KOC (K homology domain containing protein overexpressed in cancer): a novel molecular marker that distinguishes between benign and malignant lesions of the pancreas.
KOC (K homology domain containing protein overexpressed in cancer) is a novel oncofetal RNA-binding protein highly expressed in pancreatic carcinomas. Recently, Corixa Corporation developed a monoclonal antibody specific for KOC that can be used with standard immunohistochemical techniques. The purposes of this study were 1) to assess KOC mRNA expression in pancreatic carcinoma, 2) to determine the pattern of KOC immunoexpression among benign, borderline, and malignant pancreatic epithelial lesions, and 3) to evaluate the utility of the KOC antibody in distinguishing between these entities. mRNA was isolated from fresh pancreatic tissues (19 carcinomas, 2 normal pancreas, 1 chronic pancreatitis) and amplified using standard RT-PCR techniques. Fifteen of 19 (79%) carcinomas overexpressed KOC mRNA relative to non-neoplastic tissue samples and expression increased progressively with tumor stage: the mean copy number of KOC mRNA transcripts was 1.5, 11.1, 31, and 28 for stage I, II, III, and IV carcinomas, respectively, compared with 0.9 and 1 for normal pancreatic tissue and chronic pancreatitis, respectively. Immunostains using the KOC antibody were performed on 50 surgical resection specimens (38 invasive adenocarcinomas, 3 intraductal papillary-mucinous neoplasms, 2 mucinous cystic neoplasms, 7 chronic pancreatitis). KOC staining was present in 37 of 38 (97%) carcinomas: the staining reaction was moderate or strong in 36 of 38 (94%) and present in >50% of the tumor cells in 35 of 38 (92%) cases. Severe dysplasia of the ductal epithelium, present in 19 foci of intraductal papillary mucinous carcinoma, mucinous cystadenocarcinoma, and grade 3 pancreatic intraepithelial neoplasia (PanIN3) showed strong or moderate staining in 15 (79%) cases, whereas foci of mild and moderate dysplasia (intraductal papillary-mucinous neoplasms and mucinous cystic neoplasms with adenoma and/or moderate dysplasia, PanIN1, and PanIN2) were uniformly negative for this marker in 25 and 22 cases, respectively. In the normal pancreas, weak background staining of acini was present in 12 of 50 (24%) cases but was easily distinguishable from the type of staining identified in neoplastic epithelium, and benign ducts and ductules were negative in all cases. Four of 38 (11%) foci of chronic pancreatitis, present in the 7 resections performed for chronic pancreatitis as well as 31 foci of peritumoral chronic pancreatitis, showed weak staining in <10% of the ductules. We conclude that KOC is a sensitive and specific marker for carcinomas and high-grade dysplastic lesions of the pancreatic ductal epithelium. Therefore, immunostains directed against KOC may be of diagnostic utility in the evaluation of pancreatic lesions, particularly when biopsy material is limited.


MRI tracking of polyethylene glycol-coated superparamagnetic iron oxide-labelled placenta-derived mesenchymal stem cells toward glioblastoma stem-like cells in a mouse model.
Mesenchymal stem cells (MSCs) that display homing and infiltration properties towards tumor cells are a promising cellular targeting vector for brain tumor therapy but are limited to local-regional delivery in current preclinical models. Here, we investigated whether placenta-derived MSCs (P-MSCs) are a superior cellular vector for systemic targeting of glioblastoma stem-like cells (GSCs), with an imaging modality to real-time monitor the trafficking P-MSCs to glioblastoma sites. Results demonstrated that P-MSCs had greater migratory activity towards GSCs and across blood-brain barrier compared with bone marrow-derived MSCs, and this activity was enhanced by hypoxia precondition. Chemokine ligand 5 was identified as a chemoattractant responsible for the glioblastoma tropism of P-MSCs. Polyethylene glycol-coated superparamagnetic iron oxide (PEG-SPIO) was synthesized for cellular labelling and imaging P-MSCs, displaying high cellular uptake and no cytotoxic effect on P-MSCs cell proliferation or stemness property. The homing effects of intravenously administered PEG-SPIO-labelled P-MSCs towards intracerebral GSCs were able to be detected in mice models through T2-weighted magnetic resonance imaging (MRI). This study suggests the possibility of innovative systemic P-MSC-based cell therapy for aggressive GSCs, developing a state-of-the-art theranostic technique for real-time tracking of therapeutic P-MSCs tumor infiltration through cellular MRI.


Rabies post-exposure prophylaxis for a child with severe allergic reaction to rabies vaccine.
Most adverse events (AEs) during the immunization of rabies vaccine were slight, there was little information about the allergic reaction induced by rabies vaccines and had to stop or change the immunization program. Here, we reported a case that a 4-year-old boy had category II exposure to rabies and showed severe allergic reaction after being immunized with lyophilized purified vero cell rabies vaccine (PVRV). After the anti-allergy therapy with hormone, allergy testing indicated medium allergy to egg and milk, and implied the allergic reaction most likely associated with animal-sourced gelatin in lyophilized PVRV. Therefore, a new immunization program with liquid PVRV without stabilizers under the Zegrab regimen (2-1-1) was enrolled at day 7 post-exposure. Although lower than the levels of normal <5 -year population at day 14 and 45, the neutralizing antibody (RVNA) titers of this boy showed adequate protective antibody (≥ 0.5 IU/ml), even after 365 d post-immunization. This study not only highlighted the importance of several types of rabies vaccines co-existing in the market, but also implied the necessary for doctors to fully understand the allergies history of patients prior to immunize rabies vaccine.


Genome-wide deficiency screen for the genomic regions responsible for heat resistance in Drosophila melanogaster.
Temperature adaptation is one of the most important determinants of distribution and population size of organisms in nature. Recently, quantitative trait loci (QTL) mapping and gene expression profiling approaches have been used for detecting candidate genes for heat resistance. However, the resolution of QTL mapping is not high enough to examine the individual effects of various genes in each QTL. Heat stress-responsive genes, characterized by gene expression profiling studies, are not necessarily responsible for heat resistance. Some of these genes may be regulated in association with the heat stress response of other genes. To evaluate which heat-responsive genes are potential candidates for heat resistance with higher resolution than previous QTL mapping studies, we performed genome-wide deficiency screen for QTL for heat resistance. We screened 439 isogenic deficiency strains from the DrosDel project, covering 65.6% of the Drosophila melanogaster genome in order to map QTL for thermal resistance. As a result, we found 19 QTL for heat resistance, including 3 novel QTL outside the QTL found in previous studies. The QTL found in this study encompassed 19 heat-responsive genes found in the previous gene expression profiling studies, suggesting that they were strong candidates for heat resistance. This result provides new insights into the genetic architecture of heat resistance. It also emphasizes the advantages of genome-wide deficiency screen using isogenic deficiency libraries.


[Violence against the elderly in the home environment: prevalence and associated factors (Recife, State of Pernambuco)].
The scope of this paper was to determine the prevalence and factors associated with domestic violence against the elderly. It is a cross-sectional study with 274 subjects, aged 60 years or more, of both sexes. Data were collected through interviews at home or in the USF based on a script structured in three parts: questionnaire with socio-demographic and bio-demographic information, two rating scales and a tool for identifying abuse. Among the respondents, 20.8% reported having experienced at least one type of violence in their home environment. An association was revealed between those living with a greater number of individuals, among women and elderly people who are dependent for day-to-day activities. After applying the logistic regression model, only the variables of sex and family configuration were significantly associated, with evidence of greater frequency among those who lived with six or more residents and women. These findings highlight the magnitude and seriousness of the problem and point to the need for action to combat violence against the elderly.


The role of osteochondral progenitor cells in fracture repair.
The repair of a fracture necessarily entails synthesis of osseous tissue requiring the transformation of undifferentiated osteochondral progenitor cells to mature osteoblasts and chondrocytes. Owen and Friedenstein proposed that there are stem cells for all mesenchymal tissues, resident in bone marrow throughout life, that have a lineage comparable to that described for hematopoiesis. Subsequent with this initial study, marrow derived and periosteal derived progenitor cells have been shown to produce bone and cartilage in numerous in vivo and in vitro studies. The differentiation process appears to depend heavily on the influences of numerous cytokines, especially the transforming growth factor beta superfamily. Initial cartilage formation from progenitor cells is important in any secondary fracture repair. In the in vitro study of chondrogenesis, the marrow derived progenitor cells were shown to differentiate into their terminal phenotype, the hypertrophic chondrocyte, as indicated by the detection of Type X collagen messenger ribonucleic acid and protein. A concomitant elevation in the alkaline phosphatase level suggests that these cells are ready to mineralize. Despite the importance of these cells in fracture repair, the characterization of these cells and the mechanism of their differentiation have only begun to be explored.


Quantitative methylation-specific polymerase chain reaction gene patterns in urine sediment distinguish prostate cancer patients from control subjects.
Aberrant promoter hypermethylation of several known or putative tumor suppressor genes occurs frequently during the pathogenesis of prostate cancers and is a promising marker for cancer detection. We sought to develop a test for prostate cancer based on a quantitative methylation-specific polymerase chain reaction (QMSP) of multiple genes in urine sediment DNA. We tested urine sediment DNA for aberrant methylation of nine gene promoters (p16INK4a, p14(ARF), MGMT, GSTP1, RARbeta2, CDH1 [E-cadherin], TIMP3, Rassf1A, and APC) from 52 patients with prostate cancer and 21 matched primary tumors by quantitative fluorogenic real-time polymerase chain reaction. We also analyzed urine sediments from 91 age-matched individuals without any history of genitourinary malignancy as controls. Promoter hypermethylation of at least one of the genes studied was detected in urine samples from all 52 prostate cancer patients. Urine samples from the 91 controls without evidence of genitourinary cancer revealed no methylation of the p16, ARF, MGMT, and GSTP1 gene promoters, whereas methylation of RARbeta2, TIMP3, CDH1, Rassf1A, and APC was detected at low levels. Overall, methylation found in urine samples matched the methylation status in the primary tumor. A combination of only four genes (p16, ARF, MGMT, and GSTP1) would theoretically allow us to detect 87% of prostate cancers with 100% specificity. Our data support further development of the noninvasive QMSP assay in urine DNA for early detection and surveillance of prostate cancer.


