Psoriasis patients often report dissatisfaction with treatment. However, it is less clear how the severity of key psoriasis symptoms (painful skin, itching, and scaling) as well as overall disease ...severity influence patient dissatisfaction levels. Using the Adelphi 2011/2013 Psoriasis Disease Specific Programmes, two "real world" surveys of US dermatologists and their patients, patient satisfaction was evaluated. Dermatologists provided data on disease characteristics, while patients indicated their satisfaction with existing treatment. Physician-reported severity (none, mild, moderate/severe) of psoriasis-related itching, pain, and scaling, overall disease severity (mild, moderate and severe) and therapy type were compared by patient satisfaction levels (satisfied vs. dissatisfied). Multivariate regressions examined the relationship between patient satisfaction, clinical symptoms, and psoriasis overall disease severity, controlling for differences in patient demographics and comorbidities. The sample comprised 633 psoriasis patients (56% male) with a mean age of 45. Overall, 18% of patients reported dissatisfaction with their psoriasis treatment. Dissatisfied patients were more likely to have moderate (65% vs. 40%) or severe (21% vs 3%) psoriasis compared to patients who were satisfied (both p<0.05). Dissatisfied patients were also more likely to have more severe pain (30% moderate-to-severe pain vs. 9%), more severe itching (61% moderate-to-severe itching vs. 25%), and more severe scaling (68% moderate-to-severe scaling vs. 33%) than satisfied patients (all p< 0.05). Multivariate analyses confirmed these results. Clinicians should be aware that some psoriasis patients, especially those with severe overall disease or symptoms, may be dissatisfied and are in need of better treatment.
Platelet-activating factor (PAF) is a potent biologically active phospholipid that mediates human physiological and pathophysiologic responses. PAF levels increase transiently and are typically ...assessed by techniques with limitations related to expense, sensitivity, pre-analysis derivatization and interference with isobaric molecules. This study elucidates a facile, accurate liquid chromatography–mass spectrometry analytical method for PAF. In negative ion mode using electrospray ionization, collisionally-activated dissociation analysis showed a unique product ion for acetate adducts of PAF molecular species representing the loss of methyl acetate from the polar head group and loss of a part of the acetate group from the
sn
-2 position. This product ion was exploited for selected reaction monitoring of PAF molecular species following separation by reversed-phase liquid chromatography. Standard calibration responses were determined, and this method was able to detect as low as 100 fmol of PAF. Finally, PAF molecular species were quantified in human neutrophils and monocytes.
Mutations have been described in the ataxia telangiectasia mutated (ATM) gene in small numbers of cases of lymphoid neoplasia. However, surveys of the ATM mutation status in lymphoma have been ...limited due to the large size (62 exons) and complex mutational spectrum of this gene. We have used microarray-based assays with 250,000 oligonucleotides to screen lymphomas from 120 patients for all possible ATM coding and splice junction mutations. The subtypes included were diffuse large B cell, mantle cell, immunoblastic large B cell, follicular, posttransplant lymphoproliferative disorder, and peripheral T cell lymphoma. We found the highest percentage of ATM mutations within the mantle cell (MCL) subtype (43%, 12 of 28 cases), followed by a lower level (10% of cases) in the other subtypes. A frame-shift ATM mutation was found in one peripheral T cell lymphoma patient. In six MCL cases examined, four ATM variants were due to somatic mutation in the tumor cells whereas two others seemed to be germ-line in origin. There was no difference in p53 mutation status in the ATM mutant and wild-type groups of MCL. There was no statistically significant difference in the median overall survival of patients with wild-type vs. mutated ATM in MCL. Additional mutational and functional analyses are needed to determine whether ATM mutations contribute to the development and progression of MCL or are just the consequence of genomic instability in MCL.
Introduction
The absence of a reliable clinical test to predict bleeding tendency leaves factor XI (FXI)‐deficient individuals at risk of overtreatment or under treatment.
Aim
To assess whether ...rotational thromboelastometry has value in detection of FXI deficiency and identification of bleeding tendency.
Methods
Thromboelastometry was measured in whole blood and platelet‐rich plasma (PRP) samples containing corn trypsin inhibitor (CTI) from controls (n = 50) and FXI‐deficient individuals (n = 93) at tissue factor (TF) 0.12 pm. The effect of tissue plasminogen activator was also assessed. For analysis, FXI‐deficient individuals were divided into bleeders (n = 24) and non‐bleeders (n = 44) based on experience of tonsillectomy and/or dental extraction prior to diagnosis.
Results
In whole blood, thromboelastometry distinguished those with major FXI deficiency (FXI:C ≤ 15 IU dL−1) but not partial deficiency from control populations, but did not identify bleeding phenotype. In PRP, bleeders had significantly longer clot formation time CFT; 434 ± 179 s vs. 277 ± 70 s (mean ± SD); P < 0.05 and smaller α angle 43.8 ± 9.5° vs. 52.4 ± 5.8° (mean ± SD); P < 0.05 compared to non‐bleeders. However, these parameters were found to depend on multiple additional variables and on an individual basis, ROC analysis showed test specificity for bleeding phenotype identification to be only 38.5% at 100% sensitivity: CFT (area under first derivative curve: AUC = 0.8091, P = 0.0014), α angle (AUC = 0.7804, P = 0.006).
Conclusion
Thromboelastometry in PRP with CTI samples triggered with TF 0.12 pm was able to distinguish between bleeders and non‐bleeders in FXI deficiency, but poor specificity restricts its clinical application as a test to identify bleeding phenotype. Further technical advances to the assay may allow better discrimination.
