Recurrence of Kikuchi's lymphadenitis after 12 years.
A 40 year old woman developed recurrent Kikuchi's disease 12 years after the original episode. The recurrence affected the same site (axilla) and occurred after the longest delay so far recorded in a European resident. Care must be taken to avoid misdiagnosis of Kikuchi's disease as lymphoma.


Immune complexes present in the sera of autoimmune mice activate rheumatoid factor B cells.
The fate of an autoreactive B cell is determined in part by the nature of the interaction of the B cell receptor with its autoantigen. In the lpr model of systemic autoimmunity, as well as in certain human diseases, autoreactive B cells expressing rheumatoid factor (RF) binding activity are prominent. A murine B cell transgenic model in which the B cell receptor is a RF that recognizes IgG2a of the j allotype (IgG2aj), but not the b allotype, was used in this study to investigate how the form of the autoantigen influences its ability to activate B cells. We found that sera from autoimmune mice, but not from nonautoimmune mice, were able to induce the proliferation of these RF+ B cells but did not stimulate B cells from RF- littermate controls. The stimulatory factor in serum was found to be IgG2aj, but the IgG2aj was stimulatory only when in the form of immune complexes. Monomeric IgG2aj failed to stimulate. Immune complexes containing lupus-associated nuclear and cytoplasmic autoantigens were particularly potent B cell activators in this system. Appropriate manipulation of such autoantibody/autoantigen complexes may eventually provide a means for therapeutic intervention in patients with certain systemic autoimmune disorders.


Intracerebral haemorrhage and drug abuse in young adults.
The epidemic of abuse of the so-called 'designer drugs' amphetamine, cocaine and ecstasy--is fast replacing traditional aetiological factors as the largest cause of intracerebral haemorrhage among young adults. Traditional teaching is that these represent hypertensive haemorrhages. Recent reports, however, have indicated that these patients may harbour underlying vascular malformations. We review 13 patients with a positive history of drug abuse preceding the onset of intracerebral haemorrhage. These patients presented to the National Hospital for Neurology and Neurosurgery in central London over a 7-month period. Of the 13 patients (eight male, five female), average age 31 years (19-43) years), 10 were well enough to undergo cerebral angiography. Intracranial aneurysms were demonstrated in six patients and arteriovenous malformations in three patients. In only one of the patients was the angiogram normal. A further patient was subsequently shown to have a middle cerebral artery aneurysm at autopsy. The epidemiology, pharmacology and systemic effects of these drugs are considered. The mechanisms by which these compounds cause intracerebral complications and their influence on prognosis are discussed. The incidence of intracerebral haemorrhage (ICH), ischaemic cerebral infarctions and subarachnoid haemorrhage (SAH) following drug abuse is increasing. Contrary to historical opinion, drug-related ICH is frequently related to an underlying vascular malformation. Arteriography should be part of the evaluation of most young patients with nontraumatic ICH. A thorough history focusing on the use of illicit substances and toxicological screening of urine and serum should be part of the evaluation of any young patient with a stroke.


Microcystic adenoma of the pancreas: clinical, radiologic, and cytologic features.
Cytology literature on pancreatic microcystic adenoma is sparse. It is important to separate microcystic adenoma from adenocarcinoma and mucinous cystic neoplasms on aspiration cytology, because patients with microcystic adenoma can be treated conservatively unless they are symptomatic. Potential pitfalls with endoscopic ultrasound (EUS) sampling of these lesions is discussed. From January 1991 through June 2003, 10 patients with microcystic adenoma of the pancreas were diagnosed on fine-needle aspiration cytology. An additional patient, who was diagnosed with a mucinous cystic neoplasm by EUS sampling, was rediagnosed with microcystic adenoma on the excised specimen. Aspirate smears, cell blocks, core biopsies, subsequent excision (if any), and special stains were reviewed. Imaging studies and clinical data were available from the majority of patients. The patients included 5 females and 6 males who ranged in age from 45 years to 84 years. Radiology studies showed tumors, which were heterogeneous with areas of fluid density and septations, located in the head, body, or tail of the pancreas. The masses ranged in size from 1 cm to 17 cm. The radiographic impression was highly suggestive of microcystic adenoma in six patients; detailed radiologic information was not available from three patients. On follow-up, six patients were alive and well at the last follow-up available, two patients died of unrelated sepsis, and three patients were lost to follow-up. Three of 11 patients underwent a Whipple resection. Cytology results: The cytologic features identified included the following: 1) Bland tumor cells were seen in sheets or small groups with a lack of nuclear abnormalities and moderate-to-scant cytoplasm with occasional clearing or vacuolation. Naked nuclei were present occasionally. Tumor cells were distinguishable from acinar cells based on larger cell size and granular cytoplasm in which prominent nucleoli were seen. 2) Relatively acellular, fibrovascular stroma was seen, usually located between tumor cells. 3) Calcifications were seen in four of eleven tumors. One tumor sampled by EUS revealed fragments of glandular-type epithelium with minimal atypia and was diagnosed erroneously as a mucinous cystic neoplasm. Cell blocks or core biopsies from most tumors showed fragments of dense stroma and cystic spaces lined by flattened epithelial cells. Subsequent Whipple resection in three patients showed histologic features of microcystic adenoma. Special stains performed in select tumors were positive for cytokeratin, carbohydrate antigen 19.9, and periodic acid-Schiff stain. Calretinin staining was negative in the tumor cells. A cytologic diagnosis of microcystic adenoma is possible based on the criteria described above. Cell block and/or core biopsy, special stains, and radiologic information are key in making a definitive diagnosis. Patients with microcystic adenoma are spared a major surgical procedure unless they are symptomatic. With the EUS-guided modality of pancreatic sampling, caution should be exercised in misinterpreting benign glandular epithelium derived from the stomach or small bowel as a mucinous cystic neoplasm.


Do Mental Health and Vitality Mediate the Relationship between Perceived Control over Time and Fear of COVID-19? A Survey in an Italian Sample.
Several studies evidenced increased elevated symptomatology levels in anxiety, general stress, depression, and post-traumatic stress related to COVID-19. Real difficulties in the effective control of time that could be responsible for mental health issues and loss of vitality were also reported. Prior literature highlighted how perceived control over time significantly modulates anxiety disorders and promotes psychological well-being. To verify the hypothesis that perceived control over time predicts fear of COVID-19 and mental health and vitality mediate this relationship, we performed an online survey on a sample of 301 subjects (female = 68%; Mage = 22.12, SD = 6.29; age range = 18-57 years), testing a parallel mediation model using PROCESS macro (model 4). All participants responded to self-report measures of perceived control over time, COVID-19 fear, mental health, and vitality subscales of the Short-Form-36 Health Survey. Results corroborate the hypotheses of direct relationships between all the study variables and partially validate the mediation's indirect effect. Indeed, mental health (a1b1 = -0.06; CI: LL = -0.11; UL = -0.01; p < 0.001) rather than vitality (a2b2 = -0.06; CI: LL = -0.09; UL = 0.03; n.s.) emerges as a significant mediator between perceived control over time and fear of COVID-19. Practical implications of the study about treatment programs based on perceived control over time and emotional coping to prevent fear and anxiety toward the COVID-19 pandemic are discussed.


Humic acid as a feed additive in poultry diets: a review.
Many studies tested different feed additives, among these additives, humic substances (HS) have been used in livestock and poultry diets. Humic substances commonly present in nature as they are created from the organic matter decomposition, and are normally found in the soil and natural water. Active components of HS consist of humic acid (HA), humus, ulmic acid, fulvic acid, humin and certain microelements. Humic acid is widely used as an alternative growth promoter for antibiotics in improving poultry performance and health. Moreover, supplementation of a commercial substance as a source of HS through the drinking water or diet improved the feed consumption, feed efficiency and weight gain of broiler chickens, and also improved egg weight, egg mass, and egg production of laying hens. This review describes the useful applications and recent facets of HA including its modes of action and various valuable uses in improving the production and health safeguarding of livestock and poultry.


Development and preclinical characterization of a humanized antibody targeting CXCL12.
Our goal was to develop a potent humanized antibody against mouse/human CXCL12. This report summarized its in vitro and in vivo activities. Cell surface binding and cell migration assays were used to select neutralizing hamster antibodies, followed by testing in several animal models. Monoclonal antibody (mAb) 30D8 was selected for humanization based on its in vitro and in vivo activities. 30D8, a hamster antibody against mouse and human CXCL12α, CXCL12β, and CXCL12γ, was shown to dose-dependently block CXCL12α binding to CXCR4 and CXCR7, and CXCL12α-induced Jurkat cell migration in vitro. Inhibition of primary tumor growth and/or metastasis was observed in several models. 30D8 alone significantly ameliorated arthritis in a mouse collagen-induced arthritis model (CIA). Combination with a TNF-α antagonist was additive. In addition, 30D8 inhibited 50% of laser-induced choroidal neovascularization (CNV) in mice. Humanized 30D8 (hu30D8) showed similar in vitro and in vivo activities as the parental hamster antibody. A crystal structure of the hu30D8 Fab/CXCL12α complex in combination with mutational analysis revealed a "hot spot" around residues Asn(44)/Asn(45) of CXCL12α and part of the RFFESH region required for CXCL12α binding to CXCR4 and CXCR7. Finally, hu30D8 exhibited fast clearance in cynomolgus monkeys but not in rats. CXCL12 is an attractive target for treatment of cancer and inflammation-related diseases; hu30D8 is suitable for testing this hypothesis in humans.


