Identification of opportunities for quality improvement and outcome measurement in pediatric otolaryngology.
Despite increased emphasis on measuring safety outcomes and quality indicators for surgical care, little is known regarding which operative procedures should be prioritized for quality-improvement initiatives in pediatric otolaryngology. To describe the 30-day adverse event rates and relative contributions to morbidity for procedures in pediatric otolaryngology surgery using data from the American College of Surgeons' National Surgical Quality Improvement Program Pediatric database (ACS-NSQIP-P). Analysis of records contained in the ACS-NSQIP-P 2011-2012 clinical database. The ACS-NSQIP-P is a nationwide risk-adjusted, clinical outcomes-based program aimed at measuring and improving pediatric surgical care. Fifty hospitals participated in the 2011-2012 ACS-NSQIP-P program. Medical records of patients who underwent tracked otolaryngologic procedures were accrued in the ACS-NSQIP-P database. These were inclusive of specific otolaryngologic surgical procedures and do not represent the entire spectrum of pediatric otolaryngology surgical procedures. Individual 30-day adverse events, composite morbidity, composite serious adverse events, and composite hospital-acquired infections were compiled. Clinically related procedure groups were used to broadly evaluate outcomes. Procedures and groups were evaluated according to their relative contribution to otolaryngologic morbidity and their incidence of major complications. A total of 8361 patients underwent 1 of 40 selected otolaryngology procedures; 90% were elective; 76% were performed on an outpatient or ambulatory basis; and 46% were American Society of Anesthesiologists (ASA) class 2 cases. Individual 30-day adverse event rates were highest for return to the operating room (4%), surgical site infection (2%), pneumonia (1%), sepsis (1%), and reintubation (1%). The highest rates of composite morbidity were seen for tracheostomy in patients younger than 2 years (23%), airway reconstruction (19%), and tympanoplasty with mastoidectomy (2%). Airway reconstruction procedures had the highest rates of composite serious adverse events (16%), followed by tracheostomy (13%) and abscess drainage (5%). Tracheostomy (31%) and airway reconstruction (16%) made the largest relative contributions to composite morbidity rate of the procedures studied. Tracheostomy in patients younger than 2 years had the highest composite hospital-acquired infection rate (14%), followed by airway reconstruction procedures (11%) and tympanoplasty with mastoidectomy (2%). While the overall rate of major postoperative morbidity in pediatric otolaryngology is low, areas for targeted quality-improvement interventions include tracheostomy, airway reconstruction, mastoidectomy, and abscess drainage. Measurement of outcomes specific to otolaryngologic procedures will be necessary to further identify and measure the impact of quality-improvement initiatives in pediatric otolaryngology.


Spike-and-wave neocortical patterns in rats: genetic and aminergic control.
Spontaneously occurring and drug-induced high voltage spike-and-wave electroencephalogram patterns were examined in inbred rats of the Fischer 344 and Buffalo strains and of the random-bred Sprague-Dawley strain at different ages. In addition, tyrosine hydroxylase activity and dopamine D2 receptor density were determined in the substantia nigra, corpus striatum, olfactory tubercle and ponsmedulla areas of Fisher 344 and Buffalo animals. High voltage spike-and-wave episodes were present in 87.5% of the 3-month-old and in 100% of the older Fischer 344 rats. High voltage spike-and-wave episodes were completely absent in 3-month-old Buffalo and Sprague-Dawley animals but could be induced by systemic injection of pentylenetetrazol and at an older age they appeared in 58.3% (12-month) and 71.4% (greater than 26-month) of the subjects of these strains. The incidence and duration of high voltage spike-and-wave episodes were significantly higher/longer in Fischer 344 rats than in the age-matched Buffalo and Sprague-Dawley animals. The dopamine blocker acepromazine induced a several-fold increase of the incidence and duration of high voltage spike-and-wave episodes in 3-month-old Fischer 344 rats, but failed to induce high voltage spike-and-wave episodes in Buffalo animals at this age. However, acepromazine also triggered high voltage spike-and-wave episodes in Buffalo rats when they were pretreated with subthreshold doses of pentylenetetrazol. Tyrosine hydroxylase activity was significantly higher in the substantia nigra, corpus striatum and olfactory tubercle of the Fischer 344 strain than in Buffalo rats. The higher tyrosine hydroxylase activity was paralleled with significantly higher D2 binding values in the corpus striatum and olfactory tubercle of Fischer 344 rats. These findings suggest that the neocortical high voltage spike-and-wave phenotype is genetically mediated and that the inbred Fischer 344 and Buffalo rats with defined bilineal origin will facilitate future works aimed at the identification of genetic elements involved in the generation of neocortical high voltage spike-and-wave episodes. The significant genotype x age interaction supports the suggestion, however, that high voltage spike-and-wave episodes are likely to be influenced by more than one gene; some of them are probably related to the regulation of brain aminergic systems.


Possible genotype-phenotype correlations in children with mild clinical course of Canavan disease.
Canavan disease is characterised as a rare, neurodegenerative disease that usually causes death in early childhood. It is an autosomal recessive disorder due to an aspartoacylase (ASPA) deficiency. The causative gene has been mapped to chromosome 17 pter-p13. Here we describe three affected children from two Greek families with an unusually mild course of Canavan disease. All children presented with muscular hypotonia and macrocephaly. Diagnosis was based on elevated N-acetylaspartate in urine, reduced aspartoacylase activity in fibroblasts, and marked white matter changes on cerebral imaging. All three affected individuals exhibited continuous psychomotor development without any regression. Genetic analyses revealed compound heterozygous mutations (Y288 C; F295 S) in two individuals. The Y288 C variant was previously described in a child with macrocephaly, mild developmental delay, increased signal intensity in the basal ganglia, partial cortical blindness and retinitis pigmentosa, and slightly elevated N-acetylaspartate in the urine. Demonstration of the same variant in two unusually mildly affected Canavan disease patients and absence of this variant in 154 control chromosomes suggest a possible pathogenic role in mild Canavan disease. In the third individual, two homozygous sequence variants were identified, which comprise the known G274R mutation and a novel K213E variant.


True vasculitis in lupus nephritis.
Vascular lesions are encountered frequently in renal biopsy specimens of patients with systemic lupus erythematosus (SLE) and can present in a variety of morphologic forms. True renal lupus vasculitis (TRLV) is one of the rare vascular lesions associated with lupus nephritis that has been infrequently reported in the medical literature. The primary focus on glomerular pathology and collective classification of the vascular lesions under lupus vasculopathy is one of the reasons why this form of inflammatory vasculitis has been under-recognized as a separate disease entity. Here we have comprehensively reviewed the literature on renal vascular involvement in SLE for a better understanding of the epidemiology, morphologic features, pathogenesis, clinical course and treatment of TRLV. It can be morphologically differentiated from other forms of renal vascular lesions in lupus nephritis, i.e. arteriosclerosis, uncomplicated vascular immune deposits, non-inflammatory necrotizing vasculopathy, and thrombotic microangiopathy. Despite close similarities with antineutrophil cytoplasmic autoantibody associated vasculitis (AASV), there are certain morphological differences that warrant a thorough investigation of the possible pauci-immune mechanism of pathogenesis. The vasculitis follows a severe clinical course in general with rapid progression to renal failure, although favorable outcomes have been reported in certain cases. The standard use of steroids and cytotoxic drugs has yielded variable results in the treatment of TRLV. Current treatment modalities being used in lupus nephritis and AASV have been compared in this article with focus on drugs acting on the inflammatory cells implicated in TRLV pathogenesis.


Management of HIV infection in treatment-naive patients: a review of the most current recommendations.
The most current guidelines issued by the Department of Health and Human Services (DHHS) on the management of human immunodeficiency virus (HIV) infection in treatment-naive patients are reviewed. Treatment guidelines are updated frequently because of the emergence of data demonstrating the risks and benefits of antiretroviral therapy. The DHHS guidelines strongly recommend initiating therapy in patients with certain conditions regardless of CD4 cell count and in patients with CD4 cell counts of <350 cells/mm(3). Although supporting data are less definitive, treatment is also recommended for patients with CD4 cell counts of 350-500 cells/mm(3). Treatment for patients with CD4 cell counts of >500 cells/mm(3) is controversial. Although cumulative observational data and biological evidence support treatment at higher CD4 cell counts, randomized controlled trial data to support this are not available, and the risk of antiretroviral toxicities, resistance, non-adherence, and cost should be considered in individual patients. The preferred regimens have been consolidated to four options, including a dual-nucleoside reverse transcriptase inhibitor backbone (tenofovir plus emtricitabine) with a nonnucleoside reverse transcriptase inhibitor (efavirenz), a ritonavir-boosted protease inhibitor (atazanavir plus ritonavir or darunavir plus ritonavir), or an integrase strand-transfer inhibitor (raltegravir). Regimens are classified as alternative or acceptable when they have potential safety or efficacy concerns, have higher pill burdens, or require more-frequent administration compared with preferred regimens. The DHHS 2011 guidelines advocate earlier antiretroviral therapy initiation than recommended in recent years, and preferred regimens have been refined to maximize efficacy, safety, and quality of life for treatment-naive HIV-infected patients.


Excitatory neurons in the lateral parabrachial nucleus mediate the interruptive effect of inflammatory pain on a sustained attention task.
Attentional deficits are among the most common pain-induced cognitive disorders. Pain disrupts attention and may excessively occupy attentional resources in pathological states, leading to daily function impairment and increased disability. However, the neural circuit mechanisms by which pain disrupts attention are incompletely understood. We used a three-choice serial reaction time task (3CSRTT) to construct a sustained-attention task model in male C57BL/6J mice. Formalin or complete Freund's adjuvant was injected into a paw to establish an inflammatory pain model. We measured changes in 3CSRTT performance in the two inflammatory pain models, and investigated the neural circuit mechanisms of pain-induced attentional deficits. Acute inflammatory pain impaired 3CSRTT performance, while chronic inflammatory pain had no effect. Either inhibition of the ascending pain pathway by blockade of the conduction of nociceptive signals in the sciatic nerve using the local anesthetic lidocaine or chemogenetic inhibition of Ca2+/calmodulin-dependent protein kinase IIα (CaMKIIα) neurons in the lateral parabrachial nucleus (LPBN) attenuated the acute inflammatory pain-induced impairment of 3CSRTT performance, while chemogenetic activation of CaMKIIα neurons in the LPBN disrupted the 3CSRTT. Furthermore, the activity of CaMKIIα neurons in the LPBN was significantly lower on Day 2 after complete Freund's adjuvant injection than on the day of injection, which correlated with the recovery of 3CSRTT performance during chronic inflammatory pain. Activation of excitatory neurons in the LPBN is a mechanism by which acute inflammatory pain disrupts sustained attention. This finding has implications for the treatment of pain and its cognitive comorbidities.