Summary We report two patients with multidrug-resistant KPC-carbapenemase-producing Klebsiella pneumoniae urinary tract infections. A blaKPC-2 gene was detected in both of the isolates by polymerase ...chain reaction and sequencing. The isolates had identical pulsed-field gel electrophoresis patterns and belonged to sequence type ST11. The index patient probably acquired the KPC-producing strain while in hospital in Curaçao, with subsequent nosocomial transmission to the second patient occurring in our hospital. We describe the interventions that were taken to prevent its further spread within the acute Trust and the community.
Six hundred sixty-five crossbred beef heifers initially weighing 225 kg were used in a completely randomized design to measure plasma glucose, lactate, and urea N concentrations at time of initial ...processing, determine the incidence of apparent bovine respiratory disease (BRD) in receiving cattle, and evaluate the effect of apparent BRD on subsequent cattle growth and carcass characteristics. Heifers were processed within 24 h of arrival, and processing included vaccination against common viral and clostridial diseases, recording rectal temperature, and sampling whole blood for subsequent measurement of plasma glucose, lactate, and urea concentrations. Heifers were monitored for clinical signs of apparent BRD, including depression, lethargy, anorexia, coughing, rapid breathing, and nasal or ocular discharge. Heifers exhibiting signs of apparent BRD received antibiotic therapy, and the number of times a heifer was treated for apparent BRD was recorded. Following the 36-d receiving period, heifers were transported to native grass pastures and allowed to graze for 136 d. At the end of the grazing season, heifers were transported to a commercial feedlot where they were adapted to a common finishing diet offered for ad libitum consumption. Following the 124-d finishing period, heifers were slaughtered and carcass data were collected. Heifers treated for apparent BRD had decreased plasma glucose (linear, P < 0.01), lactate (linear, P < 0.01), and urea N concentrations (linear, P < 0.06) measured at time of initial processing. Rectal temperature measured at time of initial processing tended to be greater (linear, P < 0.11) for heifers treated for apparent BRD. Heifers treated for apparent BRD during the receiving period had decreased overall ADG (linear, P < 0.10), final BW (linear, P < 0.01), HCW (linear, P < 0.01), fat thickness (linear, P < 0.01), and marbling score (linear, P < 0.03). These data suggest that initial plasma glucose and lactate concentrations might be affected by the health status of receiving cattle and that increased incidence of apparent BRD in cattle decreases ADG and carcass quality.
The mannose-binding lectin associated-protease-3 (MASP-3) is a member of the lectin pathway of the complement system, a key component of human innate and active immunity. Mutations in MASP-3 have ...recently been found to be associated with Carnevale, Mingarelli, Malpuech, and Michels (3MC) syndrome, a severe developmental disorder manifested by cleft palate, intellectual disability, and skeletal abnormalities. However, the molecular basis for MASP-3 function remains to be understood. Here we characterize the substrate specificity of MASP-3 by screening against a combinatorial peptide substrate library. Through this approach, we successfully identified a peptide substrate that was 20-fold more efficiently cleaved than any other identified to date. Furthermore, we demonstrated that mutant forms of the enzyme associated with 3MC syndrome were completely inactive against this substrate. To address the structural basis for this defect, we determined the 2.6-Å structure of the zymogen form of the G666E mutant of MASP-3. These data reveal that the mutation disrupts the active site and perturbs the position of the catalytic serine residue. Together, these insights into the function of MASP-3 reveal how a mutation in this enzyme causes it to be inactive and thus contribute to the 3MC syndrome.
Background: Mutants of the serine protease, mannose-binding lectin associated-protease-3 (MASP-3), are associated with Carnevale, Mingarelli, Malpuech and Michels (3MC) syndrome.
Results: The lack of activity and the structure of the G666E mutant of MASP-3 reveals a molecular basis for 3MC syndrome.
Conclusion: Mutants of MASP-3 associated with 3MC syndrome are inactive.
Significance: The catalytic activity of MASP-3 is required for normal developmental processes.
Background: The Australian Imaging, Biomarkers and Lifestyle (AIBL) flagship study of aging aimed to recruit 1000 individuals aged over 60 to assist with prospective research into Alzheimer's disease ...(AD). This paper describes the recruitment of the cohort and gives information about the study methodology, baseline demography, diagnoses, medical comorbidities, medication use, and cognitive function of the participants. Methods: Volunteers underwent a screening interview, had comprehensive cognitive testing, gave 80 ml of blood, and completed health and lifestyle questionnaires. One quarter of the sample also underwent amyloid PET brain imaging with Pittsburgh compound B (PiB PET) and MRI brain imaging, and a subgroup of 10% had ActiGraph activity monitoring and body composition scanning. Results: A total of 1166 volunteers were recruited, 54 of whom were excluded from further study due to comorbid disorders which could affect cognition or because of withdrawal of consent. Participants with AD (211) had neuropsychological profiles which were consistent with AD, and were more impaired than participants with mild cognitive impairment (133) or healthy controls (768), who performed within expected norms for age on neuropsychological testing. PiB PET scans were performed on 287 participants, 100 had DEXA scans and 91 participated in ActiGraph monitoring. Conclusion: The participants comprising the AIBL cohort represent a group of highly motivated and well-characterized individuals who represent a unique resource for the study of AD. They will be reassessed at 18-month intervals in order to determine the predictive utility of various biomarkers, cognitive parameters and lifestyle factors as indicators of AD, and as predictors of future cognitive decline.
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