Celiac Disease on the Bed-Side: Embedding Case Finding and Screening in Hospitalized Children.
Strategies for diagnosing celiac disease (CD) include case-finding and population-screening programs. Case finding consists of testing individuals at increased risk for the disease due to symptoms or associated conditions. Screening programs are widespread campaigns, which definitely perform better in terms of unveiling CD diagnoses but nowadays are still debatable. The global prevalence of CD is around 1% but it almost doubles when considering screening programs among school children. Within this framework, we aimed to estimate the prevalence of CD among hospitalized children in the Pediatric Department of a Southern Italy University Hospital in the period from January 2018 through December 2021. In addition, we attempted to explore, at the time of diagnosis, the prevalence of leading clinical alerts due to malabsorption/malnutrition such as anemia or failure to thrive or due to systemic inflammation/immune dysfunction as hypertransaminasemia and thyroid dysfunction. Data records of pediatric patients admitted as inpatients and tested by anti-transglutaminase IgA antibodies (TGA-IgA) were retrospectively analyzed. CD was diagnosed according to either 2012 or 2020 ESPGHAN guidelines, depending on the year of diagnosis. CD autoimmunity (CDA) was a wider group defined within our protocol if patients had elevated TGA-IgA on at least one occasion, regardless of anti-endomysial antibodies (EMA-IgA) and without biopsy confirmation. During the observation period, 3608 pediatric patients were admitted and 1320 were screened for CD (median age 5 years, IQR 2-9 years; CD test rate: 36.6% out of all admissions). The available prevalence of newly diagnosed CD was 1.59% (21 patients diagnosed) and the available prevalence of CDA was 3.86% (51 subjects). Among CD patients, underweight/malnourished children accounted for 28.6% (6 out of 21). The estimated prevalence of CD diagnoses within our setting was comparable to the most recent population-screening programs. The estimated prevalence of CDA was even higher. A hospital-admission CD testing during routine blood draws might be a non-invasive, cost-effective and valuable approach to reduce discrepancy of prevalence between case-finding and population-screening programs.


Patterns of breast parenchyma on mammography.
The hypothesis that two of four mammographic patterns show a marked predisposition to develop breast cancer was examined in a retrospective study. Four hundred patients with breast carcinoma were randomly chosen. The xeromammograms of the opposite breasts in these patients had been done and were studied. The conclusion of Wolfe was not supported by our findings.


Effect of bile salts on monolayer curvature of a phosphatidylethanolamine/water model membrane system.
A partial phase diagram of the ternary system dioleoylphosphatidylethanolamine (DOPE)/sodium cholate/water has been determined using 31P Nuclear Magnetic Resonance (NMR) spectroscopy. In the absence of cholate, it is well known that the DOPE/water system forms a reversed hexagonal (HII) phase. We have found that addition of even small amounts of cholate to the DOPE/water system leads to a transition to a lamellar (L alpha) phase. At higher cholate concentrations, a cubic (I) phase (low water content) or a micellar solution (L1) phase (high water content) is present. Thus, cholate molecules have a strong tendency to alter the lipid monolayer curvature. Increasing the concentration of cholate changes the curvature of DOPE from negative (HII phase), through zero (L alpha phase), and finally to a phase of positive curvature (micellar solution). This observation can be rationalized in terms of the molecular structure of cholate, which is amphipathic and has one hydrophobic and one hydrophilic side of the steroid ring system. The cholate molecules have a tendency to lie flat on the lipid aggregate surface, thereby increasing the effective interfacial area of the polar head groups, and altering the curvature free energy of the system.


Current Practice of Therapeutic Mammaplasty: A Survey of Oncoplastic Breast Surgeons in England.
Therapeutic mammaplasty (TM) is a useful technique in the armamentarium of the oncoplastic breast surgeon (OBS). There is limited guidance on patient selection, technique, coding, and management of involved margins. The practices of OBS in England remain unknown. Questionnaires were sent to all OBS involved with the Training Interface Group. We assessed the number of TM cases performed per surgeon, criteria for patient selection, pedicle preference, contralateral symmetrisation, use of routine preoperative MRI, management of involved margins, and clinical coding. We had an overall response rate of 43%. The most common skin resection technique utilised was wise pattern followed by vertical scar. Superior-medial pedicle was preferred by the majority of surgeons (62%) followed by inferior pedicle (34%). Twenty percent of surgeons would always proceed to a mastectomy following an involved margin, whereas the majority would offer reexcision based on several parameters. The main absolute contraindication to TM was tumour to breast ratio >50%. One in five surgeons would not perform TM in smokers and patients with multifocal disease. There is a wide variation in the practice of TM amongst OBS. Further research and guidance would be useful to standardise practice, particularly management of involved margins and coding for optimal reimbursement.


[Nutrition in Warsaw nursing homes in the opinion of their residents].
The aim of the study was to meet the opinions of NHs' residents about the meals quality and nutrition system, with special consideration of meal ambience in canteens (appearance, atmosphere, etc.). Besides, other information about residents was collected: their self-perceived health status, psychical condition, physical activity, appetite and nutritional habits. Most of the subjects were single women, mainly with medium/technical education level, living in NHs over 3 years. Most of the NHs' residents evaluated their health status as average or bad, independently of the age or gender. Every second person indicated that health, loneliness and the feeling of isolation in their homes were the main reasons for coming to NH. Every third person still felt the loneliness or depression after staying in NH. The physical and intellectual activity of elderly depended on self-perceived health status. Over half of the subjects assessed their appetite as good, and said that their body mass was stable during staying in NH. The statistically significant relationship was found between the self-evaluated weight change and both age and gender. Additionally, the relationship was observed between psychical condition of residents and their appetite as also between the psychical condition and weight change during living in NH. The majority of the subjects (85%) said that they liked the canteen appearance, and they did not want to change anything in it. More women than men thought that canteens were spacious, clean and furnished with good taste, and those differences were significant. Part of studied population (25%) had some reservations about the atmosphere in canteen during the meals, mostly because of too much noise. In the opinions of most of the residents (over 80%) the nutrition organisation in NHs was good. Over half of the subjects assessed the meals quality in NHs also as good. Only some comments were about insufficient quantities of fruits and vegetables and meal monotony.


Fc gamma RIIB regulates nasal and oral tolerance: a role for dendritic cells.
Mucosal tolerance prevents the body from eliciting productive immune responses against harmless Ags that enter the body via the mucosae, and is mediated by the induction of regulatory T cells that differentiate in the mucosa-draining lymph nodes (LN) under defined conditions of Ag presentation. In this study, we show that mice deficient in FcgammaRIIB failed to develop mucosal tolerance to OVA, and demonstrate in vitro and in vivo a critical role for this receptor in modulating the Ag-presenting capacity of dendritic cells (DC). In vitro it was shown that absence of FcgammaRIIB under tolerogenic conditions led to increased IgG-induced release of inflammatory cytokines such as MCP-1, TNF-alpha, and IL-6 by bone marrow-derived DC, and increased their expression of costimulatory molecules, resulting in an altered immunogenic T cell response associated with increased IL-2 and IFN-gamma secretion. In vivo we could show enhanced LN-DC activation and increased numbers of Ag-specific IFN-gamma-producing T cells when FcgammaRIIB(-/-) mice were treated with OVA via the nasal mucosa, inferring that DC modulation by FcgammaRIIB directed the phenotype of the T cell response. Adoptive transfer of CD4(+) T cells from the spleen of FcgammaRIIB(-/-) mice to naive acceptor mice demonstrated that OVA-responding T cells failed to differentiate into regulatory T cells, explaining the lack of tolerance in these mice. Our findings demonstrate that signaling via FcgammaRIIB on DC, initiated by local IgG in the mucosa-draining LN, down-regulates DC activation induced by nasally applied Ag, resulting in those defined conditions of Ag presentation that lead to Tr induction and tolerance.


[Catamnesis of patients with a history of mitral commissurotomy in childhood and adolescence].
In 129 children catamnesis was traced over a period from 6 months to 12 years after commissurotomy. Late after surgery the course of rheumatism proved more favourable than before the operation. On expiration of 6 months good results were recorded in 93.2, in 1-3 years-in 83.5 and after 7-12 years-in 50 per cent of the patients. With lengthened periods of observation the number of good results was diminishing due to restenosis and formation of new defects. Most patients with unfavourable results had earlier undergone a fully effective commissurotomy and during the first follow-up years the results were good. Relapses, new defects and progressive deterioration of the initial ones were registered in 36.4 per cent of the cases and 1/3 of the patients are in need of repeated surgery.


Secretion of tissue inhibitors of matrix metalloproteinases by human fetal membranes, decidua and placenta at parturition.
At parturition, breakdown of extracellular matrix in the fetal membranes may play a part in the rupture of the membranes and in the aetiology of premature rupture, in addition to having a regulatory role in the cell-cell interactions and signalling at the feto-maternal interface to stimulate myometrial contractility. The matrix metalloproteinases (MMPs) are important enzymes for the breakdown of extracellular matrix and their activity is regulated by a family of endogenous inhibitors, the tissue inhibitors of matrix metalloproteinases (TIMPs). At parturition, alteration in the balance between MMPs and TIMPs may mediate this extracellular matrix breakdown during rupture of fetal membranes. The aims of this study were to determine if the intrauterine secretion of TIMPs changes at labour, and to characterise their cellular sources. A broad range of TIMP activities (27-30 kDa, 24 kDa and 21 kDa) were detected by reverse zymography in term amniotic fluid. There was a significant (P<0.05) decrease in the amount of TIMPs in amniotic fluid and their release with the onset of labour. The TIMPs were characterised by immunoblot as TIMPs-1, -2, -3 and -4. High levels of TIMPs were secreted by explants of chorio-decidua, decidua parietalis and placenta, with less being released by amnion. Immunolocalisation studies revealed a specific distribution pattern for each of the TIMP isoforms. Trophoblast cells of chorion laeve, decidua parietalis and placental syncytiotrophoblast demonstrated specific immunoreactivity for all four isoforms. TIMPs were also found bound to selective regions of extracellular matrix. The decrease in TIMPs during labour may permit increased breakdown of extracellular matrix in the fetal membranes and decidua at parturition, thus altering cell signalling at the feto-maternal interface and facilitating membrane rupture.


[Effect of 1 alpha-hydroxycholecalciferol and various dietary phosphorus levels on phosphorus and calcium metabolic indices in rats during hypokinesia].
The exposure of rats to hypokinesia and a phosphorus-enriched diet (Ca : P = 1:3) was accompanied by hypocalciemia, hyperphosphatemia, calcium losses from bones and formation of calcificates in the kidneys. The decrease of the phosphorus content in the diet (Ca : P = 1:0.5--1:1) prevented these disorders. The administration of 1 alpha OHD3 at a dose of 0.025 microgram/day arrested hypokinesia-associated hypocalciemia and bone changes. The administration of 1 alpha OHD3 together with a high phosphorus consumption enhanced nephrolithiasis and induced aortal mediacalcinosis in hypokinetic rats. These data indicate that phosphorus consumption should be reduced in order to prevent disorders in phosphorus-calcium metabolism during hypokinesia. They also suggest that administration of 1 alpha OHD3 may be hazardous in case of excessive phosphorus consumption.