Fludarabine, cytarabine, and idarubicin with or without venetoclax in patients with relapsed/refractory acute myeloid leukemia.
Treatment options for relapsed and refractory acute myeloid leukemia patients (R/R AML) are limited. This retrospective cohort study compares safety and efficacy of fludarabine, cytarabine, and idarubicin (FLA-IDA) with or without venetoclax in patients with R/R AML. Thirty-seven and 81 patients received one course FLA-IDA with or without a 7-day course of venetoclax, respectively. The overall response rate (ORR) was significantly higher in FLAVIDA compared to FLA-IDA treated patients (78% vs. 47%; P=0.001), while MRD was negative at a similar proportion in responding patients (50% vs. 57%), respectively. Eightyone percent and 79% of patients proceeded to allogeneic hematopoietic cell transplantation (alloHCT) or donor lymphocyte infusion (DLI) after FLAVIDA and FLA-IDA, respectively. Event-free and overall survival were similar in FLAVIDA and FLA-IDA treated patients. Refractory patients could be salvaged more successfully after FLA-IDA compared to FLAVIDA pretreatment. Neutrophil and platelet recovery times were similar in the venetoclax and the control group. In conclusion, short-term venetoclax in combination with FLA-IDA represents an effective treatment regimen in R/R AML identifying chemosensitive patients rapidly and inducing MRD negative remission in a high proportion of R/R AML patients.


Synaptogenesis in the mouse olfactory bulb during glomerulus development.
Synaptogenesis is essential for the development of neuronal networks in the brain. In the olfactory bulb (OB) glomeruli, numerous synapses must form between sensory olfactory neurons and the dendrites of mitral/tufted and periglomerular cells. Glomeruli develop from E13 to E16 in the mouse, coincident with an increment of the neuropil in the border between the external plexiform (EPL) and olfactory nerve layers (ONL), coupled to an extensive labelling of phalloidin and GAP-43 from the ONL to EPL. We have tracked synaptogenesis in the OB during this period by electron microscopy (EM) and immunolabelling of the transmembrane synaptic vesicle glycoprotein SV-2. No SV-2 labelling or synapses were detected at E13, although electrodense junctions lacking synaptic vesicles could be observed by EM. At E14, sparse SV-2 labelling appears in the most ventral and medial part of the incipient OB, which displays a ventro-dorsal gradient by E15 but covers the entire OB by E16. These data establish a spatio-temporal pattern of synaptogenesis, which perfectly matches with the glomeruli formation in developing OB.


Localization, epidemic transitions, and unpredictability of multistrain epidemics with an underlying genotype network.
Mathematical disease modelling has long operated under the assumption that any one infectious disease is caused by one transmissible pathogen spreading among a population. This paradigm has been useful in simplifying the biological reality of epidemics and has allowed the modelling community to focus on the complexity of other factors such as population structure and interventions. However, there is an increasing amount of evidence that the strain diversity of pathogens, and their interplay with the host immune system, can play a large role in shaping the dynamics of epidemics. Here, we introduce a disease model with an underlying genotype network to account for two important mechanisms. One, the disease can mutate along network pathways as it spreads in a host population. Two, the genotype network allows us to define a genetic distance between strains and therefore to model the transcendence of immunity often observed in real world pathogens. We study the emergence of epidemics in this model, through its epidemic phase transitions, and highlight the role of the genotype network in driving cyclicity of diseases, large scale fluctuations, sequential epidemic transitions, as well as localization around specific strains of the associated pathogen. More generally, our model illustrates the richness of behaviours that are possible even in well-mixed host populations once we consider strain diversity and go beyond the "one disease equals one pathogen" paradigm.


Speciation and diversity on tropical rocky shores: a global phylogeny of snails of the genus Echinolittorina.
A phylogenetic approach to the origin and maintenance of species diversity ideally requires the sampling of all species within a clade, confirmation that they are evolutionarily distinct entities, and knowledge of their geographical distributions. In the marine tropics such studies have mostly been of fish and reef-associated organisms, usually with high dispersal. In contrast, snails of the genus Echinolittorina (Littorinidae) are restricted to rocky shores, have a four-week pelagic development (and recorded dispersal up to 1400 km), and show different evolutionary patterns. We present a complete molecular phylogeny of Echinolittorina, derived from Bayesian analysis of sequences from nuclear 28S rRNA and mitochondrial 12S rRNA and COI genes (nodal support indicated by posterior probabilities, maximum likelihood, and neighbor-joining bootstrap). This consists of 59 evolutionarily significant units (ESUs), including all 50 known taxonomic species. The 26 ESUs found in the Indo-West Pacific region form a single clade, whereas the eastern Pacific and Atlantic species are basal. The earliest fossil occurred in the Tethys during the middle Eocene and we suggest that the Indo-West Pacific clade has been isolated since closure of the Tethyan seaway in the early Miocene. The geographical distributions of all species (based on more than 3700 locality records) appear to be circumscribed by barriers of low temperature, unsuitable sedimentary habitat, stretches of open water exceeding about 1400 km, and differences in oceanographic conditions on the continuum between oceanic and continental. The geographical ranges of sister species show little or no overlap, indicating that the speciation mode is predominantly allopatric. Furthermore, range expansion following speciation appears to have been limited, because a high degree of allopatry is maintained through three to five branching points of the phylogeny. This may be explained by infrequent long-distance colonization, habitat specialization on the oceanic/continental gradient, and perhaps by interspecific competition. In the eastern Pacific plus Atlantic we identify five cases of divergence on either side of the Isthmus of Panama, but our estimates of their ages pre-date the emergence of the Isthmus. There are three examples of sister relationships between species in the western Atlantic and eastern Atlantic, all resulting from dispersal to the east. Within the Indo-West Pacific, we find no geographical pattern of speciation events; narrowly endemic species of recent origin are present in both peripheral and central parts of the region. Evidence from estimated divergence times of sister species, and from a plot of the number of lineages over time, suggest that there has been no acceleration of diversification during the glacio-eustatic cycles of the Plio-Pleistocene. In comparison with reefal organisms, species of Echinolittorina on rocky shores may be less susceptible to extinction or isolation during sea-level fluctuations. The species richness of Echinolittorina in the classical biogeographic provinces conforms to the common pattern of highest diversity (11 species) in the central "East Indies Triangle" of the Indo-West Pacific, with a subsidiary focus in the eastern Pacific and western Atlantic, and lowest diversity in the eastern Atlantic. The diversity focus in the East Indies Triangle is produced by a mosaic of restricted allopatric species and overlap of a few widespread ones, and is the result of habitat specialization rather than historical vicariance. This study emphasizes the plurality of biogeographic histories and speciation patterns in the marine tropics.


Effect of endogenous cholecystokinin on the course of acute pancreatitis in rats.
To examine the effects of pancreatic rest, stimulation and rest/stimulation on the natural course of recovery after acute pancreatitis. Acute hemorrhagic pancreatitis (AP) was induced in male rats by intraductal infusion of 40 μL/100 g body weight of 3% sodium taurocholate. All rats took food ad libitum. At 24 h after induction of AP, rats were divided into four groups: control (AP-C), pancreas rest (AP-R), stimulation (AP-S), and rest/stimulation (AP-R/S). Rats in the AP-C, AP-R and AP-S groups received oral administration of 2 mL/kg body weight saline, cholecystokinin (CCK)-1 receptor antagonist, and endogenous CCK release stimulant, respectively, twice daily for 10 d, while those in the AP-R/S group received twice daily CCK-1 receptor antagonist for the first 5 d followed by twice daily CCK release stimulant for 5 d. Rats without any treatment were used as control group (Control). Biochemical and histological changes in the pancreas, and secretory function were evaluated on day 12 at 24 h after the last treatment. Feeding ad libitum (AP-C) delayed biochemical, histological and functional recovery from AP. In AP-C rats, bombesin-stimulated pancreatic secretory function and HOMA-β-cell score were significantly lower than those in other groups of rats. In AP-R rats, protein per DNA ratio and pancreatic exocrine secretory function were significantly low compared with those in Control rats. In AP-S and AP-R/S rats, the above parameters recovered to the Control levels. Bombesin-stimulated pancreatic exocrine response in AP-R/S rats was higher than in AP-S rats and almost returned to control levels. In the pancreas of AP-C rats, destruction of pancreatic acini, marked infiltration of inflammatory cells, and strong expression of α-smooth muscle actin, tumor necrosis factor-α and interleukin-1β were seen. Pancreatic rest reversed these histological alterations, but not atrophy of pancreatic acini and mild infiltration of inflammatory cells. In AP-S and AP-R/S rats, the pancreas showed almost normal architecture. The favorable treatment strategy for AP is to keep the pancreas at rest during an early stage followed by pancreatic stimulation by promoting endogenous CCK release.


[Elental prevented and reduced oral mucositis during chemotherapy in patients esophageal cancer].
Stomatitis is a side effect caused frequently by chemotherapy in patients with esophageal cancer, but a standard treatment for it has not been established. Reactive oxygen species are known to be among the causes of stomatitis induced by chemotherapy or radiotherapy, and some reports suggest that their influences might be reduced by the oral supplementation of glutamine. Elental® is one of the widely-used nutritional supplements, and its pack contains 1, 932 mg of L-glutamine (an especially high amount.). Therefore, we examined the preventive or reducing effects Elental® mey have on oral mucositis. Fifteen patients with esophageal cancer received chemotherapy, six of whom had grade one oral mucositis. All of those six patients entered the investigation, and seven courses of Elental® were administered. After seven courses, all six patients oral mucositis declined from grade 1 to grade 0. This result suggests that Elental® has preventive or reducing effects on oral mucositis.