Using symptom and interference questionnaires to identify recovery among children with anxiety disorders.
Questionnaires are widely used in routine clinical practice to assess treatment outcomes for children with anxiety disorders. This study was conducted to determine whether 2 widely used child and parent report questionnaires of child anxiety symptoms and interference (Spence Child Anxiety Scale [SCAS-C/P] and Child Anxiety Impact Scale [CAIS-C/P]) accurately identify recovery from common child anxiety disorder diagnoses as measured by a 'gold-standard' diagnostic interview. Three hundred thirty-seven children (7-12 years, 51% female) and their parents completed the ADIS-IV-C/P diagnostic interview and questionnaire measures (SCAS-C/P and CAIS-C/P) before (Time 1) and after (Time 2) treatment or wait-list. Time 2 parent reported interference (CAIS-P) was found to be a good predictor of absence of any diagnoses (area under the curve [AUC] = .81). In terms of specific diagnoses, Time 2 SCAS-C/P separation anxiety subscale (SCAS-C/P-SA) identified recovery from separation anxiety disorder well (SCAS-C-SA, AUC = .80; SCAS-P-SA, AUC = .82) as did the CAIS-P (AUC = .79). The CAIS-P also successfully identified recovery from social phobia (AUC = .78) and generalized anxiety disorder (AUC = .76). These AUC values were supported by moderate to good sensitivity (.70-.78) and specificity (.70-.73) at the best identified cut-off scores. None of the measures successfully identified recovery from specific phobia. The results suggest that questionnaire measures, particularly the CAIS-P, can be used to identify whether children have recovered from common anxiety disorders, with the exception of specific phobias. Cut-off scores have been identified that can guide the use of routine outcome measures in clinical practice. (PsycINFO Database Record


Detecting hepatitis B virus in surgical smoke emitted during laparoscopic surgery.
Hepatitis B virus (HBV) transmission is known to occur through direct contact with infected blood. There has been some suspicion that the virus can also be detected in aerosol form. However, this has never been directly shown. The purpose of this study was to sample and analyse surgical smoke from laparoscopic surgeries on patients with hepatitis B to determine whether HBV is present. A total of 11 patients who underwent laparoscopic or robotic abdominal surgeries between October 2014 and February 2015 at Korea University Anam Hospital were included in this study. A high efficiency collector was used to obtain surgical smoke in the form of hydrosol. The smoke was analysed by using nested PCR. Robotic or laparoscopic colorectal resections were performed in 5 cases, laparoscopic gastrectomies in 3 cases and laparoscopic hepatic wedge resections in another 3 cases. Preoperatively, all of the patients had positive hepatitis B surface antigen (HBsAg). 2 patients had detectable HBsAb, and 2 were positive for hepatitis B e antigen. 3 patients were taking antihepatitis B viral medications at the time of the study. The viral load measured in the patients' blood was undetectable to 1.7×108 IU/mL. HBV was detected in surgical smoke in 10 of the 11 cases. HBV is detectable in surgical smoke. This study provides preliminary data in the investigation of airborne HBV infection.


Clinical outcome of patients with papillary thyroid carcinoma who have recurrence after initial radioactive iodine therapy.
Among patients with well differentiated papillary thyroid carcinoma who generally have an excellent prognosis and a near-normal lifespan, there exist subsets of patients who have significant risk for morbidity and mortality from this disease. It is important to define the patterns of disease progression and the clinical outcome of such patients to develop effective surveillance and treatment strategies. Patients with recurrence after surgery and therapeutic administration of radioactive iodine (RAI) for papillary thyroid carcinoma represent one such subset of high-risk patients. At the University of Texas M. D. Anderson Cancer Center, 65 patients with papillary thyroid carcinoma were diagnosed between 1970 and 1990. Their medical records were reviewed with particular attention to disease recurrence and outcome as well as RAI imaging and treatment. Following diagnosis and initial therapy, 19 patients died from thyroid carcinoma after a median of 64 months; 34 had no evidence of disease for a median of 112 months of available follow-up; and 7 are alive with disease 61 to 153 months after diagnosis. Cervical lymph node metastases were present in 41 patients and extrathyroidal or extranodal tumor invasion was seen in 25 patients at the time of initial surgery; distant metastases (lung, bone, brain, liver, and adrenal) developed later in 18 patients. RAI uptake by recurrent tumor deposits in the neck was seen most frequently in patients with no direct invasion of adjacent tissues but with recurrence limited to cervical lymphadenopathy; this group of patients was the most likely to become clinically and radiologically disease free. RAI generally did not concertrate in invasive cancers with extrathyroidal or extranodal extension in the neck; patients with this type of invasive carcinoma were also more likely to die from the disease. We suggest that among patients with recurrent papillary thyroid carcinoma, invasive cancers are less likely to concertrate RAI, whereas patients with disease confined to lymph nodes are more likely to have RAI-avid tumors and to benefit from RAI therapy.


Antidiabetic therapies and male reproductive function: where do we stand?
Diabetes mellitus has been increasing at alarming rates in recent years, thus jeopardizing human health worldwide. Several antidiabetic drugs have been introduced in the market to manage glycemic levels, and proven effective in avoiding, minimizing or preventing the appearance or development of diabetes mellitus-related complications. However, and despite the established association between such pathology and male reproductive dysfunction, the influence of these therapeutic interventions on such topics have been scarcely explored. Importantly, this pathology may contribute toward the global decline in male fertility, giving the increasing preponderance of diabetes mellitus in young men at their reproductive age. Therefore, it is mandatory that the reproductive health of diabetic individuals is maintained during the antidiabetic treatment. With this in mind, we have gathered the available information and made a critical analysis regarding the effects of several antidiabetic drugs on male reproductive function. Unlike insulin, which has a clear and fundamental role on male reproductive function, the other antidiabetic therapies' effects at this level seem incoherent. In fact, studies are highly controversial possibly due to the different experimental study approaches, which, in our opinion, suggests caution when it comes to prescribing such drugs to young diabetic patients. Overall, much is still to be determined and further studies are needed to clarify the safety of these antidiabetic strategies on male reproductive system. Aspects such as the effects of insulin levels variations, consequent of insulin therapy, as well as what will be the impact of the side effect hypoglycemia, common to several therapeutic strategies discussed, on the male reproductive system are still to be addressed.


Calcium signalling and pancreatic cell death: apoptosis or necrosis?
Secretagogues, such as cholecystokinin and acetylcholine, utilise a variety of second messengers (inositol trisphosphate, cADPR and nicotinic acid adenine dinucleotide phosphate) to induce specific oscillatory patterns of calcium (Ca(2+)) signals in pancreatic acinar cells. These are tightly controlled in a spatiotemporal manner, and are coupled to mitochondrial metabolism necessary to fuel secretion. When Ca(2+) homeostasis is disrupted by known precipitants of acute pancreatitis, for example, hyperstimulation or non-oxidative ethanol metabolites, Ca(2+) stores (endoplasmic reticulum and acidic pool) become depleted and sustained cytosolic [Ca(2+)] elevations replace transient signals, leading to severe consequences. Sustained mitochondrial depolarisation, possibly via opening of the mitochondrial permeability transition pore (MPTP), elicits cellular ATP depletion that paralyses energy-dependent Ca(2+) pumps causing cytosolic Ca(2+) overload, while digestive enzymes are activated prematurely within the cell; Ca(2+)-dependent cellular necrosis ensues. However, when stress to the acinar cell is milder, for example, by application of the oxidant menadione, release of Ca(2+) from stores leads to oscillatory global waves, associated with partial mitochondrial depolarisation and transient MPTP opening; apoptotic cell death is promoted via the intrinsic pathway, when associated with generation of reactive oxygen species. Apoptosis, induced by menadione or bile acids, is potentiated by inhibition of an endogenous detoxifying enzyme NAD(P)H:quinone oxidoreductase 1 (NQO1), suggesting its importance as a defence mechanism that may influence cell fate.


Noradrenaline-functionalized hyperbranched fluoropolymer-poly(ethylene glycol) cross-linked networks as dual-mode, anti-biofouling coatings.
The strategy of decorating antibiofouling hyperbranched fluoropolymer-poly(ethylene glycol) (HBFP-PEG) networks with a settlement sensory deterrent, noradrenaline (NA), and the results of biofouling assays are presented. This example of a dual-mode surface, which combines both passive and active modes of antibiofouling, works in synergy to improve the overall antibiofouling efficiency against barnacle cyprids. The HBFP-PEG polymer surface, prior to modification with NA, was analyzed by atomic force microscopy, and a significant distribution of topographical features was observed, with a nanoscopic roughness measurement of 110 ± 8 nm. NA attachment to the surface was probed by secondary ion mass spectrometry to quantify the extent of polymer chain-end substitution with NA, where a 3- to 4-fold increase in intensity for a fragment ion associated with NA was observed and 39% of the available sites for attachment were substituted. Cytoskeletal assays confirmed the activity of tethered NA on adhering oyster hemocytes. Settlement assays showed deterrence toward barnacle cyprid settlement, while not compromising the passive biofouling resistance of the surface. This robust strategy demonstrates a methodology for the incorporation of actively antibiofouling moieties onto a passively antibiofouling network.


Extracellular vesicles produced by Cryptococcus neoformans contain protein components associated with virulence.
Cryptococcus neoformans produces vesicles containing its major virulence factor, the capsular polysaccharide glucuronoxylomannan (GXM). These vesicles cross the cell wall to reach the extracellular space, where the polysaccharide is supposedly used for capsule growth or delivered into host tissues. In the present study, we characterized vesicle morphology and protein composition by a combination of techniques including electron microscopy, proteomics, enzymatic activity, and serological reactivity. Secretory vesicles in C. neoformans appear to be correlated with exosome-like compartments derived from multivesicular bodies. Extracellular vesicles manifested various sizes and morphologies, including electron-lucid membrane bodies and electron-dense vesicles. Seventy-six proteins were identified by proteomic analysis, including several related to virulence and protection against oxidative stress. Biochemical tests indicated laccase and urease activities in vesicles. In addition, different vesicle proteins were recognized by sera from patients with cryptococcosis. These results reveal an efficient and general mechanism of secretion of pathogenesis-related molecules in C. neoformans, suggesting that extracellular vesicles function as "virulence bags" that deliver a concentrated payload of fungal products to host effector cells and tissues.