Optimum culture duration for growing oocytes to attain meiotic and fertilization competence.
To determine the optimum culture duration for porcine growing oocytes (GOs) to attain maturation competence, we examined the meiotic competence, chromatin configuration, and fertilization ability of porcine oocytes obtained from early antral follicles and cultured for 10-16 days. The survival rate of oocytes after 10 days of culture (62.8%) was similar to that of oocytes after 12 days of culture (55%) and significantly higher than that of oocytes cultured for 14 and 16 days (52.9 and 24.3%, respectively). No significant difference was observed in the diameter of ooplasm from oocytes cultured for different durations (117.4-118.3 μm). The maturation rates of surviving oocytes after 10 and 16 days of culture (38.3 and 22.7%, respectively) were significantly lower than those of oocytes cultured for 12 and 14 days, and their in vivo counterparts (52.8-62.4%). The number of oocytes with surrounded-nucleolus chromatin was significantly lower in the 10-day culture group (78.4%) as compared with 14-day culture and in vivo counterpart groups (93.6 and 95.1%, respectively). After in vitro maturation and intracytoplasmic sperm injection, no significant difference was observed in the rate of fertilization among oocytes cultured for 12 and 14 days, and their in vivo counterparts (40.5-47.2%). Thus, porcine GOs required at least 12 days to acquire meiotic and fertilization competence, and the culture duration to maximize the number of mature oocytes ranged from 12 to 14 days.


Internal architecture of the mandibular condyle of rabbits is related to dietary resistance during growth.
Although there is considerable evidence that bone responds to the loading environment in which it develops, few analyses have examined phenotypic plasticity or bone functional adaptation in the masticatory apparatus. Prior work suggests that masticatory morphology is sensitive to differences in food mechanical properties during development; however, the importance of the timing/duration of loading and variation in naturalistic diets is less clear. Here, we examined microstructural and macrostructural differences in the mandibular condyle in four groups of white rabbits (Oryctolagus cuniculus) raised for a year on diets that varied in mechanical properties and timing of the introduction of mechanically challenging foods, simulating seasonal variation in diet. We employed sliding semilandmarks to locate multiple volumes of interest deep to the mandibular condyle articular surface, and compared bone volume fraction, trabecular thickness and spacing, and condylar size/shape among experimental groups. The results reveal a shared pattern of bony architecture across the articular surface of all treatment groups, while also demonstrating significant among-group differences. Rabbits raised on mechanically challenging diets have significantly increased bone volume fraction relative to controls fed a less challenging diet. The post-weaning timing of the introduction of mechanically challenging foods also influences architectural properties, suggesting that bone plasticity can extend well into adulthood and that bony responses to changes in loading may be rapid. These findings demonstrate that bony architecture of the mandibular condyle in rabbits responds to variation in mechanical loading during an organism's lifetime and has the potential to track dietary variation within and among species.


Reprogramming cells and tissue patterning via bioelectrical pathways: molecular mechanisms and biomedical opportunities.
Transformative impact in regenerative medicine requires more than the reprogramming of individual cells: advances in repair strategies for birth defects or injuries, tumor normalization, and the construction of bioengineered organs and tissues all require the ability to control large-scale anatomical shape. Much recent work has focused on the transcriptional and biochemical regulation of cell behavior and morphogenesis. However, exciting new data reveal that bioelectrical properties of cells and their microenvironment exert a profound influence on cell differentiation, proliferation, and migration. Ion channels and pumps expressed in all cells, not just excitable nerve and muscle, establish resting potentials that vary across tissues and change with significant developmental events. Most importantly, the spatiotemporal gradients of these endogenous transmembrane voltage potentials (Vmem ) serve as instructive patterning cues for large-scale anatomy, providing organ identity, positional information, and prepattern template cues for morphogenesis. New genetic and pharmacological techniques for molecular modulation of bioelectric gradients in vivo have revealed the ability to initiate complex organogenesis, change tissue identity, and trigger regeneration of whole vertebrate appendages. A large segment of the spatial information processing that orchestrates individual cells' programs toward the anatomical needs of the host organism is electrical; this blurs the line between memory and decision-making in neural networks and morphogenesis in nonneural tissues. Advances in cracking this bioelectric code will enable the rational reprogramming of shape in whole tissues and organs, revolutionizing regenerative medicine, developmental biology, and synthetic bioengineering.


Investigation of factors impacting mobility and gait in Parkinson disease.
Mobility and gait limitations are major issues for people with Parkinson disease (PD). Identification of factors that contribute to these impairments may inform treatment and intervention strategies. In this study we investigated factors that predict mobility and gait impairment in PD. Participants with mild to moderate PD and without dementia (n=114) were tested in one session 'off' medication. Mobility measures included the 6-Minute Walk test and Timed-Up-and-Go. Gait velocity was collected in four conditions: forward preferred speed, forward dual task, forward fast as possible and backward walking. The predictors analyzed were age, gender, disease severity, balance, balance confidence, fall history, self-reported physical activity, and executive function. Multiple regression models were used to assess the relationships between predictors and outcomes. The predictors, in different combinations for each outcome measure, explained 55.7% to 66.9% of variability for mobility and 39.5% to 52.8% for gait velocity. Balance was the most relevant factor (explaining up to 54.1% of variance in mobility and up to 45.6% in gait velocity). Balance confidence contributed to a lesser extent (2.0% to 8.2% of variance) in all models. Age explained a small percentage of variance in mobility and gait velocity (up to 2.9%). Executive function explained 3.0% of variance during forward walking only. The strong predictive relationships between balance deficits and mobility and gait impairment suggest targeting balance deficits may be particularly important for improving mobility and gait in people with PD, regardless of an individual's age, disease severity, fall history, or other demographic features.


Envenomation by sea snake in Queensland.
A case of a near-fatal sea snake bite, believed to the the first such case in Australia, is presented. The two-year-old girl victim became unconscious and apnoeic soon after envenomation by an Astrotia stokesii, and required artificial ventilation for 22 hours. She regained consciousness 4 1/2 hours after the administration of antivenom. The recovery phase was marked by hallucinations and tonic spasms. The patient made a full recovery before discharge from hospital.


Adsorption of glyphosate on resin supported by hydrated iron oxide: equilibrium and kinetic studies.
Hydrated iron oxide supported on resin (D301) was prepared as a new sorbent for the removal of glyphosate from wastewater. Batch adsorption studies were performed on glyphosate aqueous solutions with different initial glyphosate concentrations and temperatures. Experimental data were analyzed using the Langmuir and Freundlich isotherms, and the adsorption data were best fit to the Langmuir isotherm model. The thermodynamic parameters AG, AH, and AS also were calculated for the adsorption processes. Adsorption rate constants were determined using the pseudo-first-order and pseudo-second-order rate equations and Kannan-Sundaram intraparticle diffusion models. Adsorption of glyphosate clearly followed the pseudo-second-order model and was controlled by both film diffusion and intraparticle diffusion.


Current Application of Advancing Spectroscopy Techniques in Food Analysis: Data Handling with Chemometric Approaches.
In today's era of increased food consumption, consumers have become more demanding in terms of safety and the quality of products they consume. As a result, food authorities are closely monitoring the food industry to ensure that products meet the required standards of quality. The analysis of food properties encompasses various aspects, including chemical and physical descriptions, sensory assessments, authenticity, traceability, processing, crop production, storage conditions, and microbial and contaminant levels. Traditionally, the analysis of food properties has relied on conventional analytical techniques. However, these methods often involve destructive processes, which are laborious, time-consuming, expensive, and environmentally harmful. In contrast, advanced spectroscopic techniques offer a promising alternative. Spectroscopic methods such as hyperspectral and multispectral imaging, NMR, Raman, IR, UV, visible, fluorescence, and X-ray-based methods provide rapid, non-destructive, cost-effective, and environmentally friendly means of food analysis. Nevertheless, interpreting spectroscopy data, whether in the form of signals (fingerprints) or images, can be complex without the assistance of statistical and innovative chemometric approaches. These approaches involve various steps such as pre-processing, exploratory analysis, variable selection, regression, classification, and data integration. They are essential for extracting relevant information and effectively handling the complexity of spectroscopic data. This review aims to address, discuss, and examine recent studies on advanced spectroscopic techniques and chemometric tools in the context of food product applications and analysis trends. Furthermore, it focuses on the practical aspects of spectral data handling, model construction, data interpretation, and the general utilization of statistical and chemometric methods for both qualitative and quantitative analysis. By exploring the advancements in spectroscopic techniques and their integration with chemometric tools, this review provides valuable insights into the potential applications and future directions of these analytical approaches in the food industry. It emphasizes the importance of efficient data handling, model development, and practical implementation of statistical and chemometric methods in the field of food analysis.


Impaired distractor inhibition on a selective attention task in unmedicated, depressed subjects.
Impaired distractor inhibition may contribute to the selective attention deficits observed in depressed patients, but studies to date have not tested the distractor inhibition theory against the possibility that processes such as transient memory review processes may account for the observed deficits. A negative priming paradigm can dissociate inhibition from such a potentially confounding process called object review. The negative priming task also isolates features of the distractor such as colour and location for independent examination. A computerized negative priming task was used in which colour, identification and location features of a stimulus and distractor were systematically manipulated across successive prime and probe trials. Thirty-two unmedicated subjects with DSM-IV diagnoses of non-psychotic unipolar depression were compared with 32 age, sex and IQ matched controls. Depressed subjects had reduced levels of negative priming for conditions where the colour feature of the stimulus was repeated across prime and probe trials but not when identity or location was the repeated feature. When both the colour and location feature were the repeated feature across trials, facilitation in response was apparent. The pattern of results supports studies that found reduced distractor inhibition in depressed subjects, and suggests that object review is intact in these subjects. Greater impairment in negative priming for colour versus location suggests that subjects may have greater impairment in the visual stream associated with processing colour features.