Large-scale prediction of ADAR-mediated effective human A-to-I RNA editing.
Adenosine-to-inosine (A-to-I) editing by adenosine deaminase acting on the RNA (ADAR) proteins is one of the most frequent modifications during post- and co-transcription. To facilitate the assignment of biological functions to specific editing sites, we designed an automatic online platform to annotate A-to-I RNA editing sites in pre-mRNA splicing signals, microRNAs (miRNAs) and miRNA target untranslated regions (3' UTRs) from human (Homo sapiens) high-throughput sequencing data and predict their effects based on large-scale bioinformatic analysis. After analysing plenty of previously reported RNA editing events and human normal tissues RNA high-seq data, >60 000 potentially effective RNA editing events on functional genes were found. The RNA Editing Plus platform is available for free at https://www.rnaeditplus.org/, and we believe our platform governing multiple optimized methods will improve further studies of A-to-I-induced editing post-transcriptional regulation.


Antimicrobial-specific cell-mediated immune reconstitution in children with advanced human immunodeficiency virus infection receiving highly active antiretroviral therapy.
To identify virological and immunological correlates of microbial-specific immune reconstitution in children with advanced human immunodeficiency virus (HIV) infection, Candida- and tetanus-specific lymphocyte proliferation was measured in 165 children initiating a new highly active antiretroviral therapy (HAART) regimen. During the study, the proportions of children with immunity to Candida and tetanus increased from 53% to 66% and 19% to 22%, respectively. Tetanus immunity was associated with an HIV load < or =400 RNA copies/mL and with Candida immunity. At the end of the study, 23% of the patients with baseline negative lymphocyte proliferation had tetanus immunity, and 65% had Candida immunity. Reconstitution of tetanus immunity correlated with lower end-of-study HIV loads and activated CD8+ cell percentages and higher baseline and in-study CD4+ cell percentages, but not with a gain of CD4+ cells. Reconstitution of Candida immunity showed similar trends. In conclusion, children with advanced HIV infection receiving HAART reconstituted Candida immunity more readily than they did tetanus immunity, suggesting a role for antigen reexposure. Additional factors for immune reconstitution were low HIV load, high CD4+ cell percentages, and low levels of activated CD8+ cells.


Effect of experimentally-induced hepatic cirrhosis on the pharmacokinetics of orally administered praziquantel in the rat.
The effects of pretreatment with the hepatotoxin, thioacetamide, on the pharmacokinetics of praziquantel, a broad spectrum schistosomicidal agent with a high hepatic clearance, were studied in male Wistar rats. Animals were pretreated with either thioacetamide (25 mg in 100 ml of drinking water, n = 5) for 24 weeks or received plain drinking water (n = 5) over the same period. After the treatment period, praziquantel was administered orally (25 mg/kg as a 20 mg/ml solution in PEG 200) as a single dose. Blood samples (0.3 ml) were collected from the clipped tail at various times up to 4 h post administration. Plasma was analysed for praziquantel using an HPLC method. Mean peak plasma praziquantel concentrations were approximately 1.0 mg/l for both groups. The time to reach peak concentrations, and post-peak elimination half-life, were approximately 0.7 h and 1.0 h, respectively, for both groups. Similarly, mean AUC was approximately 2.0 mg.h/l for both groups. Statistical comparisons indicated that there were no significant differences in the pharmacokinetic parameters estimated in the two groups of animals. It was concluded that thioacetamide-induced hepatic cirrhosis has no effect on the pharmacokinetics of orally administered praziquantel in the rat, at the dose level studied.


Porcine ex vivo liver phantom for dynamic contrast-enhanced computed tomography: development and initial results.
: To demonstrate the feasibility of developing a fixed, dual-input, biologic liver phantom for dynamic contrast-enhanced computed tomography (CT) imaging and to report initial results of use of the phantom for quantitative CT perfusion imaging. : Porcine livers were obtained from completed surgical studies and perfused with saline and fixative. The phantom was placed in a body-shaped, CT-compatible acrylic container and connected to a perfusion circuit fitted with a contrast injection port. Flow-controlled contrast-enhanced imaging experiments were performed using 128-slice and 64-slice dual-source multidetector CT scanners. CT angiography protocols were used to obtain portal venous and hepatic arterial vascular enhancement, reproduced over a period of 4 to 6 months. CT perfusion protocols were used at different input flow rates to correlate input flow with calculated tissue perfusion, to test reproducibility, and to determine the feasibility of simultaneous dual-input liver perfusion. Histologic analysis of the liver phantom was also performed. : CT angiogram 3-dimensional reconstructions demonstrated homogenous tertiary and quaternary branching of the portal venous system to the periphery of all lobes of the liver as well as enhancement of the hepatic arterial system to all lobes of the liver and gallbladder throughout the study period. For perfusion CT, the correlation between the calculated mean tissue perfusion in a volume of interest and input pump flow rate was excellent (R = 0.996) and color blood flow maps demonstrated variations in regional perfusion in a narrow range. Repeat perfusion CT experiments demonstrated reproducible time-attenuation curves, and dual-input perfusion CT experiments demonstrated that simultaneous dual input liver perfusion is feasible. Histologic analysis demonstrated that the hepatic microvasculature and architecture appeared intact and well preserved at the completion of 4 to 6 months of laboratory experiments and contrast-enhanced imaging. : We have demonstrated successful development of a porcine liver phantom using a flow-controlled extracorporeal perfusion circuit. This phantom exhibited reproducible dynamic contrast-enhanced CT of the hepatic arterial and portal venous system over a 4- to 6-month period.


Withdrawal of warfarin after deep vein thrombosis: effects of a low fixed dose on rebound thrombin generation.
The optimal procedure for withdrawal of warfarin in patients with deep vein thrombosis (DVT) is still not defined. Rebound thrombin generation, which occurs after the withdrawal of warfarin, has been said to be associated with early recurrence of DVT. The aim of this study was to compare two procedures for warfarin withdrawal after the first episode of DVT with respect to rebound thrombin generation. Forty-one consecutive patients were randomly assigned to abrupt withdrawal of warfarin (group A), or to an additional month of warfarin, at the fixed dose of 1.25 mg/day (group B). Plasma samples were withdrawn for the assay of prothrombin fragment F1+2 (F1+2), protein C, factor VII and International Normalized Ratio (INR), before any anticoagulant treatment (I), during initial heparin (II) and full dose warfarin (III), at the end of full dose warfarin (IV) and then 1 (V), 4 (VI), 5 (VII) and 9 (VIII) weeks after randomization. The mean duration of full-dose warfarin treatment, the mean warfarin dose and the mean INR during full-dose warfarin treatment were similar in the two groups. A decrease in F1+2 was observed during heparin and warfarin treatment (II, 1.7 nmol/ml; III, 1.0 nmol/ml; IV, 0.7 nmol/ml; versus I, 3.5 nmol/ml; P<0.01). After the withdrawal of warfarin, an increase in F1+2 was observed in both groups, but without significant statistical differences (group A: V, 1.2 nmol/ml; VI, 1.5 nmol/ml; VII, 1.6 nmol/ml; VIII, 1.1 nmol/ml; group B: V, 1.3 nmol/ml; IV, 1.5 nmol/ml; VII, 1.4 nmol/ml; VIII, 1.4 nmol/ml). No significant difference between the two groups was observed in the recovery of protein C and factor VII. Four patients experienced a recurrence of DVT, three in group B and one in group A. Our findings confirm that rebound thrombin generation occurs in patients with DVT after the withdrawal of warfarin. Rebound thrombin generation is not reduced by a low, fixed dose of warfarin.


[Maxillary osteonecrosis after denosumab treatment].
A 58-year-old patient with a history of intravenous use of denosumab was referred to the department of oral and maxillofacial surgery with inadequate recovery after a series of extractions. During physical and radiological examination, several sites of exposed necrotic bone with purulent discharge were seen, and the maxilla appeared fractured at the level of Le Fort 1. Treatment consisted of intravenous administration of antibiotics with consecutive sequestrectomy of the maxilla under general anaesthesia. While Medication Related Osteonecrosis of the Jaw (MRONJ) is most commonly seen in patients treated with bisphosphonates, in the past decade, it has become apparent that other types of medication, most notably denosumab, can cause comparable disorders. Treatment of MRONJ strongly depends on the stage the disease is in. In patients with a history of denosumab or bisphosphonate use (administered either intravenously or orally in combination with corticosteroids), abnormal radiological findings, or developing osteonecrosis, referral to a department of oral and maxillofacial surgery is recommended.


Safety and effectiveness of interferon β-1a intramuscular therapy: results of the postmarketing drug surveillance in Japan.
To investigate the safety and effectiveness of the interferon β-1a intramuscular injection under clinical conditions in Japan, we conducted an all-case postmarketing surveillance with a 2-year follow-up of patients who were registered during the period between November 2006 (product launch) and December 2010. Case reports were collected from 397 institutions. The safety analysis included 1,476 patients, and the effectiveness analysis included 1,441 patients. Of the patients included in the safety analysis, 86.3% had relapsing-remitting multiple sclerosis. The most common adverse drug reaction was pyrexia (19.24%). Serious adverse events included multiple sclerosis relapse (26 cases) and abnormal hepatic function (10 cases). In the effectiveness analysis, the annualized relapse rate improved significantly from 1.07 to 0.29 (P < 0.001). There was also a significant improvement in in the expanded disability status scale from 3.08 to 2.94 (P < 0.001). The results of the safety and effectiveness profile were consistent with those in previous reports.