The ORFanage: an ORFan database.
As each newly sequenced genome contains a significant number of protein-coding ORFs that are species-, family- or lineage-specific, many interesting questions arise about the evolution and role of these ORFs and of the genomes they are part of. We refer to these poorly conserved ORFs as singleton or paralogous ORFans if they are unique to one genome, or as orthologous ORFans if they appear only in a family of closely related organisms and have no homolog in other genomes. In order to study and classify ORFans we have constructed the ORFanage, an ORFan database. This database consists of the predicted ORFs in fully sequenced microbial genomes, and enables searching for the three types of ORFans in any subset of the genomes chosen by the user. The ORFanage could help in choosing interesting targets for further genomic and evolutionary studies. The ORFanage is accessible via http://www.bioinformatics.buffalo. edu/ORFanage.


A pilot audit of a protocol for ambulatory investigation of predicted low-risk patients with possible pulmonary embolism.
Patients with possible pulmonary embolism (PE) commonly present to acute medical services. Research has led to the identification of low-risk patients suitable for ambulatory management. We report on a protocol designed to select low-risk patients for ambulatory investigation if confirmatory imaging is not available that day. The protocol was piloted in the Emergency Department and Medical Assessment Area at the Royal Infirmary of Edinburgh. We retrospectively analysed electronic patient records in an open observational audit of all patients managed in the ambulatory arm over five months of use. We analysed 45 patients' records. Of these, 91.1% required imaging to confirm or refute PE, 62.2% received a computed tomography pulmonary angiogram (CTPA). In 25% of patients, PE was confirmed with musculoskeletal pain (22.7%), and respiratory tract infection (15.9%) the next most prevalent diagnoses. Alternative diagnoses was provided by CTPA in 32% of cases. We identified no adverse events or readmissions but individualised follow-up was not attempted. The data from this audit suggests this protocol can be applied to select and manage low-risk patients suitable for ambulatory investigation of possible PE. A larger prospective comparative study would be required to accurately define the safety and effectiveness of this protocol.


Health information exchange improves identification of frequent emergency department users.
We hypothesized that using communitywide data from a health information exchange (HIE) could improve the ability to identify frequent emergency department (ED) users-those with four or more ED visits in thirty days-by allowing ED use to be measured across unaffiliated hospitals. When we analyzed HIE-wide data instead of site-specific data, we identified 20.3 percent more frequent ED users (5,756 versus 4,785) and 16.0 percent more visits by them to the ED (53,031 versus 45,771). Additionally, we found that 28.8 percent of frequent ED users visited multiple EDs during the twelve-month study period, versus 3.0 percent of all ED users. All three differences were significant ($$p ). An improved ability to identify frequent ED users allows better targeting of case management and other services that can improve frequent ED users' health and reduce their use of costly emergency medical services.


Operative repair or endovascular stent graft in blunt traumatic thoracic aortic injuries: results of an American Association for the Surgery of Trauma Multicenter Study.
The purpose of this American Association for the Surgery of Trauma multicenter study is to assess the early efficacy and safety of endovascular stent grafts (SGs) in traumatic thoracic aortic injuries and compare outcomes with the standard operative repair (OR). Prospective, multicenter study. Data for the following were collected: age, blood pressure, and Glasgow Coma Scale (GCS) at admission, type of aortic injury, injury severity score, abbreviate injury scale (AIS), transfusions, survival, ventilator days, complications, and intensive care unit and hospital days. The outcomes between the two groups (open repair or SG) were compared, adjusting for presence of critical extrathoracic trauma (head, abdomen, or extremity AIS >3), GCS score </=8, systolic blood pressure <90 mm Hg, and age >55 years. Separate multivariable analysis was performed, one for patients without and one for patients with associated critical extrathoracic injuries (head, abdomen, or extremity AIS >3), to compare the outcomes of the two therapeutic modalities adjusting for hypotension, GCS score </=8, and age >55 years. One hundred ninety-three patients met the criteria for inclusion. Overall, 125 patients (64.9%) were selected for SG and 68 (35.2%) for OR. SG was selected in 71.6% of the 74 patients with major extrathoracic injuries and in 60.0% of the 115 patients with no major extrathoracic injuries. SG patients were significantly older than OR patients. Overall, 25 patients in the SG group (20.0%) developed 32 device-related complications. There were 18 endoleaks (14.4%), 6 of which needed open repair. Procedure-related paraplegia developed in 2.9% in the OR and 0.8% in the SG groups (p = 0.28). Multivariable analysis adjusting for severe extrathoracic injuries, hypotension, GCS, and age, showed that the SG group had a significantly lower mortality (adjusted odds ratio: 8.42; 95% CI: [2.76-25.69]; adjusted p value <0.001), and fewer blood transfusions (adjusted mean difference: 4.98; 95% CI: [0.14-9.82]; adjusted p value = 0.046) than the OR group. Among the 115 patients without major extrathoracic injuries, higher mortality and higher transfusion requirements were also found in the OR group (adjusted odds ratio for mortality: 13.08; 95% CI [2.53-67.53], adjusted p value = 0.002 and adjusted mean difference in transfusion units: 4.45; 95% CI [1.39-7.51]; adjusted p value = 0.004). Among the 74 patients with major extrathoracic injuries, significantly higher mortality and pneumonia rate were found in the OR group (adjusted p values 0.04 and 0.03, respectively). Multivariate analysis showed that centers with high volume of endovascular procedures had significantly fewer systemic complications (adjusted p value 0.001), fewer local complications (adjusted p value p = 0.033), and shorter hospital lengths of stay (adjusted p value 0.005) than low-volume centers. Most surgeons select SG for traumatic thoracic aortic ruptures, irrespective of associated injuries, injury severity, and age. SG is associated with significantly lower mortality and fewer blood transfusions, but there is a considerable risk of serious device-related complications. There is a major and urgent need for improvement of the available endovascular devices.


Hyperactive CREB signaling pathway involved in the pathogenesis of polycystic ovarian syndrome revealed by patient-specific induced pluripotent stem cell modeling.
To study whether and how the pathogenesis of polycystic ovarian syndrome (PCOS) is related to epigenetic aberrations. A case-control experimental study. Tertiary university hospital. Eighteen patients with PCOS and ten non-PCOS control subjects. Patient-specific induced pluripotent stem cells (iPSCs) were obtained from skin fibroblasts through the application of nonviral episomal reprogramming and were differentiated into ovarian granulosa cells (GCs) with the use of a cocktail of growth factors. Primary ovarian GCs were collected during transvaginal oocyte retrieval surgery. Characterization and functional validation of iPSC-derived GCs were conducted. Whole-genomic DNA methylation profiles in women with and without PCOS in both iPSC-derived GCs and primary adult GCs were analyzed with the use of the Illumina 850K MethylationEPIC Beadchip. The iPSC-derived GCs successfully expressed GC-associated genes and aromatase activity after differentiation. Whole-genomic DNA methylation analysis of the iPSC-derived GCs and adult GCs both revealed a hyperactive CREB signaling pathway in the PCOS group compared with the control group. The expression of CREB-binding protein (CBP) mRNA was significantly higher in the iPSC-derived GCs in the PCOS group, and the expression of CBP protein was also significantly higher in the primary GCs from women with PCOS. The combination of DNA methylomic analysis in primary adult GCs and iPSC-derived GCs showed that a preserved persistent hyperactivation of the CREB signaling pathway might be involved in the pathogenesis of PCOS. These results could have implications on the early developmental origin, inheritance nature, and environmental interaction effects of this disease.


Understanding Toxoplasmosis in the United States Through "Large Data" Analyses.
Toxoplasma gondii infection causes substantial morbidity and mortality in the United States, and infects approximately one-third of persons globally. Clinical manifestations vary. Seropositivity is associated with neurologic diseases and malignancies. There are few objective data concerning US incidence and distribution of toxoplasmosis. Truven Health MarketScan Database and International Classification of Diseases, Ninth Revision (ICD-9) codes, including treatment specific to toxoplasmosis, identified patients with this disease. Spatiotemporal distribution and patterns of disease manifestation were analyzed. Comorbidities between patients and matched controls were compared. Between 2003 and 2012, 9260 patients had ICD-9 codes for toxoplasmosis. This database of patients with ICD-9 codes includes 15% of those in the United States, excluding patients with no or public insurance. Thus, assuming that demographics do not change incidence, the calculated total is 61 700 or 6856 patients per year. Disease was more prevalent in the South. Mean age at diagnosis was 37.5 ± 15.5 years; 2.4% were children aged 0-2 years, likely congenitally infected. Forty-one percent were male, and 73% of women were of reproductive age. Of identified patients, 38% had eye disease and 12% presented with other serious manifestations, including central nervous system and visceral organ damage. Toxoplasmosis was statistically associated with substantial comorbidities, including human immunodeficiency virus, autoimmune diseases, and neurologic diseases. Toxoplasmosis causes morbidity and mortality in the United States. Our analysis of private insurance records missed certain at-risk populations and revealed fewer cases of retinal disease than previously estimated, suggesting undercoding, underreporting, undertreating, or differing demographics of those with eye disease. Mandatory reporting of infection to health departments and gestational screening could improve care and facilitate detection of epidemics and, thereby, public health interventions.


Complexity in strongly correlated electronic systems.
A wide variety of experimental results and theoretical investigations in recent years have convincingly demonstrated that several transition metal oxides and other materials have dominant states that are not spatially homogeneous. This occurs in cases in which several physical interactions-spin, charge, lattice, and/or orbital-are simultaneously active. This phenomenon causes interesting effects, such as colossal magnetoresistance, and it also appears crucial to understand the high-temperature superconductors. The spontaneous emergence of electronic nanometer-scale structures in transition metal oxides, and the existence of many competing states, are properties often associated with complex matter where nonlinearities dominate, such as soft materials and biological systems. This electronic complexity could have potential consequences for applications of correlated electronic materials, because not only charge (semiconducting electronic), or charge and spin (spintronics) are of relevance, but in addition the lattice and orbital degrees of freedom are active, leading to giant responses to small perturbations. Moreover, several metallic and insulating phases compete, increasing the potential for novel behavior.