Inferring the Evolutionary History of Your Favorite Protein: A Guide for Molecular Biologists.
Comparative genomics has proven a fruitful approach to acquire many functional and evolutionary insights into core cellular processes. Here it is argued that in order to perform accurate and interesting comparative genomics, one first and foremost has to be able to recognize, postulate, and revise different evolutionary scenarios. After all, these studies lack a simple protocol, due to different proteins having different evolutionary dynamics and demanding different approaches. The authors here discuss this challenge from a practical (what are the observations?) and conceptual (how do these indicate a specific evolutionary scenario?) viewpoint, with the aim to guide investigators who want to analyze the evolution of their protein(s) of interest. By sharing how the authors draft, test, and update such a scenario and how it directs their investigations, the authors hope to illuminate how to execute molecular evolution studies and how to interpret them. Also see the video abstract here https://youtu.be/VCt3l2pbdbQ.


Understanding molecular mechanisms in peritoneal dissemination of colorectal cancer : future possibilities for personalised treatment by use of biomarkers.
When colorectal cancer (CRC) metastasizes, this is mostly to the liver via the portal circulation. In addition, 10-25 % of CRC patients eventually show metastases in the peritoneum. A selection of these patients is treated with cytoreductive surgery (CRS) and hyperthermic intra-peritoneal chemotherapy (HIPEC). However, several clinical needs still exist in which biomarkers could play an important role. Relatively little is known about the biology of peritoneal spread of CRC. The development of peritoneal metastases (PM) involves several steps, including: detachment of malignant cells; anoikis evasion; attachment to and invasion of the peritoneal surface ultimately ending in a colonization phase in which the malignant cells thrive in the newly formed niche. In this paper, we provide an overview of molecules associated with peritoneal dissemination and explore the clinical possibilities of these candidate biomarkers. A literature search was conducted using the PubMed database of the U.S. National Library of Medicine and Medline to identify studies on the biological behaviour of PM of CRC. In a series of over 100 studies on PM published between 1990 and 2010, IGF-1, HIF1α, VEGF, EGFR and ITGB1 emerge as the most interesting candidates for possible clinical application. Even though these promising candidate biomarkers have been identified, all of these require extensive further validation prior to clinical application. Yet, the pace of the omics revolution makes that the question is not if, but when biomarkers will be introduced to improve diagnosis and ultimately outcome of patients with PM due to CRC.


Differentiating between Burkitt lymphoma and CD10+ diffuse large B-cell lymphoma: the role of commonly used flow cytometry cell markers and the application of a multiparameter scoring system.
The goal of this study was to evaluate routine flow cytometric (FC) immunophenotypic markers in differentiating between Burkitt lymphoma (BL) and CD10+ diffuse large B-cell lymphoma (DLBCL). We performed retrospective analysis of FC data from 55 patients. We evaluated 9 FC parameters: forward and side scatter (FSC and SSC); mean fluorescent intensity (MFI) for CD20, CD10, CD38, CD79b, CD43, and CD71; and the percentage of neoplastic cells positive for CD71 (%CD71). The FSC; MFIs of CD10, CD43, CD79b, and CD71; and %CD71 cells were significantly different between BL and CD10+ DLBCL (P < .05; Student t test). A 5-point scoring system (FSC, %CD71, and MFIs of CD43, CD79b, and CD71) was devised, and 6 (60%) of 10 BLs scored 3 or greater and 1 (10%) of 10 CD10+ DLBCLs scored 3 (P = .04; χ(2)). Our findings indicate that routine FC parameters can aid in differentiating BL from CD10+ DLBCL.


Non invasive imaging assessment of the biodistribution of GSK2849330, an ADCC and CDC optimized anti HER3 mAb, and its role in tumor macrophage recruitment in human tumor-bearing mice.
The purpose of this work was to use various molecular imaging techniques to non-invasively assess GSK2849330 (anti HER3 ADCC and CDC enhanced 'AccretaMab' monoclonal antibody) pharmacokinetics and pharmacodynamics in human xenograft tumor-bearing mice. Immuno-PET biodistribution imaging of radiolabeled 89Zr-GSK2849330 was assessed in mice with HER3 negative (MIA-PaCa-2) and positive (CHL-1) human xenograft tumors. Dose dependency of GSK2849330 disposition was assessed using varying doses of unlabeled GSK2849330 co-injected with 89Zr-GSK2849330. In-vivo NIRF optical imaging and ex-vivo confocal microscopy were used to assess the biodistribution of GSK2849330 and the HER3 receptor occupancy in HER3 positive xenograft tumors (BxPC3, and CHL-1). Ferumoxytol (USPIO) contrast-enhanced MRI was used to investigate the effects of GSK2849330 on tumor macrophage content in CHL-1 xenograft bearing mice. Immuno-PET imaging was used to monitor the whole body drug biodistribution and CHL-1 xenograft tumor uptake up to 144 hours post injection of 89Zr-GSK2849330. Both hepatic and tumor uptake were dose dependent and saturable. The optical imaging data in the BxPC3 xenograft tumor confirmed the tumor dose response finding in the Immuno-PET study. Confocal microscopy showed a distinguished cytoplasmic punctate staining pattern within individual CHL-1 cells. GSK2849330 inhibited tumor growth and this was associated with a significant decrease in MRI signal to noise ratio after USPIO injection and with a significant increase in tumor macrophages as confirmed by a quantitative immunohistochemistry analysis. By providing both dose response and time course data from both 89Zr and fluorescently labeled GSK2849330, complementary imaging studies were used to characterize GSK2849330 biodistribution and tumor uptake in vivo. Ferumoxytol-enhanced MRI was used to monitor aspects of the immune system response to GSK2849330. Together these approaches potentially provide clinically translatable, non-invasive techniques to support dose optimization, and assess immune activation and anti-tumor responses.


Invasive group A streptococcal disease in children and association with varicella-zoster virus infection. Ontario Group A Streptococcal Study Group.
To describe the incidence and clinical features of invasive group A streptococcal (GAS) disease in children in Ontario and determine the risk of invasive GAS infection following chickenpox. During 1992-1996, we conducted prospective, active, population-based surveillance for pediatric invasive GAS disease in Ontario, Canada (population: 11 million; 2.5 million children) and reviewed clinical and laboratory records. There were 1.9 cases of invasive GAS disease per 100,000 children per year. Streptococcal toxic shock syndrome (STSS) occurred in 7% of cases and necrotizing fasciitis (NF) in 4% for incidences of.08 and.13 per 100,000 per year, respectively. Case-fatality rates were 56% for STSS, 10% for NF, and 4% overall. The presence of chronic underlying illness other than asthma was associated with death (relative risk [RR]: 11; 95% confidence interval [CI]: 2.4-45). Fifteen percent of children identified had preceding chickenpox infection, which significantly increased the risk for acquisition of invasive GAS disease (RR: 58; 95% CI: 40-85). Children with invasive GAS and recent chickenpox were more likely to have NF (RR: 6.3; 95% CI: 1.8-22.3). Childhood invasive GAS disease occurs at an incidence similar to the adult population but has a lower rate of STSS and case-fatality. Chickenpox dramatically increases the risk for acquiring invasive GAS disease, and universal chickenpox vaccination could potentially prevent up to 15% of all pediatric invasive GAS disease.


Diagnosis and Management of Rectal Cancer in Patients Younger Than 50 Years: Rising Global Incidence and Unique Challenges.
The global incidence of colorectal adenocarcinoma is stable or decreasing overall; however, the incidence of colorectal cancer in patients aged <50 years is increasing. Although some of this increase is due to hereditary cancer syndromes, this is not the sole explanation. Patients with early-onset rectal cancer in particular have unique disease patterns and face distinct challenges in their treatment. Molecular patterns of disease in this patient cohort are noteworthy and often represent an opportunity to target these cancers more effectively. Recent and ongoing trials focusing on minimizing toxicities and necessary therapy modalities and maximizing response and patient outcome are of paramount importance in this patient population. Additional resources are needed for this patient population, including fertility counseling and preservation, financial guidance, genetic counseling, and psychosocial support.


The role of the esophageal obturator airway in cardiopulmonary resuscitation.
The esophageal obturator airway (EOA) has been in use for over a decade and has been inserted over 3 million times. It has given rise to a body of literature, some of it controversial, concerning the role of the device. Data concerning the ventilatory efficiency, safety, complications, limitations, indications, and contraindications as well as mortality and morbidity associated with its use are presented and its present role in CPR is described. In line with the recommendations of the 1985 Standards Committee, the EOA is regarded as a useful device in CPR, which complements the endotracheal tube in the training of paramedics.


Anatomy and surgical treatment of the depressor septi nasi muscle: a systematic review.
Although the majority of nasal alterations in rhinoplasty result from either augmentation or reduction of bone and cartilaginous substructure, modifications of influential soft-tissue provide significant contribution to the final result. The depressor septi nasi muscle is a soft-tissue structure well known to influence the final result in rhinoplasty. The objective of this study was to perform a standardized, comprehensive review of relevant data published with regard to the depressor septi nasi muscle. A comprehensive search of the terms "depressor septi muscle" and "depressor septi nasi muscle" was performed using the PubMed, MEDLINE, and Cochrane databases. Articles were reviewed for relevancy and included if criteria were met. A secondary review was performed of all articles cited, to maximize diligence. Forty-three articles were identified in the initial search. Thirteen of the 43 were found to meet inclusion criteria. Secondary search revealed additional studies meeting inclusion criteria. Altogether, there were 175 cadaver specimens and 821 surgically treated patients for which data were available. Anatomical reports and nomenclature were found to vary. Surgical approach and muscle treatment diverged, with objective data showing no superior method. Although variation exists in anatomical reports regarding the depressor septi nasi muscle, the prevailing thought is that it originates from the maxilla and/or orbicularis oris muscle. More importantly, the muscle inserts on the medial crura and adjacent soft tissue. Disruption of this relationship provides the basis for surgical treatment of tip descent on animation.