The effects of air pollutants on nasal functions of outdoor runners.
Nowadays road running is becoming more and more popular in our country. Road running is mostly done under improper conditions. The aim of this study was to investigate the effects of running on nasal response combined with the effects of air pollutants. Twenty road runners were enrolled in the study. All subjects were male and between 20 and 41 years of age. They ran for 60 min on the right side of an avenue in the center of the city. It is in a residential area but has heavy traffic. One week later they were invited to run for 60 min through a running course away from traffic that is located outside the city center. Nasal resistances were measured by active anterior rhinomanometry. Nasal transport time was also measured by saccharin transport method. There was a reduction in nasal resistance, which was statistically significant in city center runners but was not statistically significant in those running outside of the city center after the exercise. Although nasal transport times were statistically shorter in both groups, there were no differences between two groups. Nowadays, everyone is advised to do sports. Due to increase in the number of breaths, the depth of breathing, and the reduction in nasal resistance in outdoor runners during exercise, harmful air pollution particles can easily reach the lower respiratory tract. Exercise is important for our health, but it should be noted that the environment in which we run is as important as doing sports for our health, especially in outdoor runners.


Controversy and consent: achieving patient autonomy in thrombolysis for acute submassive pulmonary embolism.
Acute pulmonary embolism (PE) is associated with a wide variation in patient outcome ranging from completely asymptomatic to cardiac failure and death. This presents a challenge to clinicians in ensuring the correct treatment for individual patients is given and that adverse events secondary to treatment complications are minimised. The evidence for those with massive PEs and non-massive PEs is clear for and against the use of thrombolysis, respectively. However, in those with 'sub-massive' PE there is no clear consensus on whether there is a treatment benefit. We present the case of a patient who presented with a non-haemodynamically significant PE but with evidence of right ventricular dilatation, and discuss the difficulties in treatment decisions in such cases, including the ethical and legal principles of consent, and how clinicians might best allow their patients to make informed decisions when in clinical equipoise.


Integrin receptors are crucial for the restimulation of activated T lymphocytes.
Stimulation via the T-cell receptor results in proliferation of naive T cells and activation-induced death of activated T cells. The expression of Fas ligand and activation-induced cell death are major mechanisms by which immune responses are modulated in the lung. Although it is known that the binding of integrin receptors to extracellular matrix proteins provides co-stimulatory signals to naive T cells, it is not clear whether these signals are critical for activated T cells. The activation and differentiation of T cells is marked by significant changes in integrin expression and affinity. To determine the role of integrin signaling in restimulation of activated T cells, we blocked integrin receptors with RGD peptides. Using murine activated CD4+ T cells and the T-cell hybridoma DO11.10, we found that RGD peptides inhibit tyrosine phosphorylation of CD3 epsilon-chain and ZAP-70, clustering of T-cell receptors, extracellular signal-regulated kinase mitogen-activated protein-kinase activation, and Fas ligand expression and prevent activation-induced cell death. We demonstrate that activated T cells are sensitive to integrin co-stimulation and that integrin receptors are required for the successful restimulation of activated T cells. This indicates that matrix proteins may play a major role in regulating T-cell-mediated immune responses in the lung.


[Antimutagenic action of alpha-tocopherol acetate in carbon tetrachloride poisoning in animals].
Additional administration of alpha-tocopherol acetate to S57Bl/6 mice and Wistar rats exposed to oral CCl4 under acute and subacute experimental conditions produced no appreciable effect on the frequency of cells with chromosomal aberrations. Additional administration of alpha-tocopherol acetate to S57Bl/6 mice exposed to CCl4 inhalation significantly lessened the frequency of somatic cells with chromosomal aberrations and the frequency of dominant lethals in sexual cells. This attests to a protective action of alpha-tocopherol acetate and confirms the data obtained by other research workers.


Anopheles albimanus is a Potential Alphavirus Vector in the Americas.
Despite its ecological flexibility and geographical co-occurrence with human pathogens, little is known about the ability of Anopheles albimanus to transmit arboviruses. To address this gap, we challenged An. albimanus females with four alphaviruses and one flavivirus and monitored the progression of infections. We found this species is an efficient vector of the alphaviruses Mayaro virus, O'nyong-nyong virus, and Sindbis virus, although the latter two do not currently exist in its habitat range. An. albimanus was able to become infected with Chikungunya virus, but virus dissemination was rare (indicating the presence of a midgut escape barrier), and no mosquito transmitted. Mayaro virus rapidly established disseminated infections in An. albimanus females and was detected in the saliva of a substantial proportion of infected mosquitoes. Consistent with previous work in other anophelines, we find that An. albimanus is refractory to infection with flaviviruses, a phenotype that did not depend on midgut-specific barriers. Our work demonstrates that An. albimanus may be a vector of neglected emerging human pathogens and adds to recent evidence that anophelines are competent vectors for diverse arboviruses.


Comparisons of behavioural and TRPA1 heat sensitivities in three sympatric Cuban Anolis lizards.
Thermal tolerances of organisms play a role in defining geographic ranges and occurrence of species. In Cuba, three sympatric species of Anolis lizards (Anolis allogus, Anolis homolechis and Anolis sagrei) inhabit different thermal microhabitats. A previous study found that these species showed distinct gene expression patterns in response to temperature stimuli, suggesting the genetically distinct thermal physiology among species. To investigate whether the Anolis species inhabiting locally distinct thermal habitats diverge their thermal tolerances, we first conducted behavioural experiments to analyse the temperatures at which the three Anolis species escape from heat source. Then, for each of the three species, we isolated cDNA encoding a putative molecular heat sensor, transient receptor potential ion channel ankyrin 1 (TRPA1), which has been suggested to play a role on eliciting behavioural responses to heat stimuli. We performed electrophysiological analysis to quantify activation temperature of Anolis TRPA1 to see whether the pattern of divergence in TRPA1 responses is congruent with that of divergence in behavioural responses. We found that temperatures triggering behavioural and TRPA1 responses were significantly lower for shade-dwelling species (A. allogus) than for sun-dwelling species (A. homolechis and A. sagrei). The ambient temperature of shade habitats where A. allogus occurs stays relatively cool compared to that of open habitats where A. homolechis and A. sagrei occur and bask. The high temperature thresholds of A. homolechis and A. sagrei may reflect their heat tolerances that would benefit these species to inhabit the open habitats.


Pathology of experimental SARS coronavirus infection in cats and ferrets.
The pathology of severe acute respiratory syndrome-coronavirus (SARS-CoV) infection in cats and ferrets is poorly described, and the distribution of angiotensin-converting enzyme 2 (ACE2), a receptor for SARS-CoV, in the respiratory tracts of these species is unknown. We observed SARS-CoV antigen expression and lesions in the respiratory tracts of 4 cats and 4 ferrets at 4 days postinoculation and ACE2 expression in the respiratory tracts of 3 cats and 3 ferrets without infection. All infected cats and ferrets had diffuse alveolar damage associated with SARS-CoV antigen expression. A novel SARS-CoV-associated lesion was tracheo-bronchoadenitis in cats. SARS-CoV antigen expression occurred mainly in type I and II pneumocytes and serous cells of tracheo-bronchial submucosal glands of cats and in type II pneumocytes of ferrets. ACE2 expression occurred mainly in type I and II pneumocytes, tracheo-bronchial goblet cells, serous epithelial cells of tracheo-bronchial submucosal glands in cats, and type II pneumocytes and serous epithelial cells of tracheo-bronchial submucosal glands in ferrets. In conclusion, the pathology of SARS-CoV infection in cats and ferrets resembles that in humans except that syncytia and hyaline membranes were not observed. The identification of tracheo-bronchoadenitis in cats has potential implications for SARS pathogenesis and SARS-CoV excretion. Finally, these results show the importance of ACE2 expression for SARS-CoV infection in vivo: whereas ACE2 expression in type I and II pneumocytes in cats corresponded to SARS-CoV antigen expression in both cell types, expression of both ACE2 and SARS-CoV antigen in ferrets was limited mainly to type II pneumocytes.


[Parkinson disease: description of an interdisciplinary program of functional group rehabilitation].
Neurorehabilitation for Parkinson's disease, in the form of physical and occupational therapy, has long been advocated but also seriously questioned with respect to its specific content, its mechanisms, its efficacy and its costs. Many factors may be put forward to explain the lack of consensus surrounding these interventions, including the multiplicity of different programs proposed, the scarcity of controlled studies available and the inadequacy of some assessment methods used. In this article, we describe a new neurorehabilitation program for Parkinson's disease which is characterized by some original features. In particular, the specific functional patients' needs were taken into account instead of the symptoms related to the condition, therapeutic interventions favoured a multidisciplinary approach, patients trained in groups rather than individually, the program combined different methods and was continuously evolving over time, and finally we used simple but goal-oriented measurement methods to assess efficacy. The study included 22 patients. Statistically significant positive results were obtained by the end of the program, suggesting that the program in its current form was indeed capable to generate a functional benefit of sufficient magnitude to be objectively detected by the assessment methods used. In our opinion, our data emphasizes the usefulness of specific neurorehabilitation programs in the global management of Parkinson's disease.


The Effect of High-Intensity Interval Training on Mitochondrial-Associated Indices in Overweight and Obese Adults: A Systematic Review and Meta-Analysis.
Obesity is a significant health problem with an increasing incidence, causing a low-grade systemic inflammatory state and being implicated in various chronic diseases. Moreover, obesity has been shown to cause mitochondrial dysfunction through oxidative stress and inflammation, eventually affecting energy metabolism. However, high-intensity interval training (HIIT) can improve mitochondrial efficiency through exercise-induced mitochondrial adaptations. This systematic review and meta-analysis aims to examine the potential effects of HIIT on mitochondrial-associated indices in obese and overweight adults. PubMed, Scopus, and Web of Science databases were searched. Twenty-eight eligible studies were included, involving 530 participants. HIIT was found to significantly improve the activity of citrate synthase (CS), cytochrome C (COX-IV), beta-hydroxyacyl CoA-dehydrogenase (β-HAD), Complexes I-V as well as VO2max in overweight and obese individuals, whereas no significant changes were shown in PGC-1α and SIRT1. Interestingly, subgroup analyses revealed that CS, COX-IV, β-HAD, and Complexes I-V activity exhibited a significant improvement only in the healthy subgroup. Overall, HIIT can be utilized to enhance mitochondrial-associated indices in overweight and obese individuals. However, this improvement may be health status dependent.