Subacute sclerosing panencephalitis in South African children following the measles outbreak between 2009 and 2011.
Between 2009 and 2011, there was an outbreak of measles throughout South Africa (SA). The largest age category infected was children<5 years of age. In 2014, four patients, with a median age of 4 years and 5 months (range 4 years 3 months-4.5 years), three males and one female, presented with subacute sclerosing panencephalitis (SSPE). All were infected with measles during the period of the 2009-2011 outbreak in early infancy, at a time when their immune systems were immature and before they were vaccinated against the measles virus. One patient was immunocompromised, with vertically acquired HIV infection. All the children presented with cognitive and behavioural decline, abnormal movements and medically intractable myoclonic and atonic seizures. Outcome was poor in all and no reversibility was evident with standard therapeutic interventions. Optimal seizure control with carbamazepine is reported in patients with SSPE. Three of our patients who received carbamazepine experienced improved seizure control, but their neuroregression continued. Since submission of this case series, patient 1 (see Table 1) has died, and a further child has presented with the same clinical phenotype as described. On the basis of this clustering of patients in the Western Cape Province, SA, it is important to screen children admitted with acute cognitive decline and intractable seizures for SSPE, especially those who were infants during the measles outbreak.


Studies on the expression of intestinal lactase in different individuals.
Sixty one duodenal biopsy specimens were examined for the expression of lactase at the level of enzyme activity, protein, and messenger RNA. Of the 51 samples with normal villous architecture, 39 were lactase persistent, 11 were nonpersistent (adult type hypolactasia), and one was of indeterminate status. All the lactase persistent individuals showed high mRNA and a high level of the lactase protein as detected by sodium dodecyl sulphate polyacrylamide gel electrophoresis. All the 11 non-persistent individuals tested showed a low level of lactase protein. Nine of the 10 samples tested showed low mRNA and one high mRNA. These results suggest that the lactase persistence polymorphism is controlled at the level of the expression of the lactase gene, though there may be some heterogeneity of the lactase non-persistence phenotype.


Retethering of transected fatty filum terminales.
Untethering of a tethered spinal cord (TSC) by transecting or removing a fatty filum terminale is a relatively simple procedure that can prevent or ameliorate neurological symptoms, and the postoperative prognosis is usually good. Progressive neurological deterioration caused by recurrent tethering has been rarely reported. The authors present their experience in cases in which a sectioned fatty filum terminale has become retethered. The authors retrospectively analyzed the surgical results of pediatric patients with fatty filum terminale-TSC treated by transection of the filum. The patients' charts were reviewed for demographic data, clinical presentation, surgical therapy, and follow-up data. Of the 225 children who underwent TSC release by sectioning the fatty filum from 1992 to 2005, there were 6 patients (2.7%; 3 males, 3 females) in whom the fatty filum retethered. The mean age at the first diagnosis of TSC was 5.2 years (range 2 months-12.3 years). The mean duration from the first untethering procedure to retethering was 5.4 years. The mean age at the time of retethering was 10.6 years (range 7-17.5 years). Symptoms of retethering were urinary incontinence, low-back pain, difficulty walking, constipation, leg pain, and worsening foot deformity. Patients underwent cystometrography at the time retethering was indicated by increased bladder capacity, large post-void residual volume, decreased bladder capacity, increase in filling pressure, and poor sensation of filling. Magnetic resonance imaging revealed adherence of the rostral stump of the sectioned filum to the midline dorsal dural surface. All patients underwent the second untethering procedure. Four patients improved neurologically and experienced no retethering thereafter (mean follow-up period 5.5 years). Two patients experienced additional retethering after temporary improvement following the second untethering procedure. Retethering of the spinal cord is a rare condition occurring after the sectioning of a fatty filum terminale. Awareness of this rare sequela is necessary for appropriate long-term management of TSC caused by a fatty filum terminale. Cystometrography is useful for detecting the lesion and confirming the diagnosis of retethering.


Epidemiology of Biliary Atresia in Korea.
Biliary atresia (BA) is the major cause of cholestasis and the leading indication for liver transplantation (LT). However, the incidence of BA in Korea has not been reported. The aim of this study was to investigate the incidence and clinical outcomes of BA in Korea. We used the Korean universal health insurance database and extracted data regarding BA patients younger than 18 years of age admitted between 2011 and 2015. The incidence of BA was calculated by dividing the number of BA patients by the number of live births. Two hundred forty infants were newly diagnosed with BA. A total of 963 BA patients younger than 18 years of age were followed up for 5 years. The overall incidence of BA was 1.06 cases per 10,000 live births. The incidence of BA was 1.4 times higher for female patients than for male patients. Additionally, significant seasonal variation was observed; in particular, the incidence of BA was 2 times higher from June through August than from December through February. Congenital anomalies were found in 38 of 240 patients (15.8%). Congenital heart diseases were major associated congenital anomalies (6.3%). Several complications developed during the study period, including cholangitis (24.0%), varix (6.2%), and gastrointestinal bleeding (4.4%). Three hundred and one of the 963 BA patients under 18 years of age (31.3%) received LT for BA. The incidence of BA is higher in Korea than that in Western countries. We also report significant gender-associated differences and seasonal variation with respect to the incidence of BA.


Regulation by membrane potential of phosphatidylinositol hydrolysis in pancreatic islets.
In pancreatic islets stimulated with carbamylcholine (carbachol), hydrolysis of both phosphatidylinositol (PtdIns) and phosphatidylinositol bisphosphate (Ptd-InsP2) occurs and can be measured as the inositol monophosphates Ins(1)P1, or Ins(4)P1, respectively (Biden, T. J., Prugue, M. L., and Davison, A. G. M. (1992) Biochem. J. 285, 541-549). Our current aim was to establish whether these two events were independently regulated. Rats islets were labeled with either [3H]inositol or [3H]arachidonic acid for measurement of InsP1s by high performance liquid chromatography or diacylglycerol by TLC, respectively. The rise in Ins(1)P1 due to carbachol (1 min) was inhibited by 50% by concomitantly raising extracellular KCl ([K+]e) from 6 to 30 mM, thereby depolarizing the islets. Similar results, obtained in the absence of extracellular Ca2+, exclude the involvement of voltage-gated Ca2+ channels. Conversely, hyperpolarization, by lowering [K+]e to 3 mM, increased by 30% the rise in Ins(1)P1. In fact, over the [K+]e range of 3 to 48 mM, stimulated Ins(1)P1 accumulation was directly proportional to the calculated membrane potential. In contrast, raising [K+]e from 6 to 48 mM exerted no significant effect on carbachol-stimulated Ins(4)P1 levels, and both Ins(1)P1 and Ins(4)P1 were unaffected in the absence of carbachol. The rises in Ins(1)P1 (but not Ins(4)P1) were also inhibited by depolarization with the sodium pump inhibitor, ouabain, or the K+ channel blocker, tolbutamide. Stimulated diacylglycerol accumulation and insulin secretion (20 min) showed a biphasic dependency on [K+]e, being less pronounced at 6 mM than at either 3 or 30 mM KCl. This reflects a selective potentiation of PtdIns and PtdInsP2 hydrolysis, due, respectively, to hyperpolarization and the gating of voltage-dependent Ca2+ channels. The differential regulation of these two hydrolytic events is probably important for independent control of the activation of protein kinase C and Ca2+ mobilization and might play a role in modulating the secretory response in vivo.


Intratympanic gentamicin for intractable Meniere's disease.
The study aimed to analyze the results of the intratympanic injection of gentamicin as a treatment option for patients with unilateral Meniere's disease who were refractory to medical treatment. Prospective study in the setting of a tertiary care medical center. Seventy-one patients with unilateral Meniere's disease according to 1995 American Academy of Otolaryngology-Head and Neck Surgery 1995 guidelines who had been unresponsive to medical therapy for at least 1 year were studied. Intratympanic injections of a prepared concentration of 27 mg/mL gentamicin were performed at weekly intervals until the development of symptoms and signs indicative of vestibular hypofunction in the treated ear. As the main outcome measure, the 1995 American Academy of Otolaryngology-Head and Neck Surgery criteria for reporting treatment outcome in Meniere's disease were used. The results of treatment were expressed in terms of control of vertigo, disability status (functional level and degree of overall impairment evaluated by the Dizziness Handicap Inventory and the University of California Los Angeles Dizziness Questionnaire), hearing level, and quantitative measurement of vestibular function. Vertigo was controlled in 83.1% of the 71 patients. Recurrence of vertigo spells after initially complete control was noted in 17 patients. In 13 of these patients, this was cured by another course of intratympanic injections of gentamicin. Functional level and measures of self-reported handicap were significantly and promptly lowered after treatment in the patients who attained control of vertigo. Hearing level as pure-tone average was unchanged 2 years after treatment, but hearing loss as a result of gentamicin injections occurred in 23 patients at the end of treatment and in 9 and 11 patients at 3 months and 2 years after the treatment, respectively. Vestibular function was kept normal or reduced in 49.3% of the patients, whereas in the rest of the patients vestibular areflexia was observed. Control of vertigo did not depend on the amount of vestibular damage. Ending weekly intratympanic injections when clinical signs of vestibular deafferentation appear can control vertigo in the majority of patients, and it is a useful alternative, together with other surgical options, for the treatment of patients with Meniere's disease who do not respond to medical treatment.


Tracking the Cognitive, Social, and Neuroanatomical Profile in Early Neurodegeneration: Type III Cockayne Syndrome.
Cockayne syndrome (CS) is an autosomal recessive disease associated with premature aging, progressive multiorgan degeneration, and nervous system abnormalities including cerebral and cerebellar atrophy, brain calcifications, and white matter abnormalities. Although several clinical descriptions of CS patients have reported developmental delay and cognitive impairment with relative preservation of social skills, no previous studies have carried out a comprehensive neuropsychological and social cognition assessment. Furthermore, no previous research in individuals with CS has examined the relationship between brain atrophy and performance on neuropsychological and social cognition tests. This study describes the case of an atypical late-onset type III CS patient who exceeds the mean life expectancy of individuals with this pathology. The patient and a group of healthy controls underwent a comprehensive assessment that included multiple neuropsychological and social cognition (emotion recognition, theory of mind, and empathy) tasks. In addition, we compared the pattern of atrophy in the patient to controls and to its concordance with ERCC8 gene expression in a healthy brain. The results showed memory, language, and executive deficits that contrast with the relative preservation of social cognition skills. The cognitive profile of the patient was consistent with his pattern of global cerebral and cerebellar loss of gray matter volume (frontal structures, bilateral cerebellum, basal ganglia, temporal lobe, and occipito-temporal/occipito-parietal regions), which in turn was anatomically consistent with the ERCC8 gene expression level in a healthy donor's brain. The study of exceptional cases, such as the one described here, is fundamental to elucidating the processes that affect the brain in premature aging diseases, and such studies provide an important source of information for understanding the problems associated with normal and pathological aging.