'There's good and bad': parent perspectives on the influence of mobile touch screen device use on prenatal attachment.
The potential for human-computer interaction to have a substantial impact on adults is well documented. However, its potential importance prior to birth has rarely been reported. Parental use of smartphones and tablet computers could influence the relationship between parent and baby during pregnancy (prenatal attachment) and thus child development. Twenty-seven families were interviewed to explore how parents used these devices during pregnancy, and how device use influenced parents' thoughts, feelings and behaviours towards their baby while in utero. All used devices for a variety of purposes, and all described good levels of prenatal attachment. Parents described both disrupted and enhanced connectedness as a result of device use, and increased parental stress. The findings highlight a new opportunity for how device design and use guidelines could support families to maximise benefits and reduce detriments of device use to optimise prenatal attachment, and thus future parent-child attachment and child development. Practitioner summary: Many parents regularly use smartphones and tablet computers while pregnant. This qualitative study found that how devices were used either enhanced or disrupted feelings of prenatal attachment. Practitioners should be aware of potential beneficial and detrimental impacts of device use during pregnancy given implications for future attachment and child development.


The serum pepsinogen levels for risk assessment of gastric neoplasms: New proposal from a case-control study in Korea.
To decrease the gastric cancer related mortality rate, endoscopic screening is widely performed in Korea. However, a precise method for identifying those at a high risk of gastric neoplasms has not been established. This study aims to evaluate serum pepsinogen (PG) levels for risk assessment of gastric neoplasms. Between August 2014 and March 2016, a total of 398 subjects, including 87 with gastric neoplasms, were enrolled in this study. On the basis of the serum PG I/II ratio, the enrolled subjects were classified into 4 groups: group A, PG I/II ratio >4; group B, >3 and ≤4; group C, >2 and ≤3; group D, ≤2. Compared with group A, a stepwise increase in the risk of gastric neoplasm was observed from group B [odds ratio (OR) = 9.9, 95% confidence interval (95% CI) = 4.0-24.4] to group C (OR = 20.9, 95% CI = 8.7-50.5) to group D (OR = 37.3, 95% CI = 14.3-97.4). The optimal cutoff value of the serum PG I/II ratio for predicting gastric neoplasms was 4.5, with a sensitivity of 97.7% and a specificity of 57.6%. A decrease in the serum PG I/II ratio was strongly associated with an increased risk of gastric neoplasms. The serum PG I/II ratio can be used to identify those at a high risk of gastric neoplasms in Korean population.


Addressing access to palliative care services in the surgical intensive care unit.
Proactive case-finding using consultation triggers is a currently unexplored technique of increasing access to palliative care for patients in the surgical intensive care unit (SICU). A retrospective, pre- and postintervention study examined the effect of an initiative involving palliative care consultation in a 21-bed SICU at an urban, tertiary referral center. The initiative identified patients meeting a set of consultation triggers suggested by a group of physicians with expertise in surgical palliative care. The charts of 300 patients were reviewed retrospectively before the initiative (Group I), and 344 charts were reviewed after the initiative (Group II) for the presence of a trigger and/or subsequent palliative care consultation. Triggers were rare in both groups (Group I, 5.7%; Group II, 5.5%). Palliative care consultations were also infrequent, without change before and after the intervention (Group I, 2.3%; Group II, 3.1%). There was no difference in consultations for patients meeting a trigger after the initiative (17.6% to 27.3%; P = .704). Implementation of triggers does not increase palliative care consultations in the SICU. As an isolated intervention, triggers occur in too few patients to improve overall access to palliative care, suggesting that other methods should be further explored.


Radius and ulna fracture repair with the IMEX miniature circular external skeletal fixation system in 37 small and toy breed dogs: A retrospective study.
To determine outcome and prognostic factors after radius and ulna fracture repair with a modified IMEX miniature circular external skeletal fixation (MCESF) in small and toy breed dogs. Retrospective study. Thirty-seven young small and toy breed dogs with 41 radial and ulnar fractures. Records of radial and ulnar fractures repaired with a modified IMEX MCESF were reviewed. Constructs included 3-4 complete rings, 2 threaded rods, 4 mm-diameter nuts and 6-8 transfixation wires. MCESF configuration, type of fracture reduction, dynamization of the apparatus, inclusion of a dowel pin, and implantation of allograft were recorded. Outcome measures included complications, limb alignment, time to clinical union, and functional outcomes, scored as excellent, good, fair, or poor. Radiographic union was achieved in 40/41 fractures. Fractures reached bony union within 33-84 days after repair. Time to union was not influenced by the type of fracture reduction (P = .11), use of a dowel pin (P = .099), or implantation of an allograft (P = .45). Fracture dynamization delayed radiographic union (P = .0005). At implant removal, mean frontal (FPA) and mean sagittal plane alignments (SPA) were 7.9° ± 6.5° and 7.5° ± 5.8°, respectively. Limb alignment did not differ between radiographs obtained immediately after surgery and those obtained at time of radiographic union in the frontal (P = .062) or sagittal (P = .14) planes. Ninety-five percent of cases had good-to-excellent outcomes, based on return to function at final re-evaluations. This modified IMEX MCESF construct provided an effective alternative to treat young small and toy breed dogs with radius and ulna fractures.


A prospective study of fungal biomarkers to improve management of invasive fungal diseases in a mixed specialty critical care unit.
The diagnosis of invasive fungal diseases (IFD) in critical care patients (CrCP) is difficult. The study investigated the performance of a set of biomarkers for diagnosis of IFD in a mixed specialty critical care unit (CrCU). A prospective observational study in patients receiving critical care for ≥7days was performed. Serum samples were tested for the presence of: (1-3) - β-d-glucan (BDG), galactomannan (GM), and Aspergillus fumigatus DNA. GM antigen detection was also performed on bronchoalveolar lavage (BAL) samples. The patients were classified using published definitions for IFD and a diagnostic algorithm for invasive pulmonary aspergillosis. Performance parameters of the assays were determined. In patients with proven and probable IFD, the sensitivity, specificity, PPV and NPV of a single positive BDG were 63%, 83%, 65% and 83% respectively. Specificity increased to 86% with 2 consecutive positive results. The mean BDG value of patients with proven and probable IFD was significantly higher compared to those with fungal colonization and no IFD (p value<0.0001). New diagnostic criteria which incorporate these biomarkers, in particular BDG, and host factors unique to critical care patients should enhance diagnosis of IFD and positively impact antifungal stewardship programs.


Effects of beef, soy and conventional diets on body composition and plasma lipids of young pigs fed restricted or liberal amounts of diet.
Effects were determined of restricted and liberal feeding of beef-based, soy-based and conventional diets on growth rate, nutrient absorption, body composition and plasma lipid and urea concentrations of young pigs. Beef and soy diets contained more fat (40-50% of calories vs. 8-9%) and cholesterol (0.09 vs. 0%) than did conventional diets; calorie and protein intakes were equal across diets. Beef-fed pigs had greater average daily gain and absorption of fat and gross energy than did conventionally fed pigs; soy-fed pigs had intermediate growth rates but the greatest absorption of fat and gross energy. With restricted intakes, percentage of body fat was greater in soy-fed pigs than in pigs fed a conventional diet or beef and with liberal feeding, greater in soy- and beef-fed pigs than in pigs provided with a conventional diet. Plasma free fatty acid, triglyceride and cholesterol concentrations were greater in soy- and beef-fed pigs than in conventionally fed pigs. These results indicate that absorption and subsequent partitioning of nutrients toward body fat are influenced by composition as well as the amount of diet consumed. Our results also demonstrate that the pig can successfully be fed diets resembling human diets (i.e., high fat) and because of its physiological similarities to humans our understanding of nutrition and lipid metabolism of humans may be advanced.


I was never recruited: challenges in cross-Canada nurse mobility.
The internal migration of nurses within Canada has had limited study. This paper reports the results of a survey of registered nurses and licensed practical nurses who had migrated between the provinces and territories in Canada. Factors contributing to internal nurse mobility included seeking full-time work, opportunities for career advancement and flexible scheduling options. Few nurses received incentives to move between the provinces/territories to work. A number of challenges with internal migration are identified, including complexities related to licensing and limitations in available job information. Implications for nursing health human resources policy related to nurse retention in Canada are identified and discussed.


Markers of inflammation predict the long-term risk of developing chronic kidney disease: a population-based cohort study.
In animal models, inflammatory processes have been shown to have an important role in the development of kidney disease. In humans, however, the independent relation between markers of inflammation and the risk of chronic kidney disease (CKD) is not known. To clarify this, we examined the relationship of several inflammatory biomarker levels (high-sensitivity C-reactive protein, tumor necrosis factor-α receptor 2, white blood cell count, and interleukin-6) with the risk of developing CKD in a population-based cohort of up to 4926 patients with 15 years of follow-up. In cross-sectional analyses, we found that all these inflammation markers were positively associated with the outcome of interest, prevalent CKD. However, in longitudinal analyses examining the risk of developing incident CKD among those who were CKD-free at baseline, only tumor necrosis factor-α receptor 2, white blood cell count, and interleukin-6 levels (hazard ratios comparing highest with the lowest tertile of 2.10, 1.90, and 1.45, respectively), and not C-reactive protein (hazard ratio 1.09), were positively associated with incident CKD. Thus, elevations of most markers of inflammation predict the risk of developing CKD. Each marker should be independently verified.


Modulation of lipid and protein mediators of inflammation by cytosolic phospholipase A2alpha during experimental sepsis.
Cytosolic phospholipase A(2)alpha (cPLA(2)alpha) is one of the key enzymes in lipid mediator generation. It preferentially hydrolyzes arachidonoyl-phospholipid in response to cellular stimuli, liberating arachidonic acid, the shared precursor of PGs and leukotrienes. Mice with disruption of the cPLA(2)alpha gene exhibit a more than 80% decrease in the generation of these lipid mediators, leading to dramatic phenotypes in various models of inflammatory and allergic disease. In this study, we use the cecal ligation and puncture model of sepsis along with multiplex quantitation systems to explore interactions between eicosanoids and protein mediators. cPLA(2)alpha-deficient mice exhibited significantly less weight loss accompanied by decreased generation of PGs, leukotriene B(4), IL-6, and CCL2. Despite these differences, genetic ablation of cPLA(2)alpha did not provide any survival advantage. Unexpectedly, abundant production of 12-hydroxy-eicosatetraenoic acid, another arachidonic acid-derived lipid mediator, was found to be unaffected by disruption of the cPLA(2)alpha gene. Eicosanoid production preceded the production of cytokines. Eicosanoid modulation of IL-6 and CCL2 expression was suggested by scattergram analyses. These results provide in vivo evidence for the rapid generation of eicosanoids, regulatory role(s) for cPLA(2)alpha-derived lipid mediators on protein mediator production, and the existence of a robust cPLA(2)alpha-independent pathway(s) of eicosanoid generation.