PolySpec: polynomial spectrum models for fast and light-weight spectroscopic evaluation.
For the analysis of spectroscopic data, model fitting approaches are commonly applied. The spectrum model applied in these fitting processes significantly influences the performance of the spectroscopic evaluation, which can be critical in real-time process diagnostics and control. In this work a spectrum model is introduced that uses a polynomial description of absorbances, transmittances, or similar in dependence on parameters such as temperature, pressure, and mole fraction. Using this approach, either experimental spectra or spectrum databases can be compressed into a matrix of polynomial coefficients. The evaluation of this model consists of a single matrix multiplication and, with a slight modification, derivatives with regard to specific parameters can be calculated in the same way. Both these points are important to model fitting methods for spectroscopic data, as the simple evaluation method allows for a fast analysis and the direct calculation of derivatives simplifies the application of gradient-based fitting methods. Additionally, the easy parallelizability of the matrix multiplication promotes the application of this method in real-time evaluations on programmable logic devices.


Sterility assessment of multiple use botulinum A exotoxin vials: a prospective simulation.
A preponderance of evidence now indicates that storage of reconstituted botulinum toxin solution for longer than the 4 hours recommended by the manufacturer does not result in loss of effectiveness. Then purpose of this study was to assess whether serial re-extraction of reconstituted botulinum toxin solution from vials undergoing prolonged storage is associated with increased risk of microbial contamination. Consecutive 100-U vials of botulinun A exotoxin were reconstituted with 2.5 mL each of normal saline with preservative (benzyl alcohol). Within 1 week after reconstitution, each vial was used to treat 1 to 3 patients, for a total of 60 to 80 U used. Thereafter, each vial was stored in a plastic kidney basin in an unlocked, multiuse medication refrigerator. Two weeks later, a randomly assigned nurse removed the vial from the refrigerator and withdrew and discarded 0.1 mL (5 U) using the same technique used for therapeutic extractions. Iterations of this withdrawal and discarding procedure were continued until a 0.1-mL aliquot could not be withdrawn without prying off the metal cover. Once this threshold was reached, the vial was sent to the microbiology laboratory for sterility testing using a thioglycolate broth. In all, 127 vials were handled per protocol. On average (mean), vials underwent 4.5 access procedures, including 1.6 therapeutic extractions for a total of 76 U removed during a period of 7 weeks. Sterility analysis with thioglycolate broth indicated no evidence of contamination. Preservative-containing saline was used for reconstitution. Routine refrigerator storage of medication vials containing reconstituted botulinum toxin does not result in microbial contamination of the contents even after serial re-extraction of solution from these vials, and after handling of such vials by multiple personnel. Storage and subsequent reuse of botulinum toxin appears safe for at least 7 weeks after reconstitution.


Mycobacterium tuberculosis Reactivates HIV-1 via Exosome-Mediated Resetting of Cellular Redox Potential and Bioenergetics.
The synergy between Mycobacterium tuberculosis and human immunodeficiency virus-1 (HIV-1) interferes with therapy and facilitates the pathogenesis of both human pathogens. Fundamental mechanisms by which M. tuberculosis exacerbates HIV-1 infection are not clear. Here, we show that exosomes secreted by macrophages infected with M. tuberculosis, including drug-resistant clinical strains, reactivated HIV-1 by inducing oxidative stress. Mechanistically, M. tuberculosis-specific exosomes realigned mitochondrial and nonmitochondrial oxygen consumption rates (OCR) and modulated the expression of host genes mediating oxidative stress response, inflammation, and HIV-1 transactivation. Proteomics analyses revealed the enrichment of several host factors (e.g., HIF-1α, galectins, and Hsp90) known to promote HIV-1 reactivation in M. tuberculosis-specific exosomes. Treatment with a known antioxidant-N-acetyl cysteine (NAC)-or with inhibitors of host factors-galectins and Hsp90-attenuated HIV-1 reactivation by M. tuberculosis-specific exosomes. Our findings uncover new paradigms for understanding the redox and bioenergetics bases of HIV-M. tuberculosis coinfection, which will enable the design of effective therapeutic strategies.IMPORTANCE Globally, individuals coinfected with the AIDS virus (HIV-1) and with M. tuberculosis (causative agent of tuberculosis [TB]) pose major obstacles in the clinical management of both diseases. At the heart of this issue is the apparent synergy between the two human pathogens. On the one hand, mechanisms induced by HIV-1 for reactivation of TB in AIDS patients are well characterized. On the other hand, while clinical findings clearly identified TB as a risk factor for HIV-1 reactivation and associated mortality, basic mechanisms by which M. tuberculosis exacerbates HIV-1 replication and infection remain poorly characterized. The significance of our research is in identifying the role of fundamental mechanisms such as redox and energy metabolism in catalyzing HIV-M. tuberculosis synergy. The quantification of redox and respiratory parameters affected by M. tuberculosis in stimulating HIV-1 will greatly enhance our understanding of HIV-M. tuberculosis coinfection, leading to a wider impact on the biomedical research community and creating new translational opportunities.


Hierarchical organization of human cortical networks in health and schizophrenia.
The complex organization of connectivity in the human brain is incompletely understood. Recently, topological measures based on graph theory have provided a new approach to quantify large-scale cortical networks. These methods have been applied to anatomical connectivity data on nonhuman species, and cortical networks have been shown to have small-world topology, associated with high local and global efficiency of information transfer. Anatomical networks derived from cortical thickness measurements have shown the same organizational properties of the healthy human brain, consistent with similar results reported in functional networks derived from resting state functional magnetic resonance imaging (MRI) and magnetoencephalographic data. Here we show, using anatomical networks derived from analysis of inter-regional covariation of gray matter volume in MRI data on 259 healthy volunteers, that classical divisions of cortex (multimodal, unimodal, and transmodal) have some distinct topological attributes. Although all cortical divisions shared nonrandom properties of small-worldness and efficient wiring (short mean Euclidean distance between connected regions), the multimodal network had a hierarchical organization, dominated by frontal hubs with low clustering, whereas the transmodal network was assortative. Moreover, in a sample of 203 people with schizophrenia, multimodal network organization was abnormal, as indicated by reduced hierarchy, the loss of frontal and the emergence of nonfrontal hubs, and increased connection distance. We propose that the topological differences between divisions of normal cortex may represent the outcome of different growth processes for multimodal and transmodal networks and that neurodevelopmental abnormalities in schizophrenia specifically impact multimodal cortical organization.


Fostering mental health and well-being among workers who support refugees and asylum seekers in the Australian context.
Therapists and counsellors who provide trauma-focussed therapy and support to refugees and asylum seekers are often exposed to distressing and confronting stories of war, violence, torture, loss and grief, and other atrocities. In addition to this, working within an immigration and detention context has been reported to further contribute to experiences of burnout, vicarious trauma, and other adverse consequences of working with traumatised populations. There is a scarcity of research seeking to understand how therapists address these difficulties and maintain well-being to help them continue in this field of work. This mixed-methods research aimed to identify and explore factors associated with mental health and well-being among workers, with a particular focus on the role of clinical supervision. Participants were staff (n = 50) who identified as providing therapeutic support to refugees and asylum seekers either in Australia or in Australian-run detention facilities. Participants took part in an anonymous online survey which focussed on the psychological impact of their work, professional quality of life, and clinical supervision and incorporated free-text items. Thematic analysis of free-text data revealed four themes related to maintaining well-being at work including relationships and support seeking; physical and contemplative practices; professional growth; and balance and boundaries. Results from the quantitative analyses revealed several variables related to supervision that were important for well-being. In particular, the findings suggest that rapport and overall alliance with one's clinical supervisor are protective of secondary traumatic stress and depression, respectively. Important aspects of supervision were also explored in greater depth through qualitative and quantitative inquiry, increasing our understanding of the mechanisms underlying the relationship between clinical supervision and mental health and well-being for this group.


Do episodes of peer victimization trigger physical injury? A case-crossover study of Swedish school children.
The aim of this study was to investigate how long the effect of peer victimization on the occurrence of physical injury lasts and whether the effect varies according to how frequently an injured child is victimized. A case-crossover design was employed. Children aged 10-15 years residing in Stockholm County during two consecutive school years were eligible as cases. Further inclusion criteria were that the children had been hospitalized or called back for a medical check-up due to a physical injury. Information on children's exposure to peer victimization at school was gathered in interviews, and on their social characteristics through a questionnaire filled in by parents. A total of 575 children were included. Our analyses show that there is an increase in risk of unintentional injury after an episode of peer victimization shortly after the end of exposure to victimization (RR = 5.5) but not thereafter. The risk is substantially higher among children seldom victimized (RR = 49.9) than among those victimized on a more regular basis (RR = 2.5). The extent to which family social circumstances modify the risk is difficult to establish from the material at hand. Peer victimization may trigger the occurrence of unintentional injuries in childhood and the effect is short lasting. The results need to be replicated and special attention should be given to separating lesson time from break time to avoid confounding by time of day.


Spherical crystallization: A technique use to reform solubility and flow property of active pharmaceutical ingredients.
Tablets have been choice of manufacturers over the years due to their comparatively low cost of manufacturing, packaging, shipping, and ease of administration; also have better stability and can be considered virtually tamper proof. A major challenge in formulation development of the tablets extends from lower solubility of the active agent to the elaborated manufacturing procedures for obtaining a compressible granular material. Moreover, the validation and documentation increases, as the numbers of steps increases for an industrially acceptable granulation process. Spherical crystallization (SC) is a promising technique, which encompass the crystallization, agglomeration, and spheronization phenomenon in a single step. Initially, two methods, spherical agglomeration, and emulsion solvent diffusion, were suggested to get a desired result. Later on, the introduction of modified methods such as crystallo-co-agglomeration, ammonia diffusion system, and neutralization techniques overcame the limitations of the older techniques. Under controlled conditions such as solvent composition, mixing rate and temperature, spherical dense agglomerates cluster from particles. Application of the SC technique includes production of compacted spherical particles of drug having improved uniformity in shape and size of particles, good bulk density, better flow properties as well as better solubility so SC when used on commercial scale will bring down the production costs of pharmaceutical tablet and will increase revenue for the pharmaceutical industries in the competitive market. This review summarizes the technologies available for SC and also suggests the parameters for evaluation of a viable product.


