective Ventricular assist devices (VADs) are associated with increased anti–human leukocyte antigen antibody production. The purpose of this study is to characterize differences in sensitization ...patterns in patients receiving axial flow, implantable VADs versus pulsatile, paracorporeal biventricular assist devices (BIVADs) as bridges to transplantation. Methods The study is a retrospective review of 68 patients who were bridged to transplantation with either a VAD or a BIVAD, as described, from January 2007 to June 2010, at a university medical center. Results Five of 15 (33.3%) VAD patients became sensitized during treatment, compared with 30 of 53 (56.6%) BIVAD patients, P = .15. Multivariable analysis comparing BIVAD with VAD, while controlling for previous cardiac surgery, pregnancy, and packed red blood cell transfusion produced an odds ratio of 2.99, P = .14. Of sensitized patients, all 5 (100%) of the VAD patients had pre-existing antibodies before VAD placement, compared with 9 of 30 (30.0%) BIVAD patients, P = .006. Maximum cumulative mean fluorescence intensities for BIVAD were 46,259 ± 66,349 versus 42,540 ± 12,840 for VAD, P = .90. Time to maximum antibody expression was shorter for the VAD group (34 ± 28 days vs 5.8 ± 9 days, P = .04). Conclusions Device type was not a factor in patient sensitization after implantation. However, VAD patients required pre-existing sensitization before implantation to produce antibodies during their treatment interval, whereas more than two thirds of BIVAD patients developed de novo antibodies. These data suggest that the mechanism of sensitization between VAD and BIVAD patients may differ, and further mechanistic studies into the impact of device types on patient sensitization are warranted.
Despite the high co-occurrence between depression and asthma, few studies have addressed methods assessing the severity of depressive symptoms among patients with asthma.
To evaluate the psychometric ...properties of the Quick Inventory of Depressive Symptomatology-Self-report (QIDS-SR16), a 16-item measure of depressive symptom severity, in patients with asthma.
The psychometric properties of the QIDS-SR16 were compared at treatment exit with those of the 30-item self-report Inventory of Depressive Symptomatology (IDS-SR30) and the 17-item clinician-rated Hamilton Rating Scale for Depression (HRSD17) in 73 outpatients with asthma who were treated with citalopram or placebo for nonpsychotic major depressive disorder. Correlations between the depression rating scales and the Mini Asthma Quality of Life Questionnaire were calculated.
Internal consistency at exit was strong for the QIDS-SR16 (Cronbach alpha values are .87 for the QIDS-SR16, .95 for the IDS-SR30, and .87 for the HRSD17). The QIDS-SR16 and HRSD17 total scores were highly correlated (r = 0.85), as were the QIDS-SR16 and IDS-SR30 total scores (r = 0.97). All QIDS-SR16 item total score correlations were significant (P < .001). The QIDS-SR16, IDS-SR30, and HRSD17 showed comparable sensitivity to symptom change, indicating high concurrent validity for all 3 scales. The total QIDS-SR16 baseline to exit change score demonstrated a significant negative correlation (r = -0.49, P < .001) with the Mini Asthma Quality of Life Questionnaire. Thus, greater depressive symptom severity was associated with lower asthma-related quality of life.
The QIDS-SR16 showed good reliability and impressive construct validity. Strong psychometric properties of this brief self-report format and its sensitivity to treatment change suggest that the QIDS-SR16 is a valuable clinical tool.
The Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2016 provided comprehensive estimates of health loss globally. Decision makers in Kenya can use GBD subnational data to target ...health interventions and address county-level variation in the burden of disease.
We used GBD 2016 estimates of life expectancy at birth, healthy life expectancy, all-cause and cause-specific mortality, years of life lost, years lived with disability, disability-adjusted life-years, and risk factors to analyse health by age and sex at the national and county levels in Kenya from 1990 to 2016.
The national all-cause mortality rate decreased from 850·3 (95% uncertainty interval UI 829·8–871·1) deaths per 100 000 in 1990 to 579·0 (562·1–596·0) deaths per 100 000 in 2016. Under-5 mortality declined from 95·4 (95% UI 90·1–101·3) deaths per 1000 livebirths in 1990 to 43·4 (36·9–51·2) deaths per 1000 livebirths in 2016, and maternal mortality fell from 315·7 (242·9–399·4) deaths per 100 000 in 1990 to 257·6 (195·1–335·3) deaths per 100 000 in 2016, with steeper declines after 2006 and heterogeneously across counties. Life expectancy at birth increased by 5·4 (95% UI 3·7–7·2) years, with higher gains in females than males in all but ten counties. Unsafe water, sanitation, and handwashing, unsafe sex, and malnutrition were the leading national risk factors in 2016.
Health outcomes have improved in Kenya since 2006. The burden of communicable diseases decreased but continues to predominate the total disease burden in 2016, whereas the non-communicable disease burden increased. Health gains varied strikingly across counties, indicating targeted approaches for health policy are necessary.
Bill & Melinda Gates Foundation.
Background The fraction of exhaled nitric oxide (F eno ) value is a biomarker of eosinophilic airway inflammation and is associated with childhood asthma. Identification of common genetic variants ...associated with childhood F eno values might help to define biological mechanisms related to specific asthma phenotypes. Objective We sought to identify the genetic variants associated with childhood F eno values and their relation with asthma. Methods F eno values were measured in children age 5 to 15 years. In 14 genome-wide association studies (N = 8,858), we examined the associations of approximately 2.5 million single nucleotide polymorphisms (SNPs) with F eno values. Subsequently, we assessed whether significant SNPs were expression quantitative trait loci in genome-wide expression data sets of lymphoblastoid cell lines (n = 1,830) and were related to asthma in a previously published genome-wide association data set (cases, n = 10,365; control subjects: n = 16,110). Results We identified 3 SNPs associated with F eno values: rs3751972 in LYR motif containing 9 ( LYRM9 ; P = 1.97 × 10−10 ) and rs944722 in inducible nitric oxide synthase 2 ( NOS2 ; P = 1.28 × 10−9 ), both of which are located at 17q11.2-q12, and rs8069176 near gasdermin B ( GSDMB ; P = 1.88 × 10−8 ) at 17q12-q21. We found a cis expression quantitative trait locus for the transcript soluble galactoside-binding lectin 9 (LGALS9) that is in linkage disequilibrium with rs944722. rs8069176 was associated with GSDMB and ORM1-like 3 (ORMDL3) expression. rs8069176 at 17q12-q21, but not rs3751972 and rs944722 at 17q11.2-q12, were associated with physician-diagnosed asthma. Conclusion This study identified 3 variants associated with F eno values, explaining 0.95% of the variance. Identification of functional SNPs and haplotypes in these regions might provide novel insight into the regulation of F eno values. This study highlights that both shared and distinct genetic factors affect F eno values and childhood asthma.
Bowel loops and eyelid droops Spiegelman, Jamie, MD; Cescon, David W., MD; Friedman, Yael, MD ...
Canadian Medical Association journal,
10/2008, Letnik:
179, Številka:
9
Journal Article
Recenzirano
Odprti dostop
A patient presented with a small-bowel obstruction associated with signs and symptoms of botulism. Fecal cultures were positive for viable Clostridium botulinum. This case emphasizes the importance ...of a broad differential diagnosis and doing a complete examination to account for all signs and symptoms.
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