Bioinspired Implementation and Assessment of a Remote-Controlled Robot.
Daily activities are characterized by an increasing interaction with smart machines that present a certain level of autonomy. However, the intelligence of such electronic devices is not always transparent for the end user. This study is aimed at assessing the quality of the remote control of a mobile robot whether the artefact exhibits a human-like behavior or not. The bioinspired behavior implemented in the robot is the well-described two-thirds power law. The performance of participants who teleoperate the semiautonomous vehicle implementing the biological law is compared to a manual and nonbiological mode of control. The results show that the time required to complete the path and the number of collisions with obstacles are significantly lower in the biological condition than in the two other conditions. Also, the highest percentage of occurrences of curvilinear or smooth trajectories are obtained when the steering is assisted by an integration of the power law in the robot's way of working. This advanced analysis of the performance based on the naturalness of the movement kinematics provides a refined evaluation of the quality of the Human-Machine Interaction (HMI). This finding is consistent with the hypothesis of a relationship between the power law and jerk minimization. In addition, the outcome of this study supports the theory of a CNS origin of the power law. The discussion addresses the implications of the anthropocentric approach to enhance the HMI.


Thermal stability and aggregation of sulfolobus solfataricus beta-glycosidase are dependent upon the N-epsilon-methylation of specific lysyl residues: critical role of in vivo post-translational modifications.
Methylation in vivo is a post-translational modification observed in several organisms belonging to eucarya, bacteria, and archaea. Although important implications of this modification have been demonstrated in several eucaryotes, its biological role in hyperthermophilic archaea is far from being understood. The aim of this work is to clarify some effects of methylation on the properties of beta-glycosidase from Sulfolobus solfataricus, by a structural comparison between the native, methylated protein and its unmethylated counterpart, recombinantly expressed in Escherichia coli. Analysis by Fourier transform infrared spectroscopy indicated similar secondary structure contents for the two forms of the protein. However, the study of temperature perturbation by Fourier transform infrared spectroscopy and turbidimetry evidenced denaturation and aggregation events more pronounced in recombinant than in native beta-glycosidase. Red Nile fluorescence analysis revealed significant differences of surface hydrophobicity between the two forms of the protein. Unlike the native enzyme, which dissociated into SDS-resistant dimers upon exposure to the detergent, the recombinant enzyme partially dissociated into monomers. By electrospray mapping, the methylation sites of the native protein were identified. A computational analysis of beta-glycosidase three-dimensional structure and comparisons with other proteins from S. solfataricus revealed analogies in the localization of methylation sites in terms of secondary structural elements and overall topology. These observations suggest a role for the methylation of lysyl residues, located in selected domains, in the thermal stabilization of beta-glycosidase from S. solfataricus.


The Endoscopic Surgical Skill Qualification System for gastric surgery in Japan.
Laparoscopic surgery has been increasing in popularity in recent years. In 2004, the Japan Society for Endoscopic Surgery developed its Endoscopic Surgical Skill Qualification System (ESSQS) to assess surgeons. To earn the ESSQS accreditation, applicants must submit an unedited operative video in which they perform either a distal gastrectomy or pylorus-preserving gastrectomy with lymph node dissection for gastric cancer. The videos are assessed by two separate judges based on detailed criteria for common and procedure-specific technical-grade slips. Common criteria from all fields of gastrointestinal and general surgery are used to evaluate the basic laparoscopic surgical skills and autonomy of the operator. The target organ determines the procedure-specific criteria are set to assess whether or not adequate oncological clearance has been achieved. Between 2004 and 2009, 154 (44.6%) out of 345 applicant surgeons assessed under the ESSQS for gastric surgery have been accredited. Interrater agreement was acceptable and ranged between 0.21 and 0.59. The ESSQS system may facilitate improvement in surgical technique and the standardization of laparoscopic surgery in Japan.


The chronnectome of musical beat.
Keeping time is fundamental for our everyday existence. Various isochronous activities, such as locomotion, require us to use internal timekeeping. This phenomenon comes into play also in other human pursuits such as dance and music. When listening to music, we spontaneously perceive and predict its beat. The process of beat perception comprises both beat inference and beat maintenance, their relative importance depending on the salience of beat in the music. To study functional connectivity associated with these processes in a naturalistic situation, we used functional magnetic resonance imaging to measure brain responses of participants while they were listening to a piece of music containing strong contrasts in beat salience. Subsequently, we utilized dynamic graph analysis and psychophysiological interactions (PPI) analysis in connection with computational modelling of beat salience to investigate how functional connectivity manifests these processes. As the main effect, correlation analyses between the obtained dynamic graph measures and the beat salience measure revealed increased centrality in auditory-motor cortices, cerebellum, and extrastriate visual areas during low beat salience, whereas regions of the default mode- and central executive networks displayed high centrality during high beat salience. PPI analyses revealed partial dissociation of functional networks belonging to this pathway indicating complementary neural mechanisms crucial in beat inference and maintenance, processes pivotal for extracting and predicting temporal regularities in our environment.


Rare Event Detection Using Error-corrected DNA and RNA Sequencing.
Conventional next-generation sequencing techniques (NGS) have allowed for immense genomic characterization for over a decade. Specifically, NGS has been used to analyze the spectrum of clonal mutations in malignancy. Though far more efficient than traditional Sanger methods, NGS struggles with identifying rare clonal and subclonal mutations due to its high error rate of ~0.5-2.0%. Thus, standard NGS has a limit of detection for mutations that are >0.02 variant allele fraction (VAF). While the clinical significance for mutations this rare in patients without known disease remains unclear, patients treated for leukemia have significantly improved outcomes when residual disease is <0.0001 by flow cytometry. In order to mitigate this artefactual background of NGS, numerous methods have been developed. Here we describe a method for Error-corrected DNA and RNA Sequencing (ECS), which involves tagging individual molecules with both a 16 bp random index for error-correction and an 8 bp patient-specific index for multiplexing. Our method can detect and track clonal mutations at variant allele fractions (VAFs) two orders of magnitude lower than the detection limit of NGS and as rare as 0.0001 VAF.


Multiple N-linked glycosylation sites critically modulate the synaptic abundance of neuroligin isoforms.
In recent years, elegant glycomic and glycoproteomic approaches have revealed an intricate glycosylation profile of mammalian brain with enormous spatial and temporal diversities. Nevertheless, at a cellular level, it is unclear how these post-translational modifications affect various proteins to influence crucial neuronal properties. Here, we have investigated the impact of N-linked glycosylation on neuroligins (NLGNs), a class of cell-adhesion molecules that play instructive roles in synapse organization. We found that endogenous NLGN proteins are differentially glycosylated across several regions of murine brain in a sex-independent but isoform-dependent manner. In both rodent primary neurons derived from brain sections and human neurons differentiated from stem cells, all NLGN variants were highly enriched with multiple N-glycan subtypes, which cumulatively ensured their efficient trafficking to the cell surface. Removal of these N-glycosylation residues only had a moderate effect on NLGNs' stability or expression levels but particularly enhanced their retention at the endoplasmic reticulum. As a result, the glycosylation-deficient NLGNs exhibited considerable impairments in their dendritic distribution and postsynaptic accumulation, which in turn, virtually eliminated their ability to recruit presynaptic terminals and significantly reduced NLGN overexpression-induced assemblies of both glutamatergic and GABAergic synapse structures. Therefore, our results highlight an essential mechanistic contribution of N-linked glycosylations in facilitating the appropriate secretory transport of a major synaptic cell-adhesion molecule and promoting its cellular function in neurons.


Kinetics of Cyclophosphamide Metabolism in Humans, Dogs, Cats, and Mice and Relationship to Cytotoxic Activity and Pharmacokinetics.
Cyclophosphamide (CP), a prodrug that is enzymatically converted to the cytotoxic 4-hydroxycyclophosphamide (4OHCP) by hepatic enzymes, is commonly used in both human and veterinary medicine to treat cancers and modulate the immune system. We investigated the metabolism of CP in humans, dogs, cats, and mice using liver microsomes; apparent K M, V max, and intrinsic clearance (V max/K M) parameters were estimated. The interspecies and intraspecies variations in kinetics were vast. Dog microsomes were, on average, 55-fold more efficient than human microsomes, 2.8-fold more efficient than cat microsomes, and 1.2-fold more efficient than mouse microsomes at catalyzing CP bioactivation. These differences translated to cell-based systems. Breast cancer cells exposed to 4OHCP via CP bioactivation by microsomes resulted in a stratification of cytotoxicity that was dependent on the species of microsomes measured by IC50: dog (31.65 μM), mouse (44.95 μM), cat (272.6 μM), and human (1857 μM). The contributions of cytochrome P450s, specifically, CYP2B, CYP2C, and CYP3A, to CP bioactivation were examined: CYP3A inhibition resulted in no change in 4OHCP formation; CYP2B inhibition slightly reduced 4OHCP in humans, cats, and mice; and CYP2C inhibition drastically reduced 4OHCP formation in each species. Semiphysiologic modeling of CP metabolism using scaled metabolic parameters resulted in simulated data that closely matched published pharmacokinetic profiles, determined by noncompartmental analysis. The results highlight differential CP metabolism delineated by species and demonstrate the importance of metabolism on CP clearance.


[Relay levels of acoustic and tactile startle reflexes in the reticular formation of the cat].
Reticular mechanisms of startle reflexes evoked by acoustic and tactile stimulation were studied in cat anesthetized with chloralose. Marked similarity in changes of both reflexes following surgical lesions and reversible hydrocompression blockade of the medial brain stem reticular formation structures were found. The data obtained evidenced for similarity of reticular substrates of these nonnociceptive reflexes (the pontine reticular formation, especially nucleus reticularis, pontis caudalis) in contrast to nociceptive spino-bulbo-spinal startle reflexes relayed mainly over the bulbar reticular formation.