OFELIA: Prevalence of Osteoporosis in Fragility Fracture Patients.
Worldwide, a care gap has been recognized between presenting with a fracture and prevention of the next fracture. Fracture Liaison Service is the most cost-effective method to close this gap, but its implementation is sparse in the Nordic countries. To assess the need for a fracture prevention program, the primary aim of this study was to estimate the prevalence of osteoporosis in patients treated for fragility fractures at Aarhus University Hospital, Denmark. Secondary aims were to identify clinical risk factors associated with osteoporosis and the up-take of anti-osteoporosis treatment. The study was conducted as a cross-sectional study and patients aged 18+ years were consecutively identified over a 12 months period. Of 1164 identified patients, 832 were included and 794 (70% women, 66% aged ≥ 50 years) patients completed the study. Bone mineral density was measured by DXA and information about clinical risk factors were obtained. The overall prevalence of osteoporosis in this cohort was 14.9%, increasing to 20.3% in patients ≥ 50 years (22.9% in women, 9.6% in men). In addition to age above 50 years, female sex, low BMI, and early menopause were significantly associated with osteoporosis. At 3-years follow-up in patients diagnosed with osteoporosis, 95% of patients who initiated anti-osteoporosis treatment after their fracture were still adherent to treatment. Given that osteoporosis was demonstrated in one in five fragility fracture patients above 50 years, OFELIA stresses the need for implementation of a program aiming at securing appropriate investigation and treatment of osteoporosis in patients presenting a fragility fracture.


The physiological roles of apolipoprotein J/clusterin in metabolic and cardiovascular diseases.
Several isoforms of apolipoprotein J/clusterin (CLU) are encoded from a single gene located on chromosome 8 in humans. These isoforms are ubiquitously expressed in the tissues, and have been implicated in aging, neurodegenerative disorders, cancer progression, and metabolic/cardiovascular diseases including dyslipidemia, diabetes, atherosclerosis and myocardial infarction. The conventional secreted form of CLU (sCLU) is thought to be a component of high density lipoprotein-cholesterol. sCLU functions as a chaperone for misfolded proteins and it is thought to promote survival by reducing oxidative stress. Nuclear CLU, a truncated CLU formed by alternative splicing, is responsible for promoting apoptosis via a Bax-dependent pathway. There are putative regulatory sites in the promoter regions of CLU, which are occupied by transcription factors such as transforming growth factor (TGF)-β inhibitory element, activator protein-1, CLU-specific elements, and carbohydrate response element. However, the molecular mechanisms underlying the distinct roles of CLU in a variety of conditions remain unclear. Although the function of CLU in cancer or neurological disease has been studied intensively for three decades, physiological roles of CLU seem unexplored in the cardiovascular system and metabolic diseases. In this review, we will discuss general characteristics and regulations of CLU based on previous literature and assess the recent findings associated with its physiological roles in different tissues including the vasculature, heart, liver, kidney, adipose tissue, and brain.


Acceptability and adherence of a candidate microbicide gel among high-risk women in Africa and India.
Vaginal microbicides currently under development are substances that may prevent the transmission of HIV. Qualitative, in-depth post-trial interview data from a Phase III clinical trial of 6% Cellulose Sulfate microbicide gel in two sites in Africa (Uganda and Benin) and two in India (Chennai and Bagalkot) were examined in order to better understand factors that influence microbicide acceptability and adherence in a clinical trial setting. Women found the gel relatively easy to use with partners with whom there were no expectations of fidelity, in situations where they had access to private space and at times when they were expecting to engage in sexual intercourse. Adherence to gel seemed significantly more difficult with primary partners due to decreased perceptions of risk, inconvenience or fear of partner disapproval. Findings suggest that women in a variety of settings may find a microbicide gel to be highly acceptable for its lubricant qualities and protective benefits but that adherence and consistent use may depend greatly on contextual and partner-related factors. These findings have important implications for future trial designs, predicting determinants of microbicide use and acceptability and marketing and educational efforts should a safe and efficacious microbicide be found.


[An experimental study to determine the most effective delay procedures on secondary vascularized skin island flaps].
Secondary vascularized flaps made from implanted vascular bundles in the subcutaneous tissues have dominant vascularities. Animal experiments were performed using white rabbits, two types of skin flaps were made on their backs. The first delay procedure was performed on the left side where the vascular bundle had been implanted with an elevation of distally based flap (size 2 cm x 7 cm). 28 out of 32, secondary vascularized skin island flaps survived either partially or completely in the first procedure. Moreover, the first delay method was observed to be efficacious in 15 out of 16 cases (p less than 0.01). The viability of vascular bundles of secondary vascularized flap was thus proved. The first stage of the second delay procedure was performed in bilateral side using the same procedure as the first delay. Two weeks later, two types of delay method were carried out. On the left side, a proximally based flap (size 2 cm x 7 cm) was made at the distal area of the first delay flap. On the right side, a bipedicled flap was made (size 2 cm x 14 cm). These flaps were elevated as secondary vascularized skin island flaps two weeks later. In all cases, the latter procedure produced a longer survival rate compared with the former (p less than 0.01). It was concluded experimentally that the most effective second delay procedure was the bipedicled flap method.


Outcome after ileal pouch-anal anastomosis for familial adenomatous polyposis compared to mucosal ulcerative colitis in a Middle Eastern population.
To compare the complications and outcome after ileal pouch-anal anastomosis (IPAA) for mucosal ulcerative colitis (MUC) and familial adenomatous polyposis (FAP). This is a retrospective study. The study was conducted at a single tertiary referral center. All patients who underwent restorative proctocolectomy with IPAA at a tertiary center in Saudi Arabia from 2001 till 2009 were retrieved. Data was obtained regarding preoperative status, postoperative complications, and functional outcome. A total of 40 patients underwent IPAA, of which 21 cases were of FAP and 19 cases of MUC. Median age at operation for FAP and MUC was 31 (range: 16-45) and 43 (range: 15-65) years, respectively (P < .05). Median length of stay was 10 days (range: 6-42) for FAP and 12 days (range: 9-27) for MUC (P=.1). Postoperative morbidity was noted in 4 cases of FAP and 6 cases of MUC (P=.36). Specifically, wound infection was noted in 2 cases of FAP compared to 3 cases of MUC (P=.55); 1 MUC case had an anastomotic leak (P=.29). One mortality was recorded among the FAP cases (P=.35). The time between the creation of IPAA and the closure of ileostomy was 4.5 and 5 months for FAP and MUC, respectively (P=.87). Median follow-up was 36 months. Median bowel frequency per 24 hours was 6 (range: 3-24) for FAP and 7 (range 3-17) for MUC (P=.54). Intestinal obstruction was reported in 3 cases of FAP and 5 cases of MUC (P=.38). One pouch was excised in a FAP patient. One case of MUC developed pouchitis. The outcome after IPAA was inferior for MUC compared to FAP, but it was not statistically significant due to the small sample size. The morbid status of the MUC cases and their older age contributed to the minor differences.


Transcutaneous electrical nerve stimulation for pain control after spinal fusion with Harrington rods. A clinical report.
During the past two years, we have been using transcutaneous electrical nerve stimulation (TENS) for pain control after spinal fusion with Harrington rods. This report describes our postoperative pain management program and our evaluation of its effectiveness. We examined postoperative pain medication usage and found that patients using TENS received fewer doses of several commonly prescribed pain drugs than did patients not using TENS devices. Difficulties we encountered in evaluating our program are described along with recommendations for other researchers interested in assessing TENS in the management of postoperative pain.


Phosphorylation of the Arp2/3 complex is necessary to nucleate actin filaments.
The actin-related protein 2/3 (Arp2/3) complex is the primary nucleator of new actin filaments in most crawling cells. Nucleation-promoting factors (NPFs) of the Wiskott-Aldrich syndrome protein (WASP)/Scar family are the currently recognized activators of the Arp2/3 complex. We now report that the Arp2/3 complex must be phosphorylated on either threonine or tyrosine residues to be activated by NPFs. Phosphorylation of the Arp2/3 complex is not necessary to bind NPFs or the sides of actin filaments but is critical for binding the pointed end of actin filaments and nucleating actin filaments. Mass spectrometry revealed phosphorylated Thr237 and Thr238 in Arp2, which are evolutionarily conserved residues. In cells, phosphorylation of only the Arp2 subunit increases in response to growth factors, and alanine substitutions of Arp2 T237 and T238 or Y202 inhibits membrane protrusion. These findings reveal an additional level of regulation of actin filament assembly independent of WASP proteins, and show that phosphorylation of the Arp2/3 complex provides a logical "or gate" capable integrating diverse upstream signals.


Efficacy of oral amoxicillin-clavulanate or azithromycin for non-severe respiratory exacerbations in children with bronchiectasis (BEST-1): a multicentre, three-arm, double-blind, randomised placebo-controlled trial.
Bronchiectasis guidelines recommend antibiotics for the treatment of acute respiratory exacerbations, but randomised placebo-controlled trials in children are lacking. We hypothesised that oral amoxicillin-clavulanate and azithromycin would each be superior to placebo in achieving symptom resolution of non-severe exacerbations in children by day 14 of treatment. In this multicentre, three-arm, parallel, double-dummy, double-blind, randomised placebo-controlled trial at four paediatric centres in Australia and New Zealand, we enrolled children aged 1-18 years with CT-confirmed bronchiectasis unrelated to cystic fibrosis, who were under the care of a respiratory physician and who had had at least two respiratory exacerbations in the 18 months before study entry. Participants were allocated (1:1:1) at exacerbation onset to receive oral suspensions of amoxicillin-clavulanate (45 mg/kg per day) plus placebo azithromycin, azithromycin (5 mg/kg per day) plus placebo amoxicillin-clavulanate, or both placebos for 14 days. An independent statistician prepared a computer-generated, permuted-block (size 2-8) randomisation sequence, stratified by centre, age, and cause. Participants, caregivers, study coordinators, and investigators were masked to treatment assignment until data analysis was completed. The primary outcome was the proportion of children with exacerbation resolution by day 14 in the intention-to-treat population. Treatment groups were compared using generalised linear models. Statistical significance was set at p<0·0245 to account for multiple comparisons. This trial is registered with the Australian New Zealand Clinical Trials Registry (ACTRN12612000011886) and is completed. Between April 17, 2012, and March 1, 2017, 604 children were screened and 252 were enrolled. Between July 31, 2012, and June 26, 2017, 197 children were allocated at the start of an exacerbation (63 to the amoxicillin-clavulanate group, 67 to the azithromycin group, and 67 to the placebo group). Respiratory viruses were identified in 82 (53%) of 154 children with available nasal swabs on day 1 of treatment. Primary outcome data were available for 196 (99%) children (one child with missing data [placebo group] was recorded as non-resolved according to criteria defined a priori). By day 14, exacerbations had resolved in 41 (65%) children in the amoxicillin-clavulanate group, 41 (61%) in the azithromycin group, and 29 (43%) in the placebo group. Compared with placebo, relative risk for resolution by day 14 was 1·50 (95% CI 1·08-2·09, p=0·015; number-needed-to-treat [NNT] 5 [95% CI 3-20]) in the amoxicillin-clavulanate group and 1·41 (1·01-1·97, p=0·042; NNT 6 [3-79]) in the azithromycin group. Adverse events were recorded in 19 (30%) children in the amoxicillin-clavulanate group, 20 (30%) in the azithromycin group, and 14 (21%) in the placebo group, but no events were severe or life-threatening. Amoxicillin-clavulanate treatment is beneficial in terms of resolution of non-severe exacerbations of bronchiectasis in children, and should remain the first-line oral antibiotic in this setting. National Health and Medical Research Council (Australia), Cure Kids (New Zealand).