Glenohumeral Dislocation Arthropathy: Etiology, Diagnosis, and Management.
Dislocation arthropathy describes the development of progressive degenerative changes of the glenohumeral joint in the setting of instability. Although the specific etiology remains unclear, the trauma of a single dislocation, repetitive injury associated with recurrent dislocations, changes in shoulder biomechanics, and complications associated with instability surgery have all been implicated in its development. Pain and restricted range of motion are the most common patient complaints. Conservative management, consisting of pain control, activity modification, and physical therapy, is the first-line treatment after the development of arthropathy. If conservative management fails, multiple surgical options exist. Arthroscopic débridement can be attempted in young, active patients and in those patients with mild-to-moderate arthropathy. Open subscapularis lengthening and capsular release can be done in patients with prior instability repairs that are overly tight. In young patients with minimal bone loss and glenoid wear, surface replacement arthroplasty and hemiarthroplasty are surgical options. In older patients with moderate-to-severe arthropathy, total shoulder or reverse shoulder arthroplasty is the preferred treatment option. Further study is needed to better predict which patients will develop dislocation arthropathy and will thus benefit from early surgical intervention.


Dietary Supplements as Surrogate of Mediterranean Diet in Healthy Smoking Subjects.
The interventions to slow aging, favoring active life expectancy, represent the new perspectives in ageing investigation. Some mechanisms that delay or prevent the onset of aging pathologies have been identified. Between them, a healthy lifestyle seems to reduce many risk factors. In particular, eating habits represent the most concrete, low-cost way to act on aging process. Mediterranean diet has received much attention since its antioxidant and anti-inflammatory effects have been consistently demonstrated. Unfortunately, many people follow a Western diet, poor in phytochemicals that represent the main source of beneficial effects of this dietary pattern. So, supplements administration should be considered, especially in subjects exposed to high level of oxidative stress and inflammation. So, we tested the properties of a commercial food supplement containing a series of plant polyphenols in combination with caffeine, bioperine (black pepper extract), and selenium in smoking healthy volunteers. Fifty participants have been recruited and hematochemical analyses and biochemistry tests have been performed, before and after 60 days of supplement intake. Thirteen subjects dropped out of the study. At the end of the intervention, the variation of inflammatory and oxidant markers has been evaluated, measuring urinary isoprostanes, serum advanced glycation end products, and oxidized low-density lipoproteins. The results showed that this supplement exhibits promising antioxidant and anti-inflammatory responses, especially in women, highlighting the role of supplementation in certain groups of subjects, for the control of oxidative stress as well as inflammatory status. So, its intake should be useful in delaying the onset of age-related diseases.


The development of cooperation and self-control in middle childhood: Associations with earlier maternal and paternal parenting.
Developmental theories and previous research have emphasized the significance of cooperation and self-control in middle childhood. The present study extends previous research by examining (a) the growth of cooperation and self-control as well as the relations between them in middle childhood (third to sixth grade) and (b) the extent to which mothers' and fathers' parenting during early childhood (54 months and first grade) was associated with children's cooperation and self-control. The sample included 705 children (51% female, 86% White) and their mothers, fathers, and teachers in the National Institute of Child Health and Human Development (NICHD) Study of Early Child Care and Youth Development (SECCYD). Children, on average, exhibited increases in self-control but not cooperation from third to sixth grade though the increases were smaller for children who had higher self-control or cooperation at third grade. Children who exhibited higher self-control at third grade tended to exhibit higher cooperation at third grade; similar positive associations emerged for the changes in self-control and cooperation over time. In addition, if a child exhibited higher self-control at one time point relative to their typical average level, they tended to also exhibit higher cooperation at the same time point relative to their typical average level. However, these relative deviations within person were not associated over time. Lastly, maternal and paternal sensitive and stimulating parenting in early childhood was positively associated with children's cooperation and self-control in middle childhood. Overall, our findings shed light on the growth of and the relations between cooperation and self-control in middle childhood and highlight the role of maternal and paternal parenting in early childhood. (PsycInfo Database Record (c) 2021 APA, all rights reserved).


Genetic control of resistance to street rabies virus in mice.
Resistance to intraperitoneally inoculated street rabies virus (SRV) in mice was shown to be under genetic control. SJL/J, CBA/J, DBA/2J, and BALB/cAn mice were resistant, whereas A/WySn/J and A.SW/SnJ mice were susceptible. In addition, female mice of the resistant BALB/cAn and DBA/2J strains were more resistant than their male counterparts. Resistance was not controlled solely by the major histocompatibility locus because susceptible A.SW/SnJ and resistant SJL/J mice have the same H-2S haplotype. Challenge of F1 hybrids produced by crossing resistant and susceptible strains indicated resistance was dominant (97% survivors). Inoculation of backcross mice produced by mating F1 hybrids with susceptible parents showed that one and/or two genes controlled susceptibility. Furthermore, inoculation of SRV obtained from six different animals indicated that differences in strain susceptibilities were not dependent on the SRV isolate. Genetic control of resistance to SRV was, however, abrogated by intracerebral inoculation of virus. Resistant strains of mice were detected that either remained asymptomatic or, in contrast, developed signs of clinical disease, but disease failed to progress and they survived. The recognition of resistant and susceptible strains of mice, differences in female-male resistance within the same resistant strain, as well as dissimilar clinical responses in different resistant mouse strains to intraperitoneally inoculated SRV provide promising probes for investigation of host resistance and mechanisms for survival after onset of clinical rabies.


Flow resistance of individual neutrophils in coronary artery disease: decreased pore transit times in acute myocardial infarction.
To investigate single neutrophil flow resistance in coronary artery disease, including myocardial infarction before initiation of reperfusion therapy. Neutrophil flow resistance was measured in 93 subjects in five groups: (group 1) 28 patients within 12 hours after the onset of myocardial infarction, before reperfusion therapy; (group 2) 18 with unstable angina; (group 3) 13 with stable angina; (group 4) 13 age matched patients without coronary disease, and (group 5) 21 healthy volunteers. MAIN PARAMETERS: Single neutrophil transit times through 8 microns oligopore filters determined with a modified cell transit analyser. Leucocyte count (10(9)/l) was increased in coronary disease, especially in myocardial infarction and unstable angina (mean and 95% confidence intervals for groups 1 to 5: 12.6 (11.0 to 14.2), 11.3 (8.5 to 14.1), 8.5 (7.4 to 9.6), 8.0 (6.0 to 10.0), 7.0 (6.1 to 7.9)). Polymorphonuclear granulocyte (PMN) flow resistance correlated negatively with white blood cell (WBC) count and was significantly decreased in coronary artery disease (CAD), especially in myocardial infarction; mean transit times (ms) for groups 1 to 5 were: 13.6 (11.8 to 15.4), 16.9 (13.9 to 19.0), 16.9 (12.8 to 21.0), 22.0 (19.6 to 24.4), and 18.6 (15.7 to 21.5). Neutrophil flow resistance was decreased in CAD, especially in myocardial infarction before reperfusion therapy. In contrast to previous findings in reperfused myocardial infarction, the present study showed that stiffened PMNs were not yet present in the circulating blood pool. Thus a pharmacological approach aimed at suppressing leucocyte activation before or during reperfusion therapy may be feasible.


Prevalence of obstructive sleep apnoea in men with type 2 diabetes.
A study was undertaken to establish the prevalence of obstructive sleep apnoea (OSA) in men with type 2 diabetes. Men with type 2 diabetes from local hospital and selected primary care practitioner databases received questionnaires about snoring, apnoeas, and daytime sleepiness based on the Berlin questionnaire. Selected respondents had overnight oximetry to establish whether they had OSA. Comparisons of oximetry were made with those from a previous general population study. HbA1c results were collected. 1682 men were sent questionnaires, 56% of whom replied. 57% scored as "high" and 39% as "low" risk for OSA; 4% were already known to have OSA. Oximetry was performed in 240 respondents from both risk groups: 31% of the "high" and 13% of the "low" risk group had significant OSA (more than 10 >4% Sao(2) dips/hour or Sao(2) tracing consistent with OSA). These results were verified by detailed sleep studies. Extrapolation of the oximetry data to the questionnaire respondent population suggests that 23% had OSA. Comparison of the oximetry results with men from a previous general population study (using only more than 10 >4% Sao(2) dips/hour to define OSA) showed the prevalence of OSA is significantly higher in this diabetes population (17% v 6%, p<0.001). Multiple linear regression revealed BMI and diabetes as significant independent predictors of OSA. Following correction for BMI (which explained 13% of the variance in OSA), diabetes explained a further 8% of the variance (p<0.001). There was a low correlation between OSA severity and HbA1c in the subgroup recruited from the hospital database (r = 0.2, p = 0.006) which remained significant after allowing for obesity (p = 0.03). OSA is highly prevalent in men with type 2 diabetes; most are undiagnosed. Diabetes itself may be a significant independent contributor to the risk of OSA.


Carrier-induced optical bistability in silicon ring resonators.
We demonstrate optical bistability in a micrometer-sized silicon ring resonator based on the free-carrier dispersion effect in silicon. We measure the transfer function of the resonator showing a hysteresis loop with an input optical power of less than 10 mW. The influence of the thermal optical effect, which is minimized in the experiment by use of nanosecond pulses, is evaluated theoretically. Applications include sequential logic operations for all-optical routing.


Genomic islands: tools of bacterial horizontal gene transfer and evolution.
Bacterial genomes evolve through mutations, rearrangements or horizontal gene transfer. Besides the core genes encoding essential metabolic functions, bacterial genomes also harbour a number of accessory genes acquired by horizontal gene transfer that might be beneficial under certain environmental conditions. The horizontal gene transfer contributes to the diversification and adaptation of microorganisms, thus having an impact on the genome plasticity. A significant part of the horizontal gene transfer is or has been facilitated by genomic islands (GEIs). GEIs are discrete DNA segments, some of which are mobile and others which are not, or are no longer mobile, which differ among closely related strains. A number of GEIs are capable of integration into the chromosome of the host, excision, and transfer to a new host by transformation, conjugation or transduction. GEIs play a crucial role in the evolution of a broad spectrum of bacteria as they are involved in the dissemination of variable genes, including antibiotic resistance and virulence genes leading to generation of hospital 'superbugs', as well as catabolic genes leading to formation of new metabolic pathways. Depending on the composition of gene modules, the same type of GEIs can promote survival of pathogenic as well as environmental bacteria.


Stage-dependent expression of PI3K/Akt‑pathway genes in neuroblastoma.
The phosphoinositide-3 kinase (PI3K) pathway plays a critical role in cancer cell growth and survival and has also been implicated in the development of the childhood cancer neuroblastoma. In neuroblastoma high mRNA expression of the PI3K catalytic isoform PIK3CD is associated to favorable disease. Yet, activation of Akt is associated with poor prognosis. Since the contribution of the numerous members of this pathway to neuroblastoma pathogenesis is mainly unknown, genes of the PI3K/Akt pathway were analyzed at the mRNA level through microarrays and quantitative real-time RT-PCR (TaqMan) and at the protein level using western blot analysis. Five genes showed lower mRNA expression in aggressive compared to more favorable neuroblastomas (PRKCZ, PRKCB1, EIF4EBP1, PIK3RI and PIK3CD) while the opposite was seen for PDGFRA. Clustering analysis shows that the expression levels of these six genes can predict aggressive disease. At the protein level, p110δ (encoded by PIK3CD) and p85α isomers (encoded by PIK3R1) were more highly expressed in favorable compared to aggressive neuroblastoma. Evaluation of the expression of these PI3K genes can predict aggressive disease, and indicates stage-dependent involvement of PI3K-pathway members in neuroblastoma.


MS4a4B, a CD20 homologue in T cells, inhibits T cell propagation by modulation of cell cycle.
MS4a4B, a CD20 homologue in T cells, is a novel member of the MS4A gene family in mice. The MS4A family includes CD20, FcεRIβ, HTm4 and at least 26 novel members that are characterized by their structural features: with four membrane-spanning domains, two extracellular domains and two cytoplasmic regions. CD20, FcεRIβ and HTm4 have been found to function in B cells, mast cells and hematopoietic cells respectively. However, little is known about the function of MS4a4B in T cell regulation. We demonstrate here that MS4a4B negatively regulates mouse T cell proliferation. MS4a4B is highly expressed in primary T cells, natural killer cells (NK) and some T cell lines. But its expression in all malignant T cells, including thymoma and T hybridoma tested, was silenced. Interestingly, its expression was regulated during T cell activation. Viral vector-driven overexpression of MS4a4B in primary T cells and EL4 thymoma cells reduced cell proliferation. In contrast, knockdown of MS4a4B accelerated T cell proliferation. Cell cycle analysis showed that MS4a4B regulated T cell proliferation by inhibiting entry of the cells into S-G2/M phase. MS4a4B-mediated inhibition of cell cycle was correlated with upregulation of Cdk inhibitory proteins and decreased levels of Cdk2 activity, subsequently leading to inhibition of cell cycle progression. Our data indicate that MS4a4B negatively regulates T cell proliferation. MS4a4B, therefore, may serve as a modulator in the negative-feedback regulatory loop of activated T cells.


Electroconvulsive therapy-induced volumetric brain changes converge on a common causal circuit in depression.
Neurostimulation is a mainstream treatment option for major depression. Neuromodulation techniques apply repetitive magnetic or electrical stimulation to some neural target but significantly differ in their invasiveness, spatial selectivity, mechanism of action, and efficacy. Despite these differences, recent analyses of transcranial magnetic stimulation (TMS) and deep brain stimulation (DBS)-treated individuals converged on a common neural network that might have a causal role in treatment response. We set out to investigate if the neuronal underpinnings of electroconvulsive therapy (ECT) are similarly associated with this causal depression network (CDN). Our aim here is to provide a comprehensive analysis in three cohorts of patients segregated by electrode placement (N = 246 with right unilateral, 79 with bitemporal, and 61 with mixed) who underwent ECT. We conducted a data-driven, unsupervised multivariate neuroimaging analysis Principal Component Analysis (PCA) of the cortical and subcortical volume changes and electric field (EF) distribution to explore changes within the CDN associated with antidepressant outcomes. Despite the different treatment modalities (ECT vs TMS and DBS) and methodological approaches (structural vs functional networks), we found a highly similar pattern of change within the CDN in the three cohorts of patients (spatial similarity across 85 regions: r = 0.65, 0.58, 0.40, df = 83). Most importantly, the expression of this pattern correlated with clinical outcomes (t = -2.35, p = 0.019). This evidence further supports that treatment interventions converge on a CDN in depression. Optimizing modulation of this network could serve to improve the outcome of neurostimulation in depression.


Orthologous nuclear markers and new transcriptomes that broadly cover the phylogenetic diversity of Acanthaceae.
Information on orthologous groups of genes, their sequence variability, and annotation is required for project design in phylogenetic reconstruction. This resource is unavailable for the flowering plant family Acanthaceae (>4000 species). We compared transcriptome sequences spanning the extant diversity of Acanthaceae in order to provide a set of orthologous low-copy nuclear genes and assess their utility for reconstructing phylogenetic relationships within this group of plants. We present new transcriptome assemblies for eight species representing all major clades of Acanthaceae. The assemblies of five of these species are entirely based on new sequence data. Of these five species, three are from subfamilies for which no genomic resources were previously available (Nelsonioideae and Thunbergioideae). These five new transcriptomes are more complete than all others from public databases. Furthermore, we provide alignments with sequence information, annotation, and statistics for potential phylogenetic utility of 1619 orthologous low-copy nuclear markers. Our method of inferring assemblies from multiple pooled tissue samples delivers more complete transcriptomes than any available ones from Acanthaceae. We make available to the community new resources (e.g., sequence information, variability, and annotation of orthologous low-copy nuclear genes) that will help phylogenetic reconstruction in Acanthaceae.


Brain and liver insulin binding is decreased in Zucker rats carrying the 'fa' gene.
Insulin binding was measured in membrane particles prepared from the liver and several brain regions of 4-month-old female Zucker fa/fa (obese), Fa/fa (heterozygous), and Fa/Fa (lean) rats. High affinity insulin binding was decreased in the olfactory bulb of fatty (0.23 pmol bound/mg protein) and heterozygous (0.16 pmol/mg) rats compared with that in the lean controls (0.64 pmol/mg). Total binding was not changed in the cerebral cortex or hypothalamus. High affinity insulin binding was also decreased in the liver of both fatty (0.44 +/- 0.22 pmol/mg; P less than 0.01) and heterozygous (0.75 +/- 0.35 pmol/mg) animals compared with that in the lean rats (2.10 +/- 1.55 pmol/mg). This decreased binding is probably not due to down-regulation of receptors in the heterozygous rats, as they do not exhibit the hyperinsulinemia observed in the fatty rats. Rather, our findings suggest that there is a gene-related alteration in insulin binding in the Zucker rat, as low binding was observed in rats carrying either one (Fa/fa) or two (fa/fa) doses of the gene. We postulate that this central defect in insulin binding may contribute to inadequate perception of a central insulin feedback signal and to the hyperphagia observed in the obese rats.


Access to Top-Cited Emergency Care Articles (Published Between 2012 and 2016) Without Subscription.
Unrestricted access to journal publications speeds research progress, productivity, and knowledge translation, which in turn develops and promotes the efficient dissemination of content. We describe access to the 500 most-cited emergency medicine (EM) articles (published between 2012 and 2016) in terms of publisher-based access (open access or subscription), alternate access routes (self-archived or author provided), and relative cost of access. We used the Scopus database to identify the 500 most-cited EM articles published between 2012 and 2016. Access status was collected from the journal publisher. For studies not available via open access, we searched on Google, Google Scholar, Researchgate, Academia.edu, and the Unpaywall and Open Access Button browser plugins to locate self-archived copies. We contacted corresponding authors of the remaining inaccessible studies for a copy of each of their articles. We collected article processing and access costs from the journal publishers, and then calculated relative cost differences using the World Bank purchasing power parity index for the United States (U.S.), Germany, Turkey, China, Brazil, South Africa, and Australia. This allows costs to be understood relative to the economic context of the countries from which they originated. We identified 500 articles for inclusion in the study. Of these, 167 (33%) were published in an open access format. Of the remaining 333 (67%), 204 (61%) were available elsewhere on the internet, 18 (4%) were provided by the authors, and 111 (22%) were accessible by subscription only. The mean article processing and access charges were $2,518.62 and $44.78, respectively. These costs were 2.24, 1.75, 2.28 and 1.56 times more expensive for South African, Chinese, Turkish, and Brazilian authors, respectively, than for U.S. authors (p<0.001 all). Despite the advantage of open access publication for knowledge translation, social responsibility, and increased citation, one in five of the 500 EM articles were accessible only via subscription. Access for scientists from upper-middle income countries was significantly hampered by cost. It is important to acknowledge the value this has for authors from low- and middle-income countries. Authors should also consider the citation advantage afforded by open access publishing when deciding where to publish.


Chasing the reflected wave back into the heart: a new hypothesis while the jury is still out.
Arterial stiffness directly influences cardiac function and is independently associated with cardiovascular risk. However, the influence of the aortic reflected pulse pressure wave on left ventricular function has not been well characterized. The aim of this study was to obtain detailed information on regional ventricular wall motion patterns corresponding to the propagation of the reflected aortic wave on ventricular segments. Left ventricular wall motion was investigated in a group of healthy volunteers (n = 14, age 23 ± 3 years), using cardiac magnetic resonance navigator-gated tissue phase mapping. The left ventricle was divided into 16 segments and regional wall motion was studied in high temporal detail. Corresponding to the expected timing of the reflected aortic wave reaching the left ventricle, a characteristic "notch" of regional myocardial motion was seen in all radial, circumferential, and longitudinal velocity graphs. This notch was particularly prominent in septal segments adjacent to the left ventricular outflow tract on radial velocity graphs and in anterior and posterior left ventricular segments on circumferential velocity graphs. Similarly, longitudinal velocity graphs demonstrated a brief deceleration in the upward recoil motion of the entire ventricle at the beginning of diastole. These results provide new insights into the possible influence of the reflected aortic waves on ventricular segments. Although the association with the reflected wave appears to us to be unambiguous, it represents a novel research concept, and further studies enabling the actual recording of the pulse wave are required.