Morphology and Phylogeny of Prorocentrum texanum sp. nov. (Dinophyceae): A New Toxic Dinoflagellate from the Gulf of Mexico Coastal Waters Exhibiting Two Distinct Morphologies.
A new planktonic species of Prorocentrum is described from the Gulf of Mexico. First observed with the Imaging FlowCytobot, Prorocentrum texanum sp. nov. was characterized using LM, SEM, and TEM along with sequencing of the SSU, LSU, and ITS ribosomal regions and the mitochondrial cob and cox1 regions. P. texanum sp. nov. is a round to oval bivalvate dinoflagellate, with a prominent anterior, serrated solid flange on periflagellar a platelet and an opposing short, flat flange on the h platelet. The periflagellar area consists of 10 platelets. Both left and right valves have shallow round depressions and two-sized valve pores. The anterior ejectosome pore pattern differs between the left and right valve in relation to the periflagellar area and margins. Ten to eleven rows of tangential ejectosome pores are present on each valve. P. texanum sp. nov. has two varieties which exhibit distinct morphotypes, one round to oval (var. texanum) and the other pointed (var. cuspidatum). P. texanum var. cuspidatum is morphologically similar to P. micans in surface markings, but is smaller, and has a serrated periflagellar flange, and is genetically distinct from P. micans. Cytologically, P. texanum has two parietal chlo-roplasts, each with a compound, interlamellar pyrenoid, trichocysts, fibrous vesicles that resemble mucocysts, pusules, V- to U-shaped posterior nucleus, golgi, and tubular mitochondria. No genetic difference was found between the two varieties in the five genes examined. Phylogenetic analysis of the SSU, LSU, and ITS ribosomal regions place P. texanum sp. nov. as a sister group to P. micans. One isolate of P. texanum var. texanum produces okadaic acid.


Nucleotide sequence of satellite DNA contained in the eliminated genome of Ascaris lumbricoides.
Several restriction endonuclease fragments isolated from highly repetitive satellite DNA of the chromatin eliminating nematode Ascaris lumbricoides var. suum have been cloned. Each type of restriction fragment corresponds to a different variant of the same related ancestral sequence. These variants differ by small deletions, insertions and single base substitutions. Restriction and DBM blot analyses show that members of the same variant class are tandemly linked and therefore are physically separated from other variant classes. A comparison of all the determined sequences establishes a 121 bp long and AT rich consensus sequence. There is evidence for an internal short range periodicity of 11 bp length, indicating that the Ascaris satellite initially may have evolved from an ancestral undecamer sequence. The satellite DNA sequences are mostly but not entirely eliminated from the presumptive somatic cells during chromatin diminution. We have no evidence for transcriptional activity of satellite DNA at any stage or tissue analyzed.


Rabs on the fly: Functions of Rab GTPases during development.
The organization of intracellular transport processes is adapted specifically to different cell types, developmental stages, and physiologic requirements. Some protein traffic routes are universal to all cells and constitutively active, while other routes are cell-type specific, transient, and induced under particular conditions only. Small GTPases of the Rab (Ras related in brain) subfamily are conserved across eukaryotes and regulate most intracellular transit pathways. The complete sets of Rab proteins have been identified in model organisms, and molecular principles underlying Rab functions have been uncovered. Rabs provide intracellular landmarks that define intracellular transport sequences. Nevertheless, it remains a challenge to systematically map the subcellular distribution of all Rabs and their functional interrelations. This task requires novel tools to precisely describe and manipulate the Rab machinery in vivo. Here we discuss recent findings about Rab roles during development and we consider novel approaches to investigate Rab functions in vivo.


Distinguishing the specificities of closely related proteases. Role of P3 in substrate and inhibitor discrimination between tissue-type plasminogen activator and urokinase.
Elucidating subtle specificity differences between closely related enzymes is a fundamental challenge for both enzymology and drug design. We have addressed this issue for two intimately related serine proteases, tissue-type plasminogen activator (t-PA) and urokinase-type plasminogen activator (u-PA), by modifying the technique of substrate phage display to create substrate subtraction libraries. Characterization of individual members of the substrate subtraction library accomplished the rapid, direct identification of small, highly selective substrates for t-PA. Comparison of the amino acid sequences of these selective substrates with the consensus sequence for optimal substrates for t-PA, derived using standard substrate phage display protocols, suggested that the P3 and P4 residues are the primary determinants of the ability of a substrate to discriminate between t-PA and u-PA. Mutagenesis of the P3 and P4 residues of plasminogen activator inhibitor type 1, the primary physiological inhibitor of both t-PA and u-PA, confirmed this prediction and indicated a predominant role for the P3 residue. Appropriate replacement of both the P3 and P4 residues enhanced the t-PA specificity of plasminogen activator inhibitor type 1 by a factor of 600, and mutation of the P3 residue alone increased this selectivity by a factor of 170. These results demonstrate that the combination of substrate phage display and substrate subtraction methods can be used to discover specificity differences between very closely related enzymes and that this information can be utilized to create highly selective inhibitors.


Adipocyte plasticity in tissue regeneration, repair, and disease.
Mammalian tissue repair forms a scar that fills the injured area with a fibrotic lesion, limiting tissue function. Adipocytes, lipid-filled cells, well-known for energy storage and endocrine functions, can reside adjacent to or within many tissues, and are emerging as critical regulators of tissue repair. In this review, the plasticity and function of adipocytes to tissue repair and fibrosis in four tissues: skin, heart, skeletal muscle, and mammary gland, will be discussed. The dynamic nature of adipocytes as they release bioactive products, lipids, and adipokines, and their ability to form contractile fibroblasts, is emerging as an essential regulator of wound healing and tumorigenesis in multiple tissues. Thus, modulation of adipocytes may provide therapeutic avenues for regenerative medicine and cancer.


BMI, Mortality, and Cardiovascular Outcomes in Type 1 Diabetes: Findings Against an Obesity Paradox.
Low weight has been associated with increased mortality risks in type 1 diabetes. We aimed to investigate the importance of weight and weight gain/loss in the Swedish population diagnosed with type 1 diabetes. Patients with type 1 diabetes (n = 26,125; mean age 33.3 years; 45% women) registered in the Swedish National Diabetes Registry from 1998 to 2012 were followed from the first day of study entry. Cox regression was used to calculate risk of death from cardiovascular disease (CVD), major CVD events, hospitalizations for heart failure (HF), and total deaths. Population mean BMI in patients with type 1 diabetes increased from 24.7 to 25.7 kg/m2 from 1998 to 2012. Over a median follow-up of 10.9 years, there were 1,031 deaths (33.2% from CVD), 1,460 major CVD events, and 580 hospitalizations for HF. After exclusion of smokers, patients with poor metabolic control, and patients with a short follow-up time, there was no increased risk for mortality in those with BMI <25 kg/m2, while BMI >25 kg/m2 was associated with a minor increase in risk of mortality, major CVD, and HF. In women, associations with BMI were largely absent. Weight gain implied an increased risk of mortality and HF, while weight loss was not associated with higher risk. Risk of major CVD, HF, CVD death, and mortality increased with increasing BMI, with associations more apparent in men than in women. After exclusion of factors associated with reverse causality, there was no evidence of an obesity paradox.


Tools and guidelines to assess the appropriateness of medication and aid deprescribing: An umbrella review.
The aim of this umbrella review was to identify tools and guidelines to aid the deprescribing process of potentially inappropriate medications (PIMs), evaluate development and validation methods, and describe evidence levels for medication inclusion. Searches were conducted on MEDLINE (Ovid), Embase.com, Cochrane CDSR, CINAHL (EBSCO), Web of Science Core Collection and guideline databases from the date of inception to 7 July 2022. Following the initial search, an additional search was conducted to identify an updated versions of tools on 17 July 2023. We analysed the contents of tools and guidelines. From 23 systematic reviews and guidelines, we identified 95 tools (72 explicit, 12 mixed and 11 implicit) and nine guidelines. Most tools (83.2%) were developed to use for older persons, including 14 for those with limited life expectancy. Seven tools were for children <18 years (7.37%). Most explicit/mixed tools (78.57%) and all guidelines were validated. We found 484 PIMs and 202 medications with different appropriateness independent of disease for older persons with normal and limited life expectancy, respectively. Only two tools and eight guidelines reported the evidence level, and a quarter of medications had high-quality evidence. Tools are available for a diversity of populations. There were discrepancies, with the same medication being classified as inappropriate in some tools and appropriate in others, possibly due to low-quality evidence. In particular, tools for patients with limited life expectancy were developed based on very limited evidence, and research to generate this evidence is urgently needed. Our medication lists, along with the level of evidence, could facilitate efforts to strengthen the evidence.


Health-risk behaviors in teens investigated by U.S. Child Welfare Agencies.
The aim of this study was to examine prevalence and correlates of health-risk behaviors in 12- to 17.5-year-olds investigated by child welfare and compare risk-taking over time and with a national school-based sample. Data from the National Survey of Child and Adolescent Well-Being (NSCAW II) were analyzed to examine substance use, sexual activity, conduct behaviors, and suicidality. In a weighted sample of 815 adolescents aged 12-17.5 years, prevalence and correlates for each health-risk behavior were calculated using bivariate analyses. Comparisons to data from NSCAW I and the Youth Risk Behavior Survey were made for each health-risk behavior. Overall, 65.6% of teens reported at least one health-risk behavior with significantly more teens in the 15- to 17.5-year age group reporting such behaviors (81.2% vs. 54.4%; p ≤ .001). Almost 75% of teens with a prior out-of-home placement and 77% of teens with child behavior checklist scores ≥64 reported at least one health-risk behavior. The prevalence of smoking was lower than in NSCAW I (10.5% vs. 23.2%; p ≤ .05) as was that of sexual activity (18.0% vs. 28.8%; p ≤ .05). Prevalence of health-risk behaviors was lower among older teens in the NSCAW II sample (n = 358) compared with those of the 2011 Youth Risk Behavior Surveillance System high school-based sample with the exception of suicidality, which was approximately 1.5 times higher (11.3% [95% confidence interval, 6.5-19.0] vs. 7.8% [95% confidence interval, 7.1-8.5]). Health-risk behaviors in this population of vulnerable teens are highly prevalent. Early efforts for screening and interventions should be part of routine child welfare services monitoring.