Endoscopic appearance of the normal biliary system.
Both rigid and flexible instruments can be used for endoscopic examination of the biliary tract. The approach is via the cystic duct or by means of a choledochotomy. The stump of the ductus cysticus will be useful if it is necessary to clarify a pathological finding in the distal bile duct or in the region of the papilla of Vater. Usually, however, the instrument is introduced by means of a choledochotomy. First of all, the distal region including the papilla of Vater and then the proximal part of the biliary system are closely examined. The normal biliary duct wall appears yellowish-red without showing the vascular structure. The papilla of Vater region presents a honeycomb appearance. Special emphasis in endoscopic examination is on papilla function, i.e. the opening or closing of the papilla if liquid is allowed to flow in. Results of 935 endoscopic examinations are reported.


[Second trimester termination of pregnancy with gemeprost: a review of 306 cases].
Prostaglandin analogues provide an effective method for induction of abortion in the second trimester of pregnancy. The clinical outcome and the risk of complications were evaluated in a group of women having a medical termination of pregnancy with gemeprost. Three-hundred and six women undergoing second trimester termination of pregnancy, between January 1998 and July 2002 in our center, were studied. All women were given 1 mg vaginal gemeprost every 3 h up to a maximum of 3 doses in the first 24 hours. If the abortion did not occur within the first 24 hours after initiation of treatment, they were given a 2(nd) course of gemeprost. Outcome measures included failure of the 1st course of gemeprost, length of hospital stay after expulsion of conceptus, heavy blood loss with or without necessity of uterine packing or blood transfusion, and failure of induction. There was a significant difference, with better results in women with previous deliveries (vaginal or abdominal), as to the failure to abort after the 1(st) course of PG (P<0.01). Length of hospital stay, complications and failure of induction were independent from parity. Twelve (3.9%) women failed to abort with gemeprost and required other methods for abortion. The study confirms the efficacy of gemeprost for mid-trimester termination of pregnancy, although it is a risky and costly procedure, requiring hospitalisation and is associated with higher complication rate than the first trimester surgical abortion.


Tele-transmission of EEG recordings.
EEG recordings can be sent for remote interpretation. This article aims to define the tele-EEG procedures and technical guidelines. Tele-EEG is a complete medical act that needs to be carried out with the same quality requirements as a local one in terms of indications, formulation of the medical request and medical interpretation. It adheres to the same quality requirements for its human resources and materials. It must be part of a medical organization (technical and medical network) and follow all rules and guidelines of good medical practices. The financial model of this organization must include costs related to performing the EEG recording, operating and maintenance of the tele-EEG network and medical fees of the physician interpreting the EEG recording. Implementing this organization must be detailed in a convention between all parties involved: physicians, management of the healthcare structure, and the company providing the tele-EEG service. This convention will set rules for network operation and finance, and also the continuous training of all staff members. The tele-EEG system must respect all rules for safety and confidentiality, and ensure the traceability and storing of all requests and reports. Under these conditions, tele-EEG can optimize the use of human resources and competencies in its zone of utilization and enhance the organization of care management.


Thoracoabdominal aneurysm repair.
Aneurysms that extend from the descending thoracic aorta into the abdomen and also those that involve the visceral segments of the upper abdominal aorta are traditionally classified as thoracoabdominal. Besides the surgical exposure difficulties associated with repair of these aneurysms, the temporary interruption of renal, splanchnic, and perhaps even spinal cord flow introduces a number of potential complications that makes surgical repair of these aneurysms a daunting task. The exact incidence of thoracoabdominal aneurysms is unknown, but population studies suggest a prevalence at least a log fold less than the more common infrarenal abdominal aortic aneurysm. The poor prognosis of nonsurgically treated aneurysmal disease of the descending thoracic and abdominal aortas has been reasonably well established. Few patients with thoracoabdominal aneurysms survive beyond five years as a result of not only aneurysm rupture but also death from advanced co-morbid medical disease. Since the first successful report of thoracoabdominal aneurysm repair over 40 years ago, a number of remarkable contributions have been made in the field. These advances have led to a significant decline in operative mortality as well as procedure related morbidity. Spinal cord ischemia remains a perplexing and devastating complication following thoracoabdominal aneurysm repair. A number of surgical adjuncts have been developed over the years to reduce the incidence of cord ischemic complications, yet a great deal of controversy still exists with regards to the optimal protective strategy. A description of the incidence, natural history, and classification of thoracoabdominal aneurysms, along with associated repair techniques centered on reducing spinal cord ischemic complications will form the basis for this review.


Cytoskeleton modification and cholesterol depletion affect membrane properties and caveolae positioning of CHO cells.
The formation of protrusions is necessary for numerous biological processes. It involves extension of the plasma membrane, and the force needed for this is provided by the actin cytoskeleton. Tether pulling with optical tweezers can mimic the formation of a protrusion, so we used this method to investigate the effects of modifying not only actin (with latrunculin A) but also microtubules (with nocodazole) and the plasma membrane itself (with methyl-β-cyclodextrin) on the Chinese hamster ovary cell membrane. After these modifications, the membrane reservoir was supposed to redistribute. Caveolae constitute a small part of the reservoir, so the redistribution of caveolar proteins such as caveolin-1 and cavin-1 that represents caveolae per se was assessed. The main findings concerning protrusion force and membrane reservoir availability were as follows: (1) they correlated inversely, (2) their values underwent the greatest change after microtubule disruption, and (3) membrane composition had a major influence on the parameters studied. F-actin disruption and cholesterol depletion decreased, and microtubule disruption increased the amount of the caveolar proteins (caveolae). Caveolae presented just an example of the membrane reservoir, and from our findings, we suppose that the perturbations caused were too large to be related to caveolae redistribution alone. The integrity of the cytoskeleton and plasma membrane composition are important factors in the formation of protrusions and in determining the availability and distribution of the membrane reservoir.


Who speaks for the health consumer?
Although consumer-directed health care has become a fashionable concept in recent years, stories abound asking whether the so-called free market in health care can provide adequate access to quality health care at an affordable price. In spite of these concerns, consumer-directed health care continues as the face of legitimacy behind an industry-driven campaign to limit regulatory protections of the consumer in the market and encourage the growth of health insurance products that place spending options closer to the consumer, whether or not these options are available, affordable, or easily understood. Understanding whether this empowerment is real begins with first asking what it now means to be a health consumer. This commentary offers perspective on the dilemma faced by millions of Americans in navigating our health care system under the assumption that market-driven choices foster consumer empowerment in health care, and suggests approaches for expanding the true consumer voice.


The turmoil of aboriginal enumeration: mobility and service population analysis in a central Australian community.
This paper documents Aboriginal population change and mobility over time in a remote community in central Australia. The movement of population has implications for service delivery and resource allocation. Aboriginal population in the region is characterised by high mobility. We conducted four population surveys in a selected remote community over a 12 month period and categorised individuals into four mutually exclusive groups: residents, dual residents, visitors and absent residents. Based on these categories we developed two population classifications: actual and potential service populations. The potential service population was consistently higher than the Australian Bureau of Statistics (ABS) census figure. We question the use of ABS census estimates as appropriate population figures for determining resource allocation to remote communities. We quantify inter- and intra-community mobility. When the potential population is used as denominator, 35% of the population of this community was classified as inter-community mobile. Given this level of mobility we argue that: (1) Resources should be allocated to compensate health services for the additional time and resource requirements to deal with the high level of population mobility. (2) Health programs such as STD control, trachoma, scabies and other communicable diseases common in Central Australia should be coordinated and delivered as regional programs often crossing State/Territory borders.


Adaptive and maladaptive impulsivity, platelet monoamine oxidase (MAO) activity and risk-admitting in different types of risky drivers.
Platelet monoamine oxidase (MAO) activity reflects serotonergic functioning associated with impulsive behaviour, but the significance of these associations to real-life impulsive behaviour in healthy subjects is not clear. The present study explores impulsivity and platelet MAO activity among people with driving violations. We compared facets of impulsivity and platelet MAO activity in 1,004 male drivers, out of whom 203 had been caught by the police driving drunk and 292 had been caught exceeding speed limits and committing other non-alcohol-related driving violations. Subjects with speeding and other non-alcohol-related violations were further divided according to their self-reported risk-admitting of exceeding speed limits. While drunk driving was associated only with maladaptive types of impulsivity, exceeding speed limits was associated with functional impulsivity and excitement seeking and, to a lesser degree, with dysfunctional impulsivity. Drunk drivers had lower platelet MAO activity. Risk-admitting high-risk drivers had higher platelet MAO activity, neuroticism-related impulsivity, dysfunctional impulsivity and excitement seeking compared to all other groups and higher functional impulsivity compared to controls. Risk-denying high-risk drivers had only higher functional impulsivity compared to controls. This study demonstrates different expressions of functional and dysfunctional impulsivity in behaviour. While platelet MAO activity is lower in alcohol-related risky behaviour, non-alcohol-related self-acknowledged risky behaviour is related to higher platelet MAO activity. Thus, deviance towards lower as well as higher end of central serotonergic functioning may lead to impulsive behaviour. While self-reported impulsivity did not correlate with MAO activity, both MAO activity and impulsivity were related to risky behaviour.