Protein structure and sequence re-analysis of 2019-nCoV genome does not indicate snakes as its intermediate host or the unique similarity between its spike protein insertions and HIV-1.
As the infection of 2019-nCoV coronavirus is quickly developing into a global pneumonia epidemic, careful analysis of its transmission and cellular mechanisms is sorely needed. In this report, we re-analyzed the computational approaches and findings presented in two recent manuscripts by Ji et al. (https://doi.org/10.1002/jmv.25682) and by Pradhan et al. (https://doi.org/10.1101/2020.01.30.927871), which concluded that snakes are the intermediate hosts of 2019-nCoV and that the 2019-nCoV spike protein insertions shared a unique similarity to HIV-1. Results from our re-implementation of the analyses, built on larger-scale datasets using state-of-the-art bioinformatics methods and databases, do not support the conclusions proposed by these manuscripts. Based on our analyses and existing data of coronaviruses, we concluded that the intermediate hosts of 2019-nCoV are more likely to be mammals and birds than snakes, and that the "novel insertions" observed in the spike protein are naturally evolved from bat coronaviruses.


Drug-responsive autism phenotypes in the 16p11.2 deletion mouse model: a central role for gene-environment interactions.
There are no current treatments for autism, despite its high prevalence. Deletions of chromosome 16p11.2 dramatically increase risk for autism, suggesting that mice with an equivalent genetic rearrangement may offer a valuable model for the testing of novel classes of therapeutic drug. 16p11.2 deletion (16p11.2 DEL) mice and wild-type controls were assessed using an ethological approach, with 24 h monitoring of activity and social interaction of groups of mice in a home-cage environment. The ability of the excitation/inhibition modulator N-acetyl cysteine (NAC) and the 5-HT1B/1D/1F receptor agonist eletriptan to normalise the behavioural deficits observed was tested. 16p11.2 DEL mice exhibited largely normal behaviours, but, following the stress of an injection, showed hyperlocomotion, reduced sociability, and a strong anxiolytic phenotype. The hyperactivity and reduced sociability, but not the suppressed anxiety, were effectively attenuated by both NAC and eletriptan. The data suggest that 16p11.2 DEL mice show an autism-relevant phenotype that becomes overt after an acute stressor, emphasising the importance of gene-environmental interactions in phenotypic analysis. Further, they add to an emerging view that NAC, or 5-HT1B/1D/1F receptor agonist treatment, may be a promising strategy for further investigation as a future treatment.


A common mechanism involving the TORC1 pathway can lead to amphotericin B-persistence in biofilm and planktonic Saccharomyces cerevisiae populations.
Fungal infections are an increasing clinical problem. Decreased treatment effectiveness is associated with biofilm formation and drug recalcitrance is thought to be biofilm specific. However, no systematic investigations have tested whether resistance mechanisms are shared between biofilm and planktonic populations. We performed multiplexed barcode sequencing (Bar-seq) screening of a pooled collection of gene-deletion mutants cultivated as biofilm and planktonic cells. Screening for resistance to the ergosterol-targeting fungicide amphotericin B (AmB) revealed that the two growth modes had significant overlap in AmB-persistent mutants. Mutants defective in sterol metabolism, ribosome biosynthesis, and the TORC1 and Ras pathways showed increased persistence when treated with AmB. The ras1, ras2 and tor1 mutants had a high-persister phenotype similar to wild-type biofilm and planktonic cells exposed to the TORC1 pathway inhibitor rapamycin. Inhibition of TORC1 with rapamycin also increased the proportion of persisters in Candida albicans and Candida glabrata. We propose that decreased TORC1-mediated induction of ribosome biosynthesis via Ras can lead to formation of AmB-persister cells regardless of whether the cells are in planktonic or biofilm growth mode. Identification of common pathways leading to growth mode-independent persister formation is important for developing novel strategies for treating fungal infections.


Gating pore currents and the resting state of Nav1.4 voltage sensor domains.
Mammalian voltage-gated sodium channels are composed of four homologous voltage sensor domains (VSDs; DI, DII, DIII, and DIV) in which their S4 segments contain a variable number of positively charged residues. We used single histidine (H) substitutions of these charged residues in the Na(v)1.4 channel to probe the positions of the S4 segments at hyperpolarized potentials. The substitutions led to the formation of gating pores that were detected as proton leak currents through the VSDs. The leak currents indicated that the mutated residues are accessible from both sides of the membrane. Leak currents of different magnitudes appeared in the DI/R1H, DII/R1H, and DIII/R2H mutants, suggesting that the resting state position of S4 varies depending on the domain. Here, DI/R1H indicates the first arginine R1, in domain DI, has been mutated to histidine. The single R1H, R2H, and R3H mutations in DIV did not produce appreciable proton currents, indicating that the VSDs had different topologies. A structural model of the resting states of the four VSDs of Na(v)1.4 relaxed in their membrane/solution environment using molecular dynamics simulations is proposed based on the recent Na(v)Ab sodium channel X-ray structure. The model shows that the hydrophobic septa that isolate the intracellular and the extracellular media within the DI, DII, and DIII VSDs are ∼2 Å long, similar to those of K(v) channels. However, the septum of DIV is longer, which prevents water molecules from hydrating the center of the VSD, thus breaking the proton conduction pathway. This structural model rationalizes the activation sequence of the different VSDs of the Na(v)1.4 channel.


Teamwork and team performance in multidisciplinary cancer teams: development and evaluation of an observational assessment tool.
Team performance is important in multidisciplinary teams (MDTs), but no tools exist for assessment. Our objective was to construct a robust tool for scientific assessment of MDT performance. An observational tool was developed to assess performance in MDTs. Behaviours were scored on Likert scales, with objective anchors. Five MDT meetings (112 cases) were observed by a surgeon and a psychologist. The presentation of case history, radiological and pathological information, chair's effectiveness, and contributions to decision-making of surgeons, oncologists, radiologists, pathologists and clinical nurse specialists (CNSs) are analysed via descriptive statistics, a comparison of average scores (Mann-Whitney U) to test interobserver agreement and intraclass correlation coefficients (ICCs) to further assess interobserver agreement and learning curves. Contributions of surgeons, chair's effectiveness, presentation of case history and radiological information were rated above average (p ≤ 0.001). Contributions of histopathologists and CNS were rated below average (p ≤ 0.001), and others average. The interobserver agreement was high (ICC = 0.70+) for presentation of radiological information, and contribution of oncologists, radiologists, pathologists and CNSs; adequate for case history presentation (ICC = 0.68) and contribution of surgeons (ICC = 0.69); moderate for chairperson (ICC = 0.52); and poor for pathological information (ICC = 0.31). Average differences were found only for case-history presentation (p ≤ 0.001). ICCs improved significantly in assessment of case history, and Oncologists, and ICCs were consistently high for CNS, Radiologists, and Histopathologists. Scientific observational metrics can be reliably used by medical and non-medical observers in cancer MDTs. Such robust assessment tools provide part of a toolkit for team evaluation and enhancement.


Diagnosis of acute kidney injury: Kidney Disease Improving Global Outcomes criteria and beyond.
Acute kidney injury (AKI) is common. Clear criteria and accurate diagnostic tools are essential to diagnose AKI early and correctly. The aims of this review are to outline some of the pitfalls of the Kidney Disease Improving Global Outcomes (KDIGO) classification and to describe other traditional and novel tools to diagnose AKI. The KDIGO classification of AKI is based on changes in serum creatinine and urine output. Misdiagnosis of AKI can occur when using only the KDIGO criteria. Potential pitfalls are related to the fact that neither creatinine nor urine output are renal-specific. Other traditional tools to diagnose AKI are blood urea nitrogen, urine chemistry, urine microscopy and renal biopsy. New diagnostic tools, including novel AKI biomarkers and techniques to measure glomerular filtration rate in real time, are being developed and validated. Knowledge about the strengths and weaknesses of traditional diagnostic tests is essential to make the correct diagnosis of AKI. New tests and technical innovations offer the prospect of diagnosing AKI earlier and more accurately.


Hyperglycemia and cardiovascular disease in type 2 diabetes.
Cardiovascular disease (coronary heart disease, stroke, peripheral vascular disease) is the most important cause of mortality and morbidity among patients with type 2 diabetes. Conventional risk factors contribute similarly to macrovascular complications in patients with type 2 diabetes and nondiabetic subjects, and therefore, other explanations have been sought for enhanced atherothrombosis in type 2 diabetes. Among characteristics specific for type 2 diabetes, hyperglycemia has recently been a focus of keen research. A recent meta-analysis of 20 studies on nondiabetic subjects has demonstrated that in the nondiabetic range of glycemia (<6.1 mmol/l), increased glucose is already associated with an increased risk for cardiovascular disease. Similarly, 12 recent prospective studies have convincingly indicated that hyperglycemia contributes to cardiovascular complications in patients with type 2 diabetes. The recently published U.K. Prospective Diabetes Study has shown that intensive glucose control reduces effectively microvascular complications among patients with type 2 diabetes, but that its effect on the prevention of cardiovascular complications was limited. Given the fact that in the U.K. Prospective Diabetes Study, none of the treatment modalities was particularly effective in reducing glucose, this underestimates the true potential of the correction of hyperglycemia in the prevention of cardiovascular disease in type 2 diabetes. However, in addition to intensive therapy of hyperglycemia, other conventional risk factors should also be normalized to prevent cardiovascular disease in patients with type 2 diabetes.


A mutant of Arabidopsis lacking a chloroplast-specific lipid.
In order to investigate the functional significance of membrane lipid unsaturation, we have isolated a series of mutants of Arabidopsis thaliana which are deficient in particular membrane fatty acids. The first of these mutants completely lacks Delta3-trans-hexadecenoate, an acyl group that until now has been thought to play an important role in the structure or function of thylakoid membranes in photosynthetic eukaryotes. The apparent absence of any marked physiological effect of the mutation illustrates the potential of this approach to the analysis of membrane structure and function.


Trends in time to completion of mammographic screening and follow-up services.
The popular press has raised questions about mammographic capacity in the United States, but mammographic utilization data have not been used to inform these concerns. We used data for the period 1995-2002 from the New Mexico Mammography Project to assess trends in time to completion of mammographic screening and follow-up services. The median time to return mammographic screening changed little over time, but trends in the time required to complete recommended follow-up services varied by type of service and urban or rural residence. Further monitoring of time required to complete screening and follow-up services in other regions can inform debates on mammographic capacity.


The use of prosody during syntactic processing in children and adolescents with autism spectrum disorders.
In this study, we employed an eye-gaze paradigm to explore whether children (ages 8-12) and adolescents (ages 12-18) with autism spectrum disorders (ASDs) are able to use prosodic cues to determine the syntactic structure of an utterance. Persons with ASD were compared to typically developing (TD) peers matched on age, IQ, gender, and receptive language abilities. The stimuli were syntactically ambiguous but had a prosodic break that indicated the appropriate interpretation (feel the frog … with the feather vs. feel … the frog with the feather). We found that all groups were equally sensitive to the initial prosodic cues that were presented. Children and teens with ASD used prosody to interpret the ambiguous phrase as rapidly and efficiently as their TD peers. However, when a different cue was presented in subsequent trials, the younger ASD group was more likely to respond in a manner consistent with the initial prosodic cue rather than the new one. Eye-tracking data indicated that both younger groups (ASD and TD) had trouble shifting their interpretation as the prosodic cue changed, but the younger TD group was able to overcome this interference and produce an action consistent with the prosodic cue.


Occult glove perforation during ophthalmic surgery.
We examined the latex surgical gloves used by 56 primary surgeons in 454 ophthalmic surgical procedures performed over a 7-month period. Of five techniques used to detect pinholes, air inflation with water submersion and compression was found to be the most sensitive, yielding a 6.80% prevalence in control glove pairs and a 21.8% prevalence in postoperative study glove pairs, for a 15.0% incidence of surgically induced perforations (P = 0.000459). The lowest postoperative perforation rate was 11.4% for cataract and intraocular lens surgery, and the highest was 41.7% for oculoplastic procedures. Factors that correlated significantly with the presence of glove perforations as determined by multiple logistic regression analysis were oculoplastic and pediatric ophthalmology and strabismus surgical procedures, surgeon's status as a fellow in training, operating time, and glove size. The thumb and index finger of the nondominant hand contained the largest numbers of pinholes. These data suggest strategies for reducing the risk of cross-infection during ophthalmic surgery.


Plasmalogens in biological systems: their role in oxidative processes in biological membranes, their contribution to pathological processes and aging and plasmalogen analysis.
Plasmalogens are a specific glycerophospholipid class containing a vinyl ether moiety at the sn-1-position of the glycerol backbone. The high susceptibility of this vinyl ether bond to oxidative damage and traces of acids may indicate the possible function of plasmalogens in biological systems: The regarded cell-internal antioxidative defense of membranes by protecting other phospholipids or lipoprotein particles against oxidative stress is controversial. Reactive oxygen species preferably affect the vinyl ether function as well as the olefinic acyl residues at the sn-2-position of plasmalogens. This review is dedicated to the role of plasmalogens in different cells and tissues as spermatozoal cells or brain tissue. The first chapter of this review will discuss the molecular structure and chemistry of plasmalogen molecules, their distributions in cells and tissues and the species-specificity. In the second chapter their functions as lipid mediators will be considered and the controversial antioxidative function will be discussed. The supposed function of plasmalogens as "scavengers" for reactive oxygen species (ROS) in biological membranes is challenged by the finding that plasmalogen oxidation products as alpha-hydroxyaldehydes and plasmalogen epoxides accumulate in all chronic diseases as atherosclerosis and myocardial infarction, upon aging as well as in Alzheimers disease and other neuropathological conditions. All these conditions, characterized by increased membrane instability and oxidative damage, will be reviewed in chapter three. Chronically proceeding processes can be described by permanently invading polymorphonuclear neutrophils into inflammatory loci. The degranulation of the azurophilic granula in polymorphonuclear leukocytes causes the release of highly reactive substances, for instance the myeloperoxidase-generated hypochlorous acid (HOCl) acting as effective oxidant. Therefore, special attention will be paid to neutrophil-derived HOCl. The last chapter deals with currently used methods of detecting plasmalogens and their degradation products. Although chromatographic methods will be also discussed, special attention will be given to (31)P NMR spectroscopy and soft ionization techniques of mass spectrometry as electrospray ionization or matrix-assisted laser desorption and ionization time-of-flight mass spectrometry.


A structure refinement protocol combining NMR residual dipolar couplings and small angle scattering restraints.
We present the implementation of a target function based on Small Angle Scattering data (Gabel et al. Eur Biophys J 35(4):313-327, 2006) into the Crystallography and NMR Systems (CNS) and demonstrate its utility in NMR structure calculations by simultaneous application of small angle scattering (SAS) and residual dipolar coupling (RDC) restraints. The efficiency and stability of the approach are demonstrated by reconstructing the structure of a two domain region of the 31 kDa nuclear export factor TAP (TIP-associated protein). Starting with the high resolution X-ray structures of the two individual TAP domains, the translational and orientational domain arrangement is refined simultaneously. We tested the stability of the protocol against variations of the SAS target parameters and the number of RDCs and their uncertainties. The activation of SAS restraints results in an improved translational clustering of the domain positions and lifts part of the fourfold degeneracy of their orientations (associated with a single alignment tensor). The resulting ensemble of structures reflects the conformational space that is consistent with the experimental SAS and RDC data. The SAS target function is computationally very efficient. SAS restraints can be activated at different levels of precision and only a limited SAS angular range is required. When combined with additional data from chemical shift perturbation, paramagnetic relaxation enhancement or mutational analysis the SAS refinement is an efficient approach for defining the topology of multi-domain and/or multimeric biomolecular complexes in solution based on available high resolution structures (NMR or X-ray) of the individual domains.


Twelve Tips on usability testing to develop effective e-learning in medical education.
Usability testing is widely used in the commercial world during the process of developing new products, especially software and websites. However, it appears to be rarely used in the development of e-learning in medical education. The focus of usability testing is the user of the particular product and it informs product development by using a systematic process to identify usability problems at an early stage during product development so that these problems can be rectified. Usability testing of e-learning considers the characteristics of the learner, the technological aspects, the interaction and instructional design and finally the context. Testing under the conditions that the e-learning intervention will typically be used is the preferred method but more extreme situations can provide useful information. Product development should be iterative and rapid cycles of testing and refinement are essential to produce an effective e-learning intervention.


Second opinion and discrepancy in the diagnosis of soft tissue lesions at surgical pathology.
To determine the frequency and magnitude of discrepancies in the surgical pathological diagnosis of soft tissue lesions on review and second opinion in a histopathology center. Cross-sectional, observational. Department of Histopathology, Armed Forces Institute of Pathology, Rawalpindi, from April 2006 to May 2007. All the cases of soft tissue as well as bone lesions, irrespective of age and gender, which were referred for second opinion or review after being reported elsewhere, were included in the study. A panel of antibodies of soft tissue, epithelial and lymphoid markers was applied according to the requirements of each case. The cases were categorized as category A where there was concurrence between initial diagnosis and diagnosis at review. Category B included cases where there was disagreement in the specific diagnostic entity as per WHO classifications without therapeutic implications. Category C was cases where the category of benign or malignant diagnosis remained the same but there was disagreement in the specific diagnosis with definite therapeutic implications. Category D had diagnosis of benign changed to malignant while category E had cases where diagnosis of malignancy was changed to a benign lesion. During the study period, 34 cases of soft tissue lesions were received for review and second opinion. The mean age of the patients was 39 22 years and immunohistochemistry was performed in 21 (62%) of 34 cases. Concurrence between the review and initial diagnosis was seen in 18 (53%) cases (category A). Discrepancy in the diagnosis at review and initial consultation was seen in 16 (47%) cases. There were four (11.8%) cases that were placed in category B as the diagnosis of benign and malignant remained the same but the specific diagnostic entity was changed. Category C included eight (23.5%) cases where the review diagnosis changed the therapeutic modality despite the benign or malignant category remaining unchanged. All the cases in this category required immunohistochemistry as diagnosis of metastatic carcinoma was changed to sarcoma in two cases and diagnosis of sarcoma was changed to carcinoma in three cases. There was only one (2.9%) case in category D where a benign diagnosis was changed to malignant on review and three (8.8%) cases reported as malignant had a revised diagnosis of benign lesion, placing them in category E. In the absence of a quality assurance regulatory body to monitor and overlook the professional competence of practicing surgical pathologists, a mandatory review and second opinion should be undertaken whenever a major therapeutic endeavor is to be undertaken, regardless of the cost for the ultimate benefit of the patient.


Comparing respondent-driven sampling and targeted sampling methods of recruiting injection drug users in San Francisco.
The objective of this article is to compare demographic characteristics, risk behaviors, and service utilization among injection drug users (IDUs) recruited from two separate studies in San Francisco in 2005, one which used targeted sampling (TS) and the other which used respondent-driven sampling (RDS). IDUs were recruited using TS (n = 651) and RDS (n = 534) and participated in quantitative interviews that included demographic characteristics, risk behaviors, and service utilization. Prevalence estimates and 95% confidence intervals (CIs) were calculated to assess whether there were differences in these variables by sampling method. There was overlap in 95% CIs for all demographic variables except African American race (TS: 45%, 53%; RDS: 29%, 44%). Maps showed that the proportion of IDUs distributed across zip codes were similar for the TS and RDS sample, with the exception of a single zip code that was more represented in the TS sample. This zip code includes an isolated, predominantly African American neighborhood where only the TS study had a field site. Risk behavior estimates were similar for both TS and RDS samples, although self-reported hepatitis C infection was lower in the RDS sample. In terms of service utilization, more IDUs in the RDS sample reported no recent use of drug treatment and syringe exchange program services. Our study suggests that perhaps a hybrid sampling plan is best suited for recruiting IDUs in San Francisco, whereby the more intensive ethnographic and secondary analysis components of TS would aid in the planning of seed placement and field locations for RDS.


Failure of a novel ceramic-on-ceramic hip resurfacing prosthesis.
We report the early failure of five ceramic-on-ceramic hip resurfacings (CoCHRs). The ceramic used for the acetabular liner was a novel ceramic-composite (two thirds polyurethane and one third alumina ceramic). All cases were revised for increasing metal ion levels (blood cobalt 3.93-208.0 μg/l and chromium 1.57-17.5 μg/l) due to ceramic liner fracture and/or accelerated wear of the ceramic femoral head coating. Patients underwent bearing exchange and revision using primary hip arthroplasty implants at a mean of 3.0 years following CoCHR. Intraoperatively all patients had metallosis. At 1 to 2 years of follow-up blood metal ions normalized with no complications. We do not recommend this particular type of ceramic-on-ceramic bearing for hip resurfacing.