Sensitive and specific identification of Neospora caninum infection of cattle based on detection of serum antibodies to recombinant Ncp29.
Neosporosis is an economically important disease of dairy cattle caused by the protozoan Neospora caninum. Diagnostic tests for neosporosis are complicated by the potential for cross-reaction of antibodies to antigens that are similar between N. caninum and closely related parasites Toxoplasma gondii and Sarcocystis cruzi. To provide a sensitive and specific assay for detecting antibodies to N. caninum in the serum of infected animals, we have investigated a recombinant form of the antigen known as Ncp29 (rNcp29), which is a major surface protein of the parasite. Ncp29 is encoded by a gene that is homologous to the SAG1 gene previously characterized from T. gondii. An enzyme-linked immunosorbent assay (ELISA) was used to screen animals for the presence of serum antibodies specific to rNcp29. The rNcp29 ELISA readily distinguished between cattle known to be infected with N. caninum (optical density [OD] > 1.2 at 1:500 or greater dilution) and negative controls (OD < 0.5 at 1:500). Additionally, sera from animals that were infected with T. gondii or S. cruzi were negative. The rNcp29 ELISA developed here provides a specific and sensitive assay for detecting neosporosis in cattle.


Aluminum does not enhance beta-amyloid toxicity in rat hippocampal cultures.
A number of environmental factors have been implicated in neurodegenerative disorders, including metallotoxins such as aluminum (Al). In the present study, the toxicity of Al-quinate (AlQ), a well-characterized Al complex, was investigated in primary rat hippocampal cultures in comparison to inorganic Al (Al-S). AlQ was significantly less toxic than Al-S during both short- (3h) and long-term (24h) incubations. The neuroprotective properties of quinic acid (which constitutes the quinate moiety of AlQ) against short-term incubations with Al-S were subsequently assessed, and the organic compound was found to provide full protection, comparable to synthetic metal chelating agents desferrioxamine and clioquinol. Finally, potential synergistic actions between Al (AlQ and Al-S) and beta-amyloid (Abeta) were investigated. Neither Al form appeared to enhance Abeta toxicity, in fact, AlQ significantly reduced Abeta toxicity. Collectively, this study highlights further the impact of structural features and physiological ligands of metal complexes on toxicity profiles, and reveals promising properties of quinic acid as a metal chelator. Despite previous reports suggesting synergistic toxicity between Al and Abeta, we could not identify such a mechanism in our investigation.


Targeting Cx40 (Connexin40) Expression or Function Reduces Angiogenesis in the Developing Mouse Retina.
Cx40 (Connexin40) forms intercellular channels that coordinate the electric conduction in the heart and the vasomotor tone in large vessels. The protein was shown to regulate tumoral angiogenesis; however, whether Cx40 also contributes to physiological angiogenesis is still unknown. Here, we show that Cx40 contributes to physiological angiogenesis. Genetic deletion of Cx40 leads to a reduction in vascular growth and capillary density in the neovascularization model of the mouse neonatal retina. At the angiogenic front, vessel sprouting is reduced, and the mural cells recruited along the sprouts display an altered phenotype. These alterations can be attributed to disturbed endothelial cell functions as selective reexpression of Cx40 in these cells restores normal angiogenesis. In vitro, targeting Cx40 in microvascular endothelial cells, by silencing its expression or by blocking gap junction channels, decreases their proliferation. Moreover, loss of Cx40 in these cells also increases their release of PDGF (platelet-derived growth factor) and promotes the chemoattraction of mural cells. In vivo, an intravitreal injection of a Cx40 inhibitory peptide, phenocopies the loss of Cx40 in the retinal vasculature of wild-type mice. Collectively, our data show that endothelial Cx40 contributes to the early stages of physiological angiogenesis in the developing retina, by regulating vessel growth and maturation. Cx40 thus represents a novel therapeutic target for treating pathological ocular angiogenesis.


Audiovisual speech perception development at varying levels of perceptual processing.
This study used the auditory evaluation framework [Erber (1982). Auditory Training (Alexander Graham Bell Association, Washington, DC)] to characterize the influence of visual speech on audiovisual (AV) speech perception in adults and children at multiple levels of perceptual processing. Six- to eight-year-old children and adults completed auditory and AV speech perception tasks at three levels of perceptual processing (detection, discrimination, and recognition). The tasks differed in the level of perceptual processing required to complete them. Adults and children demonstrated visual speech influence at all levels of perceptual processing. Whereas children demonstrated the same visual speech influence at each level of perceptual processing, adults demonstrated greater visual speech influence on tasks requiring higher levels of perceptual processing. These results support previous research demonstrating multiple mechanisms of AV speech processing (general perceptual and speech-specific mechanisms) with independent maturational time courses. The results suggest that adults rely on both general perceptual mechanisms that apply to all levels of perceptual processing and speech-specific mechanisms that apply when making phonetic decisions and/or accessing the lexicon. Six- to eight-year-old children seem to rely only on general perceptual mechanisms across levels. As expected, developmental differences in AV benefit on this and other recognition tasks likely reflect immature speech-specific mechanisms and phonetic processing in children.


Proteomics and Lipidomics in Inflammatory Bowel Disease Research: From Mechanistic Insights to Biomarker Identification.
Inflammatory bowel disease (IBD) represents a group of progressive disorders characterized by recurrent chronic inflammation of the gut. Ulcerative colitis and Crohn's disease are the major manifestations of IBD. While our understanding of IBD has progressed in recent years, its etiology is far from being fully understood, resulting in suboptimal treatment options. Complementing other biological endpoints, bioanalytical "omics" methods that quantify many biomolecules simultaneously have great potential in the dissection of the complex pathogenesis of IBD. In this review, we focus on the rapidly evolving proteomics and lipidomics technologies and their broad applicability to IBD studies; these range from investigations of immune-regulatory mechanisms and biomarker discovery to studies dissecting host⁻microbiome interactions and the role of intestinal epithelial cells. Future studies can leverage recent advances, including improved analytical methodologies, additional relevant sample types, and integrative multi-omics analyses. Proteomics and lipidomics could effectively accelerate the development of novel targeted treatments and the discovery of complementary biomarkers, enabling continuous monitoring of the treatment response of individual patients; this may allow further refinement of treatment and, ultimately, facilitate a personalized medicine approach to IBD.


[Morphological study of 4 cases of T lymphoma].
Modern physiopathological studies of the lymphoid system have enabled accurate immunological identification of the different B lymphopathies. Concurrently, the categorization of T proliferations is evolving. In addition to the morphologically well known categories of T lymphomas, three different histological entities are at present termed T lymphomas by anglo-saxon authors: lymphoma with pleiomorphic cytology, or large cell lymphoma, whose identification seems to be the most difficult; Pinkus lymphoma, with subcutaneous clinical localizations which differ from the initial sites of lymphomas, composed of lymphoid cells whose morphology is very characteristic; Lennert lymphoma, whose precise nature is still under debate, but that has been immunologically identified as a T neoplasm by some American authors. We report four observations that exemplify the complex identification of these lymphomas. One case is a Lennert lymphoma which developed into T immunoblastic lymphoma rising the problem of the relationships between these two diseases. The link between these diverse histological pictures is the T immunological identification of the proliferation for which the routine use of monoclonal antibodies should prove helpful.


Fibronectin- and protein kinase C-mediated activation of ERK/MAPK are essential for proplateletlike formation.
The megakaryoblastic CHRF-288 cell line was used to investigate signal transduction pathways responsible for proplateletlike formation (PPF). The role of fibronectin (FN) and protein kinase C (PKC) activation in PPF were examined. In the presence of serum and phorbol 12-myristate 13-acetate (PMA), a PKC activator, cells exhibited full megakaryocytic differentiation, manifested by adhesion, shape change, increased cell size, polyploidy, PPF, and expression of CD41(+), CD61(+), and CD62P(+). The same morphologic and phenotypic features were observed in serum-free cultures in the presence of FN/PMA. Only partial differentiation occurred when other integrin ligands were substituted for FN. FN alone induced minimal cell adhesion and spreading, while PMA alone induced only polyploidy without adhesion. Signal transduction changes involved the activation of the extracellular signal-regulated protein kinase 1 (ERK1)/ERK2 as well as c-Jun amino-terminal kinase 1 (JNK1)/stress-activated protein kinase (SAPK). Phosphoinositide-3 kinase and p38 were not stimulated under these conditions. Inhibitors were used to identify the causal relationship between signaling pathways and PPF. PD98059 and GF109203X, inhibitors of ERK1/ERK2 pathway and PKC, respectively, blocked PPF, while adhesion, spreading, and polyploidy were normal. These studies show that activation of ERK1/ERK2 mitogen-activated protein kinase pathway plays a critical role in PPF. The elucidation of the signal transduction pathway on megakaryocyte development and PPF is of crucial importance for understanding this unique biological process.


Religious attitudes regarding organ donation.
This study of seminary students, religious leaders, and hospital chaplains illustrates the importance of educating clergy about organ donation. Religious objections are often cited as a reason for refusal to give consent for donation. Results of this study show that most clergy are supportive of organ donation. However, the survey pointed out some misunderstanding of the concept of brain death. Thus, although the clergy are supportive and influential, they tend not to receive medical information that is key to the donation process. Further education specifically focused on religious leaders is needed.


ROAST: rotation gene set tests for complex microarray experiments.
A gene set test is a differential expression analysis in which a P-value is assigned to a set of genes as a unit. Gene set tests are valuable for increasing statistical power, organizing and interpreting results and for relating expression patterns across different experiments. Existing methods are based on permutation. Methods that rely on permutation of probes unrealistically assume independence of genes, while those that rely on permutation of sample are suitable only for two-group comparisons with a good number of replicates in each group. We present ROAST, a statistically rigorous gene set test that allows for gene-wise correlation while being applicable to almost any experimental design. Instead of permutation, ROAST uses rotation, a Monte Carlo technology for multivariate regression. Since the number of rotations does not depend on sample size, ROAST gives useful results even for experiments with minimal replication. ROAST allows for any experimental design that can be expressed as a linear model, and can also incorporate array weights and correlated samples. ROAST can be tuned for situations in which only a subset of the genes in the set are actively involved in the molecular pathway. ROAST can test for uni- or bi-direction regulation. Probes can also be weighted to allow for prior importance. The power and size of the ROAST procedure is demonstrated in a simulation study, and compared to that of a representative permutation method. Finally, ROAST is used to test the degree of transcriptional conservation between human and mouse mammary stems. ROAST is implemented as a function in the Bioconductor package limma available from www.bioconductor.org.