Arthroscopic All-Inside Anterior Talofibular Ligament Repair Through a Three-Portal and No-Ankle-Distraction Technique.
Ankle instability is a common consequence of ankle sprains. Injury of the anterior talofibular ligament (ATFL) is the most common cause of ankle instability1. Arthroscopic treatment of ankle instability is an emerging field attracting increased interest among surgeons2-10. The arthroscopic all-inside ATFL repair allows the surgeon to explore the ankle joint, treat concomitant pathology when encountered, and reattach the injured ATFL to its fibular anatomical location. The aim of this article is to describe the arthroscopic all-inside ATFL repair through a 3-portal no-ankle-distraction technique. After patient positioning, anteromedial and anterolateral portals are created. An accessory anterolateral portal is created just anterior to the fibula and about 1 cm proximal to the tip of the lateral malleolus. The arthroscope is introduced through the anteromedial portal, and the instruments are introduced through the anterolateral portal. Recognition of the ligament and evaluation of the ligament tear with a probe are required. The footprint for the fibular attachment of the ATFL is debrided. The ligament is penetrated with a suture passer. A nitinol loop is pushed and then is pulled out through the accessory portal. The nitinol wire is replaced by a double high-resistance suture. The limbs of the suture located in the accessory portal are passed through the anterolateral portal. Next, one or both limbs of the suture are passed through the loop suture. Pulling of the suture limbs introduces the loop into the joint and the ligament is grasped by the suture. The tunnel for the anchor is drilled. The knotless anchor is loaded with the suture, and the anchor and suture are introduced with the ankle in dorsiflexion and valgus. Postoperatively, the ankle is immobilized with a removable walking boot for 4 weeks. Once use of the walking boot is discontinued, physical therapy is started. Nonoperative treatment with physiotherapy or sports restriction can be an alternative for patients with surgical contraindications or as a first step of treatment. Open techniques (repair or reconstruction) or other arthroscopic-assisted techniques (arthroscopic introduction of anchors and percutaneous passage of sutures, or arthroscopic-assisted reconstruction) are possible surgical alternatives to the described technique to treat ankle instability. The described technique has the advantage of being done with a minimally invasive approach and providing an anatomical repair of the ligament. Concomitant intra-articular pathology can be addressed during the procedure through the same arthroscopic approaches. Early rehabilitation and the lack of intra-articular knots are additional benefits of the technique.


Differential expression of membrane sialoglycoproteins in exudate and resident mouse peritoneal macrophages.
Wheat germ agglutinin (WGA) has been used to define biochemical differences between exudate and resident macrophages in the peritoneal cavity of mice. Western blotting with 125I-WGA identifies a restricted set of glycoproteins in elicited peritoneal macrophages (M phi) (recruited with thioglycollate or periodate) and fully activated M phi (recruited with live Bacille Calmette-Guérin, or heat-killed Corynebacterium parvum); the major species migrates with Mr 89-115 kDa in 10% acrylamide gels. These glycoproteins are not detected in resident peritoneal M phi, nor in thymocytes, neutrophils, lymphocytes and a variety of non-M phi cell lines. The binding of WGA is sensitive to neuraminidase, which exposes binding sites on these proteins for peanut agglutinin and reduces their electrophoretic mobility; these features are typical of O-linked sialo-oligosaccharides. In culture, exudate M phi increase their WGA-binding content over 48 h, and continue to display a phenotype distinct from that of resident peritoneal M phi. The stable differential expression of these sialoglycoproteins, by elicited and activated versus resident peritoneal M phi, suggests that biochemical modification during the synthesis and expression of membrane glycoproteins accompanies M phi recruitment to an inflammatory focus.


Characterization of the Adeno-Associated Virus 1 and 6 Sialic Acid Binding Site.
The adeno-associated viruses (AAVs), which are being developed as gene delivery vectors, display differential cell surface glycan binding and subsequent tissue tropisms. For AAV serotype 1 (AAV1), the first viral vector approved as a gene therapy treatment, and its closely related AAV6, sialic acid (SIA) serves as their primary cellular surface receptor. Toward characterizing the SIA binding site(s), the structure of the AAV1-SIA complex was determined by X-ray crystallography to 3.0 Å. Density consistent with SIA was observed in a pocket located at the base of capsid protrusions surrounding icosahedral 3-fold axes. Site-directed mutagenesis substitution of the amino acids forming this pocket with structurally equivalent residues from AAV2, a heparan sulfate binding serotype, followed by cell binding and transduction assays, further mapped the critical residues conferring SIA binding to AAV1 and AAV6. For both viruses five of the six binding pocket residues mutated (N447S, V473D, N500E, T502S, and W503A) abolished SIA binding, whereas S472R increased binding. All six mutations abolished or decreased transduction by at least 50% in AAV1. Surprisingly, the T502S substitution did not affect transduction efficiency of wild-type AAV6. Furthermore, three of the AAV1 SIA binding site mutants-S472R, V473D, and N500E-escaped recognition by the anti-AAV1 capsid antibody ADK1a. These observations demonstrate that common key capsid surface residues dictate both virus binding and entry processes, as well as antigenic reactivity. This study identifies an important functional capsid surface "hot spot" dictating receptor attachment, transduction efficiency, and antigenicity which could prove useful for vector engineering. The adeno-associated virus (AAV) vector gene delivery system has shown promise in several clinical trials and an AAV1-based vector has been approved as the first gene therapy treatment. However, limitations still exist with respect to transduction efficiency and the detrimental effects of preexisting host antibodies. This study aimed to identify key capsid regions which can be engineered to overcome these limitations. A sialic glycan receptor recognition pocket was identified in AAV1 and its closely related AAV6, using X-ray crystallography. The site was confirmed by mutagenesis followed by cell binding and transduction assays. Significantly, residues controlling gene expression efficiency, as well as antibody escape variants, were also identified. This study thus provides, at the amino acid level, information for rational structural engineering of AAV vectors with improved therapeutic efficacy.


Effectiveness of functional training versus resistance exercise in patients with psoriatic arthritis: randomized controlled trial.
This study aims to evaluate the effect of functional versus resistance exercise training on the functional capacity and quality of life of psoriatic arthritis patients. Forty-one psoriatic arthritis patients (18 to 65 years old) were randomized into two groups: functional training group and resistance exercise group. The functional training group underwent functional exercises with elastic band and the functional training group underwent machine resistance exercise twice a week for 12 weeks. Outcome measures were: The Bath Ankylosing Spondylitis Functional Index (BASFI) and Health Assessment Questionnaire for the Spondyloarthropathies (HAQ-S) for functional capacity and functional status, one-repetition maximum test for muscle strength, the Short Form 36 health survey questionnaire (SF-36) for quality of life, and the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) and the Disease Activity Score 28 (DAS-28) for disease activity. Analyzes were performed by a blinded evaluator at baseline (T0), six (T6) and twelve (T12) weeks after the beginning of the exercise. At baseline, the groups were homogeneous in the clinical and demographic characteristics. There was a statistical intra-group improvement for both groups in the BASFI, BASDAI, HAQ-s, and DAS-28. In the quality-of-life assessment, both groups showed statistical intra-group improvements for all domains except the "emotional aspect" domain in the resistance exercise group. In the muscle strength, there was a statistical improvement for all exercises in both groups, except for the "alternate biceps (bilateral)" exercise. Functional training and resistance exercise are similarly effective in improving functional capacity, functional status, disease activity, general quality of life, and muscle strength in patients with psoriatic arthritis. ClinicalTrials.gov: NCT04304326. Registered 11 March 2020, https://clinicaltrials.gov/ct2/show/NCT04304326?term=NCT04304326&draw=2&rank=1 .


Conscious or deep sedation: a questionnaire regarding the experience of parents, children and staff during small bowel biopsy.
The paediatric clinics of Linköping and Norrköping, Sweden, have different procedures regarding premedication and sedation during small bowel biopsy in children with suspected or diagnosed coeliac disease. In Linköping deep sedation using intravenous propofol is the method of sedation being used and parents are not present during the biopsy procedure. In Norrköping conscious sedation using intravenous midazolam is the routine and parents stay with their child throughout the whole biopsy procedure. The aim of this study was to find out whether the preprocedural and procedural differences between the clinics affected the way in which the parents and children experienced the time before and during the biopsy procedure. A questionnaire was used to ask the parents of 102 children who had undergone small bowel capsule biopsy for their opinion regarding the discomfort experienced by their children. The parents' and children's experience was also compared with that of the paediatric nurse caring for the family during the biopsy procedure, and the paediatric gastroenterologist performing the biopsy. The differences regarding premedication and sedation between the two groups did not seem to affect the parents' or the children's total experience of the biopsy procedure, nor did the presence or absence of the parents throughout the biopsy procedure. As regards the sedation given, 95% of the parents did not think that their children suffered any discomfort at all. The total experience of the biopsy procedure on a five-grade scale (5 being very good, 1 being very bad) was 5 for the parents and 4 for the children in both centres. Parents and children in both centres were very satisfied with the way in which they were taken care of during their visit to the hospital. In both units there was an obvious correlation between how the paediatric nurse experienced the biopsy procedure and how the paediatric gastroenterologist did, but only a weak correlation between the experience of the parents and that of the paediatric gastroenterologist and paediatric nurse. The anxiety of the parents was similarly estimated by the paediatric gastroenterologist and the paediatric nurse in both centres. There was no correlation between their assessment and the experience reported by the parents. The children undergoing small bowel biopsy and their parents felt well taken care of during their visit to the two hospitals. The differences between the clinics regarding method of sedation and presence or absence of the parents did not seem to affect how the parents and children experienced the biopsy